dopamine hypothesis psychology example

Dopamine Function in the Brain

Olivia Guy-Evans, MSc

Associate Editor for Simply Psychology

BSc (Hons) Psychology, MSc Psychology of Education

Olivia Guy-Evans is a writer and associate editor for Simply Psychology. She has previously worked in healthcare and educational sectors.

Learn about our Editorial Process

Karina Ascunce González

PhD Neuroscience Student, Yale University

Neuroscience B.A. (Hons), Harvard University

PhD Student at the Yale Biological & Biomedical Sciences' Interdepartmental Neuroscience Program interested in neurodegeneration, stem cell culture, and bioethics. AB in Neuroscience with a Secondary in Global Health & Health Policy from Harvard University. Karina has been published in peer reviewed journals.

Saul Mcleod, PhD

Editor-in-Chief for Simply Psychology

BSc (Hons) Psychology, MRes, PhD, University of Manchester

Saul Mcleod, PhD., is a qualified psychology teacher with over 18 years of experience in further and higher education. He has been published in peer-reviewed journals, including the Journal of Clinical Psychology.

On This Page:

Dopamine is a neurotransmitter that serves as a chemical messenger in the brain. It can function as both an excitatory and inhibitory neurotransmitter, leading to diverse effects on the brain, body, and behavior.

Dopamine is primarily known to be associated with feelings of pleasure and rewards . This chemical can also contribute to feelings of:

Dopamine is released when the brain is anticipating a reward. The flood of dopamine to the brain when experiencing a pleasurable stimulus (e.g., delicious food, video games, sex) can reinforce wanting to engage with this stimulus more due to the pleasurable feeling it causes.

This is a cycle of motivation, reward, and reinforcement. When associating a certain activity with pleasure, sometimes even mere anticipation may be enough to raise dopamine levels.

Dopamine is also implicated in learning, planning, and productivity. For instance, if someone has been working hard on a project for a long time, they can experience a surge of dopamine activity when it is finally completed.

Function of Dopamine

Dopamine is a neurotransmitter in the brain associated with pleasure, reward, motivation, and motor control. In psychology, it’s linked to feelings of gratification and is implicated in mood disorders, addiction, and certain behaviors when its levels are imbalanced.

Whilst strongly involved in pleasure and rewards, dopamine is also involved in other functions:

Motor function and movement

Mood regulation

Executive functioning

Memory and focus

Stress response

Digestion and blood flow

It is important to note that dopamine does not act in isolation. It works with other neurotransmitters and hormones, such as serotonin and adrenaline, to perform a variety of functions.

Dopamine is a catecholamine, a class of neurotransmitter which also includes epinephrine and norepinephrine. It was believed to be first identified in the brain by Kathleen Montagu in her 1957 paper demonstrating findings on key neurotransmitters.

As part of her research, she examined the quantities of norepinephrine, epinephrine, and 3-hydroxytryramine from extracted brain tissues of several species.

Montagu speculated that there might be an additional catecholamine similar to hydroxytyramine, which she later confirmed to be what is known as dopamine. Arvid Carlsson published research in the same year that confirmed dopamine was a neurotransmitter in the brain, as opposed to another precursor molecule.

Dopamine is highly concentrated in areas of the brain called the substantia nigra and the ventral tegmental area (VTA) in the midbrain. Other brain areas where dopamine can be made are the hypothalamus and the olfactory bulb.

There are dopamine pathways that can be triggered when exposed to a stimulus that is rewarding, resulting in increased amounts of dopamine circulating around brain areas.

Role Of Dopamine On Learning And Motivation

Reward system.

Dopamine plays a key role in the brain’s reward system . This neurotransmitter helps to reinforce certain behaviors that result in a reward.

In classical studies of rats, a surge of dopamine prompts the animal to press a lever to get a pellet of food repeatedly.

This works similarly in humans, for instance, when choosing to eat more pleasurable food, such as another slice of cake, because we have enjoyed the rewarding feeling the food has given us.

Reward Prediction

Some lines of study have found that midbrain dopamine neurons can be activated by proximal contact (touch, taste) with unexpected rewards.

When such events became predictable, the neurons were found to respond to the more distal (visual or auditory) stimuli that precede and predict the availability of the reward.

The neurons would then stop responding to the proximal contact with the reward (Romo & Schultz, 1990; Schultz et al., 1992).

This may be an oversimplification as the neurons that are no longer reactive to the proximal reward stimuli have been found to still be responsive to the lack of the reward.

When the expected proximal contact does not occur, the dopamine neurons become inhibited. So, although dopamine release is triggered by the earliest reliable predictor of reward, midbrain dopamine remains sensitive to the receipt or lack of reward.

The anticipation of expecting a reward was studied by researchers in a game of chance.

In the anticipation phase, where participants were told they might win money, blood flow was found in the amygdala and frontal cortex, indicating activity in the nucleus accumbens and the hypothalamus, all rich in dopamine receptors.

The bigger the potential reward, the greater dopamine-led brain activity was found.

Conditioned reinforcement

By allowing dopamine to affect choices, it can bias towards choosing the stimulus that was learned from the amount of positive or negative reinforcement the stimulus received.

Reward-associated motivational stimuli can serve as conditioned reinforcers when given after a response.

For instance, in a study on rats, when they were thirsty, they learned to work for the presentation of a light that was previously paired with water.

In this test, injections of amphetamine into the nucleus accumbens (a reward area of the brain) caused dopamine release. They enhanced response to the light (Taylor & Robbins, 1984), whereas dopamine-selective lesions of the nucleus accumbens reduced this response (Taylor & Robbins, 1986).

Therefore, dopamine can modulate the expression of conditioned reinforcement as well as is essential for the establishment of conditioned reinforcers.

What Dopamine Does In The Brain

Within the brain are dopamine receptors which are proteins found in the brain and other neurons throughout the body. As a dopamine signal approaches a nearby neuron, it binds to that neuron’s receptor.

The receptor and neurotransmitter work like a lock and key. The dopamine attaches to the dopamine receptor, delivering its chemical message by causing changes to occur in the neuron that received the signal.

Through the use of dopamine receptors, the effects of dopamine, such as movement coordination, pleasure, and cognition, can take effect.

Where is dopamine produced?

Dopamine is produced in several areas of the brain, including the ventral tegmental area (VTA: a dopamine-rich nucleus located within the midbrain) and the substantia nigra.

Once produced in the VTA, dopamine is transported to other areas of the brain through different dopamine pathways, the two main ones being the mesolimbic and the mesocorticol pathways. Other pathways include the nigrostriatal and tuberoinfundibular pathways.

Dopamine pathways are neuronal connections in which dopamine travels to areas of the brain and body to convey important information such as executive thinking, cognition, feelings of reward and pleasure, and voluntary movement.

Mesolimbic pathways

This dopamine pathway is highly involved in the functions of pleasure and reward. Beginning at the VTA, dopamine produced here projects to the nucleus accumbens.

When here, dopamine primarily mediates feelings of pleasure and reward. For instance, if someone eats a food they enjoy, dopamine is released from the VTA to the nucleus accumbens which then creates positive feelings that reinforce the behavior.

Sometimes stimuli can create intense feelings of euphoria.

The nucleus accumbens is found in the ventral striatum and is part of a complex circuit involving the amygdala and the hippocampus. The activation of the mesolimbic dopamine pathway communicates that it wants to repeat what just happened to feel the rewarding sensation again.

Since the nucleus accumbens has connections to the amygdala, a region of the limbic system associated with emotions, this attributes feelings towards the experienced reward.

Likewise, connections to the hippocampus, an area associated with memory, can attribute memories of pleasure to the experience to reinforce this sensation to happen again.

Stimulating the nucleus accumbens is important for daily activities, but over-stimulation can result in cravings for the stimulus which stimulates it.

Mesocorticol pathways

As with the mesolimbic pathways, the mesocortical pathway starts with dopamine projections originating from the VTA. From the VTA, signals are sent to the prefrontal cortex, an area involved in cognition, working memory, and decision-making.

Thus, activation of this pathway brings about the conscious experience of the pleasure and reward being experienced. Attention, concentration, and decisions can be made as a result of pleasure and reward.

Dysfunction in this pathway can therefore result in poor concentration and an inability to make decisions.

Nigrostriatal pathways

This dopamine pathway is involved in motor planning. The dopamine projections start in the substantia nigra, a basal ganglia structure located in the midbrain.

These projections go to the caudate and putamen, which are also parts of the basal ganglia. The neurons in this pathway stimulate purposeful movement and contain about 80% of the dopamine in the brain.

If there are reductions in the number of dopamine neurons in this pathway, this can result in motor control impairments, including movement disorders such as Parkinson’s disease.

Symptoms of dysfunction in this pathway may include spasms, contractions, tremors, and motor restlessness.

Tuberoinfundibular pathways

The dopamine neurons in this pathway originate in the hypothalamus, an area that plays a role in hormone production and helps to stimulate many important processes in the body.

Specifically, the neurons are in the arcuate and periventricular nuclei of the hypothalamus. These then project to the infundibular region of the hypothalamus. In this pathway, dopamine is released into the portal circulation that connects this region to the pituitary gland.

Here, dopamine functions to inhibit prolactin release. Prolactin is a protein secreted by the pituitary gland that enables milk production and has important functions in metabolism, sexual satisfaction, and the immune system.

Dopamine Hypothesis In Schizophrenia

The dopamine hypothesis for schizophrenia suggests that some of the symptoms of schizophrenia involve excess dopamine activity.

The dopamine hypothesis of schizophrenia was derived from observations in the 1960s where the effects of amphetamines resembled schizophrenia. Amphetamines increase dopamine function (Seeman et al., 1976).

Dopamine appears to play a big role in the activity of the frontal and temporal lobes, particularly parts of the cerebral cortex of these lobes that play a role in the cognitive, emotional, and perceptual functions that are often abnormal in schizophrenia.

However, inconsistencies in post-mortem findings and debates on whether certain changes were due to drugs or the disease made it challenging to pinpoint schizophrenia’s exact link with dopamine. Yet, imaging studies revealed that schizophrenic patients release more dopamine than healthy individuals in response to certain scenarios (Laruelle et al., 1996).

The discovery of organic changes in the brains of schizophrenic patients through imaging techniques shifted the focus to viewing schizophrenia as a neurodevelopmental disorder.

This suggested that schizophrenia might stem from reduced dopamine function in the prefrontal cortex, leading to increased dopamine in other areas (mesolimbic). Potential treatments now consider balancing these levels, exemplified by drugs like aripiprazole (Carlsson, 1988).

There appear to be abnormalities in the mesocortical and mesolimbic pathways that carry dopamine from the VTA to areas of the cerebral cortex.

Disruptions in the parts of the cerebral cortex are believed to cause many of the cognitive symptoms of schizophrenia, such as disorganized thinking, difficulty integrating thoughts, and poor concentration.

Abnormal activity of dopamine pathways in the limbic system is believed to be responsible for many of the negative symptoms of schizophrenia, such as lack of motivation and social withdrawal.

Also, dopamine abnormalities in the temporal and prefrontal areas of the brain are believed to be overactive in those with schizophrenia and thus can lead to some of the positive symptoms of the condition, such as hallucinations and delusions .

This hypothesis aligns with the use of some antipsychotic drug medications, which work to block dopamine receptor in the brain appear to be effective in treating the positive symptoms of schizophrenia.

Likewise, the effects of dopamine-enhancing drugs such as methamphetamine and cocaine, over repeated exposure, may gradually induce paranoid psychosis in non-schizophrenic people.

This well-documented observation shows that sustained increases in dopamine activity can cause some of the similar symptoms of schizophrenia.

However, the dopamine hypothesis for schizophrenia may be an oversimplification as there may be many other neuronal network abnormalities and neurotransmitter systems involved in causing the condition.

Research since the dopamine hypothesis has indicated that glutamate, GABA, acetylcholine, and serotonin alterations are also involved in the pathology of schizophrenia, so it may not be dopamine alone which affects this condition.

What about the future?

We know a lot about two types of dopamine receptors in the brain, but less about three others. Using mice in research , scientists discovered the importance of the D5 receptor in male and female sexual behaviors. Also, some research shows mice might like sugar even if they can’t produce dopamine.

Notably, there’s a growing consensus that studying dopamine should not be in isolation but in conjunction with other transmitter systems. This integrated approach recognizes the broader neuronal organization and connectivity in the brain.

Even though dopamine neurons comprise less than 1% of brain neurons, alterations in dopamine levels or functions can significantly influence behavior.

This underscores the idea that dopamine’s primary role might be integrating information pertinent to biologically significant stimuli rather than transmitting specific data.

What happens if dopamine is depleted?

Low dopamine levels may result in some of the following symptoms:

– Reduced alertness – Difficulty concentrating – A lack of motivation – Poor coordination – Movement difficulties – Inability to feel pleasure

In more extreme cases, a lack of dopamine could result in conditions such as Parkinson’s disease, dopamine transporter deficiency syndrome, or depression.

Although dopamine alone may not directly cause depression, low levels of dopamine have been suggested to cause specific symptoms associated with this condition, such as motivational issues, feeling hopeless and helpful, and a loss of interest in previously enjoyed activities.

It’s suggested that these symptoms may be linked to a dysfunction in the dopamine systems of the brain. A main trigger for these dysfunctions could be due to stress, pain, lack of sleep, or trauma.

A physiological explanation is that there may be a diminished dopamine release from the presynaptic neurons and/or impairment in signal transduction, possibly due to changes in the number of dopamine receptors.

Attention deficit hyperactivity disorder (ADHD) is a condition that is also associated with low levels of dopamine.

Symptoms of ADHD include difficulties with concentration and attention, impulsiveness and finding it difficult to remain still.

Since people with ADHD have lowered dopamine levels, they are more likely to carry out behaviors in order to obtain more dopamine.

What are the symptoms of high dopamine?

High levels of dopamine can make people feel euphoric in the short term; however, over time, it can be detrimental. In excess, dopamine can be a contributing factor in mania , hallucinations, and delusions.

A surplus of dopamine can result in more competitive behaviors, aggression, poor control over impulses, gambling behaviors, and addiction.

As such, addictive drugs can increase levels of dopamine, encouraging the individual to continue to use these drugs to reach that pleasurable feeling of reward.

This does not just have to be an addiction to drugs; people can be addicted to anything which gives them a surge of dopamine, such as video games, food, and social media use.

How do I get my dopamine levels back to normal?

Depending on whether dopamine levels are too high or low will determine what techniques to take. If wanting to increase dopamine levels, some ways can include:

– Establishing a good sleep schedule – Less screen time (e.g., television, phone), especially before bed – Learning to meditate or undertaking mindfulness training – Exercising regularly – Changes in diet to increase levels of vitamin D and essential fatty acids – Physical therapy for muscle stiffness and movement problems

Dopamine agonists – a class of drugs that bind to and activate dopamine receptors in the brain, mimicking the action of naturally-occurring dopamine in the brain.

For those with too much dopamine, such as individuals with schizophrenia, dopamine antagonists are usually recommended.

These are a class of drugs that bind to and block dopamine receptors, turning down the dopamine activity.

Many antipsychotic drugs are dopamine antagonists, including Chlorpromazine (Thorazine), Risperidone (Risperdal), and Clozapine (Clozaril).

What happens when you ‘dopamine fast’?

Dopamine fasting is a recent trend where people strive to ‘reset’ their dopamine levels by completely abstaining from anything that brings them pleasure. This can include phone use, social media, video games, delicious food, sex, and social interaction.

Taking breaks from behaviors that trigger strong amounts of dopamine release could allow the brain to recover and restore itself, being an antidote to the age of overstimulation we live in.

Kent Berridge, a professor of psychology and neuroscience, suggests that taking a break from a stimulating activity (or all of them) will not reset dopamine levels, but it can stop the dopamine system from turning on constantly.

Dopamine fast is not believed to be something that can reduce dopamine, but having breaks from one or two pleasurable activities at a time can help in reducing impulsive behaviors.

In addition, a specific study showed that dopamine fasting from the social media platform Facebook for a week helped students regain 13.3 hours of their time and significantly reduced depressive symptoms by 17%, which allowed them to engage in more healthy behaviors instead (Mosquere et al., 2019).

Brisch, R., Saniotis, A., Wolf, R., Bielau, H., Bernstein, H. G., Steiner, J., Bogerts, B., Braun, K., Jankowski, Z., Kumaratilake, J., Henneberg, M. & Gos, T. (2014). The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Frontiers in psychiatry , 5, 47.

Bridges, N. (2016, November 25). Dopamine Pathways. Sanesco. https://sanescohealth.com/blog/dopamine-pathways/

Cannon, C. M., Scannell, C. A., & Palmiter, R. D. (2005). Mice lacking dopamine D1 receptors express normal lithium chloride‐induced conditioned taste aversion for salt but not sucrose.  European Journal of Neuroscience ,  21 (9), 2600-2604.

Carlsson, A. (1988). The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 1 (3), 179-186.

Conrad, B. (n.d.). The Role of Dopamine as a Neurotransmitter in the Human Brain. Enzo. Retrieved 2021, November 5, from: https://www.enzolifesciences.com/science-center/technotes/2018/november/the-role-of-dopamine-as-a-neurotransmitter-in-the-human-brain/

Laruelle, M., Abi-Dargham, A., Van Dyck, C. H., Gil, R., D’Souza, C. D., Erdos, J., … & Innis, R. (1996). Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.  Proceedings of the National Academy of Sciences ,  93 (17), 9235-9240.

Mosquera, R., Odunowo, M., McNamara, T., Guo, X., & Petrie, R. (2020). The economic effects of Facebook. Experimental Economics, 23(2), 575-602.

Pietrangelo, A. (2019, November 5). How Does Dopamine Affect the Body? Healthline. https://www.healthline.com/health/dopamine-effects

Romo, R., & Schultz, W. (1990). Dopamine neurons of the monkey midbrain: contingencies of responses to active touch during self-initiated arm movements. Journal of neurophysiology, 63 (3), 592-606.

Schultz, W., Apicella, P., Scarnati, E., & Ljungberg, T. (1992). Neuronal activity in monkey ventral striatum related to the expectation of reward. Journal of Neuroscience, 12(12), 4595-4610.

Seeman, P., Lee, T., Chau-Wong, M., & Wong, K. (1976). Antipsychotic drug doses and neuroleptic/dopamine receptors.  Nature ,  261 (5562), 717-719.

Sepah, C. (2019, August 7). The Definitive Guide to Dopamine Fasting 2.0 – The Hot Silicon Valley Trend. LinkedIn. https://www.linkedin.com/pulse/dopamine-fasting-new-silicon-valley-trend-dr-cameron-sepah/

Taylor, J. R., & Robbins, T. W. (1984). Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens. Psychopharmacology, 84( 3), 405-412.

Taylor, J. R., & Robbins, T. W. (1986). 6-Hydroxydopamine lesions of the nucleus accumbens, but not of the caudate nucleus, attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine. Psychopharmacology, 90(3), 390-397.

Wise, R. A. (2004). Dopamine, learning and motivation. Nature Reviews Neuroscience, 5 (6), 483-494.

Further Reading

• Volkow, N. D., Wang, G. J., Kollins, S. H., Wigal, T. L., Newcorn, J. H., Telang, F., … & Swanson, J. M. (2009). Evaluating Dopamine Reward Pathway in ADHD. JAMA, 302 (10), 1084-1091.
• Belujon, P., & Grace, A. A. (2017). Dopamine System Dysregulation in Major Depressive Disorders. International Journal of Neuropsychopharmacology, 20( 12), 1036-1046.

Psych Scene Hub

The Dopamine Hypothesis of Schizophrenia – Advances in Neurobiology and Clinical Application

The dopamine hypothesis stems from early research carried out in the 1960’s and 1970’s when studies involved the use of amphetamine (increases dopamine levels) which increased psychotic symptoms while reserpine which depletes dopamine levels reduced psychotic symptoms.

The original dopamine hypothesis was put forward by Van Rossum in 1967 that stated that there was hyperactivity of dopamine transmission, which resulted in symptoms of schizophrenia and drugs that blocked dopamine reduced psychotic symptoms. [1]

DOPAMINE PRODUCTION AND METABOLISM

Dopamine is synthesised from the amino acid tyrosine. Tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase.

DOPA is converted into dopamine (DA) by the enzyme DOPA decarboxylase (DOPADC).

This dopamine is packed and stored into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored until its release into the synapse.

Dopamine Receptors:

When dopamine is released during neurotransmission, it acts on 5 types of postsynaptic receptors (D1-D5).

A negative feedback mechanism exists through the presynaptic D2 receptor which regulates the release of dopamine from the presynaptic neuron.

Dopamine Breakdown

Any excess dopamine is also ‘mopped up’ from the synapse by Dopamine transporter (DAT) and stored in the vesicles via VMAT2.

Dopamine is broken down by monoamine oxidase A (MAO-A), MAO-B and catechol-o-methyltransferase (COMT).

Learning points:

• Tyrosine hydroxylase is the rate-limiting step in the production of dopamine. Its expression is significantly increased in the substantia nigra of schizophrenia patients when compared to normal healthy subjects. [2]
• Carbidopa is a peripheral DOPA-decarboxylase inhibitor co-administered with levodopa. Carbidopa prevents the conversion of levodopa to dopamine in the periphery, thus allowing more levodopa to pass the blood-brain barrier to be converted into dopamine for its therapeutic effect.
• Methamphetamine increases extracellular dopamine by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT).
• Valbenazine a highly selective VMAT2 inhibitor has been approved by the FDA for the treatment of tardive dyskinesia.
• There is compelling evidence that presynaptic dopamine dysfunction results in increased availability and release of dopamine and this has been shown to be associated with prodromal symptoms of schizophrenia. Furthermore, dopamine synthesis capacity has also been shown to steadily increase with the onset of severe psychotic symptoms. [3] , [Howes & Shatalina, 2022]

• Dopaminergic transmission in the prefrontal cortex is mainly mediated by D1 receptors , and D1 dysfunction has been linked to cognitive impairment and negative symptoms of schizophrenia . [4]

THE 4 DOPAMINE PATHWAYS IN THE BRAIN

1.The Mesolimbic Pathway

• The pathway projects from the ventral tegmental area (VTA) to the nucleus accumbens in the limbic system.
• Hyperactivity of dopamine in the mesolimbic pathway mediates positive psychotic symptoms. The pathway may also mediate aggression.
• The mesolimbic pathway is also the site of the rewards pathway and mediates pleasure and reward. Antipsychotics can block D2 receptors in this pathway reducing pleasure effects. This may be one explanation as to why individuals with schizophrenia have a higher incidence of smoking as nicotine enhances dopamine in the reward pathway (self-medication hypothesis)
• Antagonism of D2 receptors in the mesolimbic pathway treats positive psychotic symptoms.
• There is an occupancy requirement with the minimum threshold at 65% occupancy for treatment to be effective. Observations support this relationship between D2-receptor occupancy and clinical response that 80% of responders have D2-receptor occupancy above this threshold after treatment. [5]

2.The Mesocortical Pathway

• Projects from the VTA to the prefrontal cortex.
• Projections to the dorsolateral prefrontal cortex regulate cognition and executive functioning.
• Projections into the ventromedial prefrontal cortex regulate emotions and affect.
• Decreased dopamine in the mesocortical projection to the dorsolateral prefrontal cortex is postulated to be responsible for negative and depressive symptoms of schizophrenia.
• Nicotine releases dopamine in the mesocortical pathways alleviating negative symptoms (self-medication hypothesis).

3.The Nigrostriatal Pathway

• Projects from the dopaminergic neurons in the substantia nigra to the basal ganglia or striatum.
• The nigrostriatal pathway mediates motor movements.
• Blockade of dopamine D2 receptors in this pathway can lead to dystonia, parkinsonian symptoms and akathisia.
• Hyperactivity of dopamine in the nigrostriatal pathway is the postulated mechanism in hyperkinetic movement disorders such as chorea, tics and dyskinesias.
• Long-standing D2 blockade in the nigrostriatal pathway can lead to tardive dyskinesia. 

4.The Tuberoinfundibular (TI) Pathway

• Projects from the hypothalamus to the anterior pituitary.
• The TI pathway inhibits prolactin release.
• Blockade of D2 receptors in this pathway can lead to hyperprolactinemia which clinically manifests as amenorrhoea, galactorrhoea and sexual dysfunction.
• Long-term hyperprolactinemia can be associated with osteoporosis.

Conceptualisation of Schizophrenia

Based on the above understanding, schizophrenia is best conceptualised as a complex entity which involves multiple pathways.

In clinical practice, there can be a disproportionate focus on positive psychotic symptoms.

It is however, important to recognise that affective (e.g depressive), negative and cognitive symptoms are a core part of schizophrenia and should be taken into account in treatment.

The aim of treatment, thus, is to modulate treatment creating a balance between effectiveness and reduction of side effects.

The balance is achieved by optimal dopamine blockade in the mesolimbic pathway while preserving (or enhancing) dopamine transmission in the other pathways.

DOPAMINE AND SCHIZOPHRENIA

The dopamine hypothesis of schizophrenia has moved from the dopamine receptor hypothesis (increased dopamine transmission at the postsynaptic receptors) to a focus on presynaptic striatal hyperdopaminergia.

According to Howes and Kapur-

This hypothesis accounts for the multiple environmental and genetic risk factors for schizophrenia and proposes that these interact to funnel through one final common pathway of presynaptic striatal hyperdopaminergia. In addition to funneling through dopamine dysregulation, the multiple environmental and genetic risk factors influence diagnosis by affecting other aspects of brain function that underlie negative and cognitive symptoms. Schizophrenia is thus dopamine dysregulation in the context of a compromised brain. [6]

Read more on the molecular imaging of dopamine abnormalities in schizophrenia. 

Clinical Implications

The hypothesis that the final common pathway is presynaptic dopamine dysregulation has some important clinical implications. Firstly, it implies that current antipsychotic drugs are not treating the primary abnormality and are acting downstream. While antipsychotic drugs block the effect of inappropriate dopamine release, they may paradoxically worsen the primary abnormality by blocking presynaptic D2 autoreceptors, resulting in a compensatory increase in dopamine synthesis. This may explain why patients relapse rapidly on stopping their medication, and if the drugs may even worsen the primary abnormality, it also accounts for more severe relapse after discontinuing treatment. This suggests that drug development needs to focus on modulating presynaptic striatal dopamine function, either directly or through upstream effects. [6]

Concept of Salience

Usually, dopamine’s role is to mediate motivational salience and thereby gives a person the ability to determine what stimulus grabs their attention and drives the subsequent behaviour.

The salience network consists of the Anterior Cingulate Cortex (ACC), insula and the amygdala.

Schizophrenia is associated with an aberrant attribution of salience due to dysregulated striatal dopamine transmission.

Dysregulation of the dopamine system ultimately leads to irrelevant stimuli becoming more prominent which provides a basis for psychotic phenomena such as ideas of reference, where everyday occurrences may be layered with a with a heightened sense of bizarre significance.  Furthermore, this misattribution of salience can lead to paranoid behaviour and persecutory delusions. [7]

A stimulus, even if initially lacking inherent salience, once paired with dopaminergic activity, maintains the ability to evoke dopaminergic activity over time. This suggests that in psychosis, once an environmental stimulus has been highlighted by aberrant dopamine signalling, it may maintain its ability to trigger dopaminergic activity, potentially cementing its position in a delusional framework, even if the system subsequently returns to normal function. [McCutcheon, et al, 2019]

LIMITATIONS OF THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

Current research shows that one-third of individuals with schizophrenia do not respond to non-clozapine antipsychotics despite high levels of D2-receptor occupancy.

Furthermore, a study using tetrabenazine (used as augmentation) which depletes presynaptic dopamine was not found to be effective in augmenting a clinical response in schizophrenia. [8]

Therefore, for a significant number of patients with schizophrenia, the basis of their symptoms is either unrelated to dopaminergic dysfunction or is associated with something more than just dopamine excess.

Alternatively, this could also mean that for some patients with schizophrenia there might be a non-dopaminergic sub-type of schizophrenia.

The current dopamine hypothesis of schizophrenia does not adequately explain the cognitive and negative symptoms. Current treatments which modulate dopamine transmission have only modest effects in improving these symptoms.

It has taken two decades for the dopamine hypothesis to evolve and reach its current state. More recent evidence shows another neurotransmitter, glutamate playing an essential role in schizophrenia.

The future likely holds a lot more secrets about schizophrenia which should unravel with the advances in understanding the brain.

Learn more:

Simplified Guide to Mechanisms of Action of Oral Antipsychotics

RECOMMENDED BOOKS

Howes O, et al . Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study. Brain . 2013

Howes OD, Shatalina E. Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance. Biol Psychiatry. 2022 Sep 15;92(6):501-513.

Howes, O., McCutcheon, R., & Stone, J. (2015). Glutamate and dopamine in schizophrenia: an update for the 21st century. Journal of psychopharmacology , 29 (2), 97-115.

Kapur S, et al . Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. American Journal of Psychiatry . 2000

Howes O, Murray R. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet . 2014

McCutcheon, R. A., Abi-Dargham, A., & Howes, O. D. (2019). Schizophrenia, dopamine and the striatum: from biology to symptoms.  Trends in neurosciences ,  42 (3), 205-220

• Bipolar Disorder
• Therapy Center
• When To See a Therapist
• Types of Therapy
• Best Online Therapy
• Best Couples Therapy
• Best Family Therapy
• Managing Stress
• Sleep and Dreaming
• Understanding Emotions
• Self-Improvement
• Healthy Relationships
• Student Resources
• Personality Types
• Guided Meditations
• Verywell Mind Insights
• 2023 Verywell Mind 25
• Mental Health in the Classroom
• Editorial Process
• Meet Our Review Board
• Crisis Support

The Relationship Between Schizophrenia and Dopamine

Arlin Cuncic, MA, is the author of The Anxiety Workbook and founder of the website About Social Anxiety. She has a Master's degree in clinical psychology.

Alla Bielikova / Getty Images

• Dopamine and Schizophrenia Symptoms
• Implications for Treatment

What Does This Mean for Patients?

• Causes of Schizophrenia
• High vs. Low Dopamine
• Implications

Serotonin and Schizophrenia

Experts do not fully understand what causes schizophrenia, but evidence suggests that dopamine abnormalities may play a role. High and low levels of dopamine in certain regions of the brain can also affect different symptoms of schizophrenia.

Schizophrenia is a debilitating mental disorder with a multitude of symptoms. These can range from disorganized speech and behavior to delusions and hallucinations. Some cases are far more disabling than others, but in most cases, people with this disorder require lifelong treatment and care.

Current research suggests that schizophrenia is a neurodevelopmental disorder with an important dopamine component. Four decades of research have focused on the role of dopamine in schizophrenia, and it seems clear that excesses or deficiencies in dopamine can lead to schizophrenic symptoms.

At a Glance

While other factors also play a role in the development of schizophrenia, dopamine imbalances have been identified as a key factor affecting symptoms. Too much dopamine in key areas of the brain results in delusions and hallucinations (positive symptoms) or cognitive deficits and reduced social/emotional activity (negative symptoms). Understanding the factors that contribute to dopamine symptoms can help doctors treat the condition more effectively.

What Is the Dopamine Hypothesis of Schizophrenia?

The dopamine hypothesis of schizophrenia was one of the first neurobiological theories for this disease.

Dopamine Hypothesis

This theory suggests that an imbalance of dopamine is responsible for schizophrenic symptoms. In other words, dopamine plays a role in controlling our sense of reality, and too much or too little can cause delusions and hallucinations.

The evidence for this theory comes from many sources, including post-mortem studies that have imbalances of dopamine as well as its metabolites in schizophrenic patients. In addition, drugs that block the receptors for dopamine can help control schizophrenic symptoms.

How Does Dopamine Cause Schizophrenic Symptoms?

There are two types of schizophrenia symptoms that an excess of dopamine may cause: positive and negative . Positive symptoms include delusions and hallucinations. Negative symptoms include a decrease in social activity, emotional range, and cognitive function.

Positive Symptoms

Positive symptoms are those that appear to come from outside the person. These can include delusions, hallucinations, or thought disorders.

Dopamine contributes to the development of positive symptoms through its effects on subtype-3A dopamine receptors (D3) of cortical neurons. The subtype-3A receptor is found in the prefrontal cortex, which controls planning, thinking, and other cortical areas.

When these receptors are activated by dopamine, they overstimulate neurons. This can lead to all three types of positive symptoms. Evidence for this idea comes from studies that show that patients with schizophrenia have significantly lower levels of the D3 receptor than healthy people.

Negative Symptoms

While positive symptoms appear to come from outside, negative symptoms appear to be internal. These include decreased social activity and emotional range, as well as cognitive deficits like poor problem-solving or memory deficit.

The mechanisms contributing to negative symptoms are linked to dopamine levels in the limbic system . Dopamine excess leads to an increase in the activity of dopamine receptors, creating overstimulation similar to that seen in positive symptoms.

Some researchers suggest that this overactivity decreases neuronal inhibition , leading to decreased social behavior and cognitive deficits.

Treatment Implications of the Dopamine Hypothesis

The dopamine hypothesis has important treatment implications. The vast majority of current antipsychotic medications target dopamine, and this makes sense, given that these drugs were discovered through serendipitous observations of their effect on schizophrenia.

The most important dopamine-affecting medications are the typical antipsychotics, which increase post-synaptic receptor stimulation by blocking dopamine receptors.

Unfortunately, these medications produce a number of debilitating side effects, most notably extrapyramidal symptoms (EPS) like tardive dyskinesia . Newer second-generation antipsychotics have fewer side effects, but none are perfect.

Treatment with dopamine agonists is a third possibility suggested by the dopamine hypothesis. Dopamine agonists stimulate post-synaptic dopamine receptors directly, and as such, they can be used to treat schizophrenia without producing EPS.

Being diagnosed with schizophrenia can be extremely hard on patients and their families. It's important that doctors and researchers continually investigate new treatments that could improve the lives of people living with this disorder.

However, it's also important to remember that schizophrenia is a complex disorder, and there are many ways the disease can manifest. Dopamine hyperactivity may not be the primary cause of schizophrenia in all patients. Furthermore, even if dopamine hyperactivity is the primary cause it still doesn't explain why some patients respond more strongly than others to the same treatment.

The best way for patients and their loved ones to navigate these issues is by staying informed and asking questions about any new or experimental treatments. They should also work with doctors to develop a personalized treatment plan that's appropriate for their own needs.

Does Too Much Dopamine Cause Schizophrenia?

Increased activity of the mesolimbic pathway is related to positive symptoms of schizophrenia (delusions, hallucinations, etc.). This means that increasing the activity of dopamine receptors in this brain system could theoretically reduce delusions and hallucinations.

A closely related idea is that by blocking post-synaptic dopamine receptors, scientists can reduce the psychotic symptoms of schizophrenia.

As mentioned previously, this is what most modern medications do: they block post-synaptic dopamine receptors in order to reduce psychotic symptoms. Unfortunately, when scientists block all available dopamine receptors they also produce a number of debilitating side effects such as extrapyramidal symptoms (EPS) and tardive dyskinesia.

Is Dopamine High or Low in Schizophrenia?

The most common theory about the cause of schizophrenia is that there are too many dopamine receptors in certain parts of the brain, specifically the mesolimbic pathway. This causes an increase in mesolimbic activity which results in delusions, hallucinations, and other psychotic symptoms.

Other research suggests that schizophrenia might be caused by a lack of dopamine activity in other parts of the brain. For example, scientists have discovered that the hippocampus is overactive in schizophrenia.

Schizophrenia might also be characterized by low dopamine in the prefrontal cortex, but again the evidence is inconclusive. Some studies have found that schizophrenics have elevated levels of dopamine in this region, while others suggest that there are too few dopamine receptors.

Implications of the Dopamine Hypothesis

It's important to note that schizophrenia is a complex disorder. Even if dopamine hyperactivity is the primary cause, certain types of schizophrenia might be characterized by increased activity in certain brain areas while others are characterized by reduced activity in certain brain areas.

Furthermore, it's also possible that different patients will respond to treatment differently based on how their disease manifests.

It's important for healthcare providers and researchers to continue investigating how schizophrenia works in the brain. This will help them develop better treatments for this complex disorder.

Research also implicates serotonin as a regulator of dopamine release. Antipsychotic medications, including olanzapine and clozapine , reduce serotonin activity and increase dopamine activity.

For example, olanzapine-induced reductions in serotonin metabolism were associated with significant improvements in negative and positive symptoms, but not cognitive deficits.

Schizophrenia is a severe mental disorder that can be treated. If you or someone you know was recently diagnosed with schizophrenia, you might be wondering what the future holds. Healthcare professionals can help you manage your symptoms and chart a course for the best possible outcome.

Sometimes, there may be periods of remission that allow you to live a productive life even when coping with schizophrenia. As new treatments are continually being developed, we can look forward to better options for people who experience this disorder in the future.

Murray RM, Lappin J, Di Forti M. Schizophrenia: from developmental deviance to dopamine dysregulation .  Eur Neuropsychopharmacol . 2008;18 Suppl 3:S129-S134. doi:10.1016/j.euroneuro.2008.04.002

Brisch R, Saniotis A, Wolf R, et al. The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue [published correction appears in Front Psychiatry. 2014;5:110. Braun, Anna Katharina [corrected to Braun, Katharina]; Kumaritlake, Jaliya [corrected to Kumaratilake, Jaliya]].  Front Psychiatry . 2014;5:47. Published 2014 May 19. doi:10.3389/fpsyt.2014.00047

Purves-Tyson TD, Owens SJ, Rothmond DA, et al. Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain .  Transl Psychiatry . 2017;7(1):e1003. Published 2017 Jan 17. doi:10.1038/tp.2016.257

Ceraso A, Lin JJ, Schneider-Thoma J, et al. Maintenance treatment with antipsychotic drugs for schizophrenia .  Cochrane Database Syst Rev . 2020;8:CD008016. doi:10.1002/14651858.CD008016.pub3

Guma E, Rocchetti J, Devenyi GA, et al. Role of D3 dopamine receptors in modulating neuroanatomical changes in response to antipsychotic administration .  Sci Rep . 2019;9(1):7850. doi:10.1038/s41598-019-43955-4

Maia TV, Frank MJ. An Integrative Perspective on the Role of Dopamine in Schizophrenia .  Biol Psychiatry . 2017;81(1):52-66. doi:10.1016/j.biopsych.2016.05.021

Weiner I. The "two-headed" latent inhibition model of schizophrenia: modeling positive and negative symptoms and their treatment .  Psychopharmacology (Berl) . 2003;169(3-4):257-297. doi:10.1007/s00213-002-1313-x

Stępnicki P, Kondej M, Kaczor AA. Current concepts and treatments of schizophrenia .  Molecules . 2018;23(8):2087. doi:10.3390/molecules23082087

Preda A, Shapiro BB. A safety evaluation of aripiprazole in the treatment of schizophrenia .  Expert Opin Drug Saf . 2020;19(12):1529-1538. doi:10.1080/14740338.2020.1832990

Gomes FV, Zhu X, Grace AA. Stress during critical periods of development and risk for schizophrenia .  Schizophr Res . 2019;213:107-113. doi:10.1016/j.schres.2019.01.030

McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment .  World Psychiatry . 2020;19(1):15-33. doi:10.1002/wps.20693

Correll CU. Current Treatment Options and Emerging Agents for Schizophrenia .  J Clin Psychiatry . 2020;81(3):MS19053BR3C. Published 2020 Apr 14. doi:10.4088/JCP.MS19053BR3C

Bever KA, Perry PJ. Olanzapine: a serotonin-dopamine-receptor antagonist for antipsychotic therapy .  Am J Health Syst Pharm . 1998;55(10):1003-1016. doi:10.1093/ajhp/55.10.1003

By Arlin Cuncic, MA Arlin Cuncic, MA, is the author of The Anxiety Workbook and founder of the website About Social Anxiety. She has a Master's degree in clinical psychology.

Do we still believe in the dopamine hypothesis? New data bring new evidence

Affiliation.

• 1 Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, USA. [email protected]
• PMID: 14972078
• DOI: 10.1017/S1461145704004110

Schizophrenia is characterized by positive symptoms, negative symptoms and cognitive impairment. The dopamine hypothesis of schizophrenia postulates that an excess of dopamine subcortically is associated with the positive symptoms. At the same time, the negative and cognitive symptoms of schizophrenia are thought to arise from a deficit of dopamine in the cortex. Evidence for the co-existence of subcortical dopamine excess and cortical dopamine deficit in the schizophrenic brain is presented. Neuroreceptor-imaging techniques, such as SPECT and PET, have been used to provide that evidence. After amphetamine challenge (to stimulate dopamine release), dopamine transmission was substantially increased in the brains of schizophrenic subjects compared with healthy controls. In addition, amphetamine challenge was associated with an increase in positive symptoms of schizophrenia. Furthermore, acute dopamine depletion studies indicated that there was an increased occupancy of D2 receptors by dopamine at baseline in schizophrenia in comparison with healthy controls. This is consistent with the notion of hyperstimulation of D2 receptors in schizophrenia. In the cortex, dopamine type-1 (D1) receptors were found to be up-regulated in patients with schizophrenia compared to controls; in the dorsolateral prefrontal cortex, a brain region involved in working memory, this increase correlated with a poor performance on the n-back task. The up-regulation of D1 receptors may represent a compensatory effect of the dopamine deficit in the cortex. These findings provide evidence for a corticalsubcortical imbalance in the schizophrenic brain.

Publication types

• Brain / physiopathology
• Brain Mapping
• Cerebral Cortex / physiopathology
• Cognition Disorders / physiopathology
• Cognition Disorders / psychology
• Delusions / diagnosis
• Delusions / drug therapy
• Delusions / physiopathology
• Dopamine / physiology*
• Hallucinations / diagnosis
• Hallucinations / drug therapy
• Hallucinations / physiopathology
• Receptors, Dopamine D1 / physiology
• Receptors, Dopamine D2 / physiology
• Schizophrenia / diagnosis
• Schizophrenia / physiopathology*
• Schizophrenic Psychology*
• Up-Regulation / physiology
• Receptors, Dopamine D1
• Receptors, Dopamine D2

Reviewed by Psychology Today Staff

Dopamine is known as the feel-good neurotransmitter—a chemical that ferries information between neurons. The brain releases it when we eat food that we crave or while we have sex , contributing to feelings of pleasure and satisfaction as part of the reward system. This important neurochemical boosts mood, motivation , and attention , and helps regulate movement, learning, and emotional responses.

• Dopamine and Behavior
• Dopamine and the Brain
• How to Increase Dopamine

In lab experiments, dopamine prompts a rat to press a lever for food again and again. This is no different in humans; it’s the reason why we partake in more than one helping of cake. This press-the-lever action applies to addiction as well. People with low levels of dopamine may be more prone to addiction; a person seeking pleasure via drugs or alcohol or food needs higher and higher levels of dopamine.

Dopamine causes you to want, desire, seek out, and search. It increases your general level of arousal and your goal-directed behavior. Dopamine makes you curious about ideas and fuels your search for information. Dopamine creates reward-seeking loops in the sense that people will repeat pleasurable behavior, from checking Instagram to taking drugs.

A person with high levels of dopamine, whether due to temperament or to a transient—perhaps chemically induced state—can be described as a  sensation seeker. The upside of sensation seeking is that people see potential stressors as challenges to be overcome rather than threats that might crush them. This mindset is a buffer against the stress of life. It increases their hardiness and  r esilience in the long term.

The release of dopamine creates a reward circuit in the brain. This circuit registers an intense experience (such as getting high) as "important" and creates lasting memories of it as pleasurable. Dopamine changes the brain on a cellular level, commanding the brain to do it again.

Swedish pharmacologist and neuroscientist Arvid Carlsson won the Nobel prize in 2000 for his research on dopamine, showing its importance in brain function. He helped show that the neurotransmitter is heavily involved in the motor system. When the brain fails to produce enough dopamine, it can result in Parkinson’s disease. The primary treatment for Parkinson’s disease is a drug called L-dopa, which spurs the production of dopamine.

Dopamine has also been implicated in schizophrenia and ADHD ; the brain systems underlying these conditions (as well as substance abuse disorder) are complex. The activity of the dopamine system depends on the state of one’s dopamine receptors, and in people with these conditions, the chemical interacts with other factors in ways that have yet to be explained.

It is no exaggeration to say that dopamine makes us human. Beginning in infant development, dopamine levels are critical, and mental disabilities can arise if dopamine is not present in sufficient quantities. Dopamine is implicated in genetic conditions like congenital hypothyroidism. Dopamine deficiency is also implicated in other conditions such as Alzheimer's, depressive disorders, binge-eating, addiction, and gambling.

Drugs currently used to treat ADHD do indeed increase the effectiveness of dopamine. This helps patients with ADHD focus and pay better attention to one thing at a time. How exactly more dopamine translates into better concentration and focus is not yet understood.

In this neurodegenerative disorder, the decline begins with the dopamine-producing cells in the brain where movement is coordinated. As these cells degrade, motor function is compromised , which includes tremors, rigidity, bradykinesia or slowed movement, as well as changes in speech and gait.

Scientists who study neurological and psychiatric disorders have long been interested in how dopamine works and how relatively high or low levels of dopamine in the brain relate to behavioral challenges and disability.

There are ways to up one's dopamine levels naturally, and basic self-care is the place to start. A night of fitful sleep, for one, can reduce dopamine drastically. Here are some tips to boost levels:

• Eat foods rich in tyrosine including cheese, meats, fish, dairy, soy, seeds, nuts, beans, lentils, among others. While tyrosine supplements are available, consuming foods is preferred.
• Up magnesium intake with foods such as seeds, nuts, soy, beans, whole grains, among others.
• Avoid processed foods, high-fats, sugar, caffeine.
• Proper sleep hygiene is mandatory, as it fuels dopamine production.
• Exercise daily.
• Avoid stress, apply techniques such as meditation , visualization , breathing exercises.
• Consider the use of natural nootropics including L-Tyrosine and L-theanine.

We all have our own personalities, preferences, and quirks, and they should all be reflected in our styles. Finding your style can lead to increased self-esteem and confidence.

More than 21 million Americans—celebrities and "regular" folks among them— have both a substance use disorder and a serious psychiatric problem. What do we know about this issue?

Capitalizing on your motivation or eliminating apathy and inaction means keen awareness of the powerful role of rewards and your unique dopamine production.

Oxytocin fuels maternal instincts, tells us who brings us the most joy, helps us make friends, and is associated with the development of empathy but also hatred and prejudice.

Discover how non-alcoholic beverages might impact alcohol recovery; Could they be the key to controlling cravings, or do they pose unseen risks?

Speedballing, combining fentanyl with cocaine or methamphetamine, is the fourth wave of the opioid crisis in the U.S.

How your brain responds to reward matters more than the power of positive emotion.

Exploring dopamine's role in addiction and consumer behavior helps us understand how it shapes our motivations and influences decision-making.

What can we do today to make a difference in the current opioid crisis?

Modern life has turned the motivation circuit in our brains against us. Here's how to reclaim it.

• Find a Therapist
• Find a Treatment Center
• Find a Psychiatrist
• Find a Support Group
• Find Teletherapy
• United States
• Brooklyn, NY
• Chicago, IL
• Houston, TX
• Los Angeles, CA
• New York, NY
• Portland, OR
• San Diego, CA
• San Francisco, CA
• Seattle, WA
• Washington, DC
• Asperger's
• Bipolar Disorder
• Chronic Pain
• Eating Disorders
• Passive Aggression
• Personality
• Goal Setting
• Positive Psychology
• Stopping Smoking
• Low Sexual Desire
• Relationships
• Child Development
• Therapy Center NEW
• Diagnosis Dictionary
• Types of Therapy

Understanding what emotional intelligence looks like and the steps needed to improve it could light a path to a more emotionally adept world.

• Coronavirus Disease 2019
• Affective Forecasting
• Neuroscience

Find Study Materials for

• Business Studies
• Combined Science
• Computer Science
• Engineering
• English Literature
• Environmental Science
• Human Geography
• Macroeconomics
• Microeconomics
• Social Studies
• Browse all subjects
• Read our Magazine

Create Study Materials

Often called the ‘feel-good’ hormone, dopamine is in charge of making you feel happy, satisfied, and motivated. When you feel good because you have accomplished something, your brain experiences a dopamine spike. What occurs, though, when there is an imbalance? Could this imbalance play a role in the development of schizophrenia ? This is where the dopamine hypothesis of schizophrenia enters the picture, examining how the imbalance of dopamine levels and the abundance of dopamine receptors contributes to schizophrenia.

Explore our app and discover over 50 million learning materials for free.

• The Dopamine Hypothesis
• Explanations
• StudySmarter AI
• Textbook Solutions
• Approaches in Psychology
• Basic Psychology
• Biological Bases of Behavior
• Biopsychology
• Careers in Psychology
• Clinical Psychology
• Cognition and Development
• Cognitive Psychology
• Data Handling and Analysis
• Developmental Psychology
• Eating Behaviour
• Emotion and Motivation
• Famous Psychologists
• Forensic Psychology
• Health Psychology
• Individual Differences Psychology
• Issues and Debates in Psychology
• Personality in Psychology
• Psychological Treatment
• Relationships
• Research Methods in Psychology
• Biological Explanations for Schizophrenia
• Cognitive Behavioural Therapy
• Cognitive Explanations for Schizophrenia
• Diagnosis and Classification of Schizophrenia
• Dysfunctional Family
• Family Therapy
• Interactionist Approach Schizophrenia
• Neural Correlates
• Psychological Explanations for Schizophrenia
• Psychological Therapies for Schizophrenia
• Reliability and Validity in Diagnosis and Classification of Schizophrenia
• Role Of Cannabis
• Schizophrenia Genetics
• Token Economy
• Treatment and Therapies for Schizophrenia
• Typical and Atypical Antipsychotics
• Ventricular Size
• Scientific Foundations of Psychology
• Scientific Investigation
• Sensation and Perception
• Social Context of Behaviour
• Social Psychology

Lerne mit deinen Freunden und bleibe auf dem richtigen Kurs mit deinen persönlichen Lernstatistiken

Nie wieder prokastinieren mit unseren Lernerinnerungen.

• We will discuss the dopamine hypothesis of schizophrenia .
• First, we will provide a dopamine hypothesis psychology definition.
• Then, we explore the various aspects of the biological explanations of the schizophrenia dopamine hypothesis. including the dopamine hypothesis of psychosis.
• Finally, we will examine the d opamine hypothesis's strengths and weaknesses through an evaluation of the dopamine hypothesis.

The D opamine Hypothesis of Schizophrenia: Definition

The dopamine hypothesis, first proposed by Van Rossum in 1967, is the theory that too much dopamine in the subcortical and limbic regions of the brain may cause positive schizophrenic symptoms . According to the dopamine hypothesis, negative symptoms are associated with less dopamine in the prefrontal cortex .

The dopamine hypothesis was later revised as research revealed schizophrenic patients might also have too many dopamine receptors.

Dopamine is a neurotransmitter that helps the brain send messages to specific body parts. Neurotransmitters are chemical messengers within the brain .

Neurotransmitters bind to receptors in nerve cells after they cross a small gap between them called the synapse. Dopamine is a neurotransmitter involved in our brain’s pleasure and reward systems. The receptors of dopamine are implicated in the dopamine hypothesis of schizophrenia, in that some researchers theorise too many receptors contribute to the overactivity of dopamine in the brain and any subsequent schizophrenic developments.

Biological Explanations of Schizophrenia: Dopamine Hypothesis

The dopamine hypothesis is a biological explanation of schizophrenia, so how does it work? What parts of the brain are involved in the dopamine hypothesis?

• Dopamine is produced in different areas of the brain, and for schizophrenia, we are concerned with the substantia nigra and the ventral tegmental area .

The dopamine produced in the substantia nigra helps us trigger physical movements, including the parts of the face and mouth needed for speech. Problems with this may be responsible for some symptoms of schizophrenia , such as alogia (lack of speech) and psychomotor disturbances.

Damage to dopaminergic neurons in the substantia nigra is correlated with the development of Parkinson's.

Dopamine produced in the ventral tegmental area is released when we expect or receive a reward. This helps both animals and humans modify their behaviour to be more likely to result in a reward or positive experience. An excess of dopamine can lead to hallucinations and delusional or confused thinking, all of which are symptoms of schizophrenia .

Studies of amphetamines given to people without a history of schizophrenia showed that the effect of high levels of dopamine the drug had induced led to symptoms very similar to those of paranoid schizophrenia.

Later revisions of the hypothesis stated that possibly an excess of dopamine in the mesolimbic areas of the brain contributes to positive symptoms, and a low level of dopamine in the brain’s prefrontal cortex contributes to negative symptoms.

Dopamine Hypothesis of Psychosis: Development of the Dopamine Hypothesis

In the 1960s and 1970s, research was conducted into the use of amphetamine drugs and their effect on dopamine levels within the brain. The researchers found that psychotic symptoms increased when these drugs were consumed, sparking the idea that dopamine may help us understand how psychotic symptoms in schizophrenia patients may come to be.

The Dopamine Hypothesis: Strengths and Weaknesses

The dopamine hypothesis has been around for close to 60 years, and has gone through a series of developments alongside facing scrutiny in research. Let's evaluate the dopamine hypothesis of schizophrenia and examine its strengths and weaknesses.

Weaknesses of the Dopamine Hypothesis

The dopamine hypothesis, like any other, has its weaknesses.

• Cause and Effect: One problem with this explanation is that it is not certain whether a dopamine imbalance causes schizophrenia or whether schizophrenia causes a dopamine imbalance. Since the causal nature of the argument is unclear, it is crucial to be careful in determining cause and effect in the development of schizophrenia.
• Farde et al. (1990): Farde et al. (1990) found no difference between the dopamine receptor (D2) levels of schizophrenia patients and control patients. Farde et al.'s (1990) finding suggests that the dopamine hypothesis may not apply to all patients with schizophrenia.
• Determinism: The dopamine hypothesis can be considered deterministic (the belief that factors beyond our control determine human behaviour) because it assumes that the development of schizophrenia depends on the amount of dopamine or dopamine receptors in our brains, which does not correspond to psychological explanations of schizophrenia. It ignores how the environment affects the development of the disorder.Deterministic theories have their limitations, as they are not compatible with societal notions of responsibility, free will and self-control, on which many of our legal and moral norms are based.

Strengths of the Dopamine Hypothesis

On the other hand, some studies are sympathetic to the role dopamine plays in the development of schizophrenia.

• Parkinson's Disease and Levodopa (L-Dopa): Some patients are given levodopa when treating Parkinson’s disease, a drug that increases dopamine levels in the brain. These patients are reported to experience psychotic side effects similar to schizophrenia symptoms, such as hallucinations and dyskinesia. The dopamine aspect supports the role that dopamine plays in the development of schizophrenic symptoms.
• Abi-Dargham et al. (2000): Abi-Dargham et al. (2000) investigated whether there was a true increased level of dopamine and dopamine 2 (D2) receptors within the brain for schizophrenic people compared to controls, accounting for the effects of patients taking antipsychotics and artificially elevating their levels. They found that their results indicated, that for the levels to match up, schizophrenic patients must have an increased level of both dopamine and dopamine receptors compared to controls.

Practical Applications of the Dopamine Hypothesis

Now that we have gained some insight into the dopamine hypothesis’s theoretical aspects, let us look at how it is applied in practice.

Typical Antipsychotic Drugs: First Generation

The dopamine hypothesis has contributed to the development of antipsychotics for schizophrenia and several other disorders in which sufferers experience psychosis.

Typical antipsychotic drugs work by blocking D2 receptors in the brain, limiting dopamine activity. Blocking dopamine receptors can help reduce positive symptoms such as hallucinations

Typical antipsychotics tend to block dopamine in all areas of the brain, not just those that cause schizophrenic symptoms, which can lead to harmful side effects.

Examples of typical antipsychotics include chlorpromazine and haloperidol .

Atypical Antipsychotic Drugs: Second Generation

Atypical antipsychotic s are newer drugs that usually do not have as severe side effects as typical antipsychotics.

Atypical antipsychotics only inhibit dopamine receptors in the limbic system rather than throughout the brain.

They help control the symptoms of schizophrenia without interfering with other systems and potentially causing the same side effects as the previous generation of medications.Atypical antipsychotics bind to dopamine receptors and act on glutamate (an excitatory neurotransmitter) and serotonin. This means that these drugs can help with positive symptoms and reduce negative symptoms such as low mood and impaired cognitive function.

Because of their effect on serotonin, these antipsychotics can also help treat some comorbidities associated with schizophrenia, such as anxiety and depression .

Evaluating Practical Applications of the Dopamine Hypothesis

Considering the practical applications of the dopamine hypothesis affect patients, it's important we evaluate it thoroughly before moving forwards.

Drug treatments such as antipsychotics, developed based on the dopamine hypothesis, help patients manage their daily lives and quality of life. These drugs are relatively easy to make and administer and can positively impact healthcare providers and the economy. This is because they help people with schizophrenia to leave treatment and return to their daily lives, such as their jobs, allowing more people to be treated.

While these drugs help with schizophrenic symptoms, it is essential to point out that they cannot cure schizophrenia. This means that we need more research to find a long-term solution to the disease.

There are some ethical questions about these drugs. In some hospitals, antipsychotic medications may be used to benefit staff rather than patients to make it easier to work with patients.

Antipsychotic medications can have serious side effects, such as tardive dyskinesia, a condition that involves involuntary facial ‘tics’ such as rapid blinking, chewing movements, or rolling of the tongue. Sometimes the side effects can be worse than the initial symptoms of schizophrenia.

The Dopamine Hypothesis - Key takeaways

• The dopamine hypothesis, first proposed by Van Rossum in 1967, is the theory that high dopamine levels may cause schizophrenic symptoms.
• In the 1960s and 70s, researchers studied amphetamines and their effect on dopamine levels in the brain. Researchers found that psychotic symptoms increased when these drugs were used. This finding gave us the idea that this could help us understand the cause of psychotic symptoms in schizophrenia patients.
• Problems with dopamine production and imbalances in dopamine in the substantia nigra and ventral tegmental area may be responsible for the symptoms of schizophrenia, such as alogia, hallucinations, and psychomotor disturbances.
• It is difficult to establish cause and effect in the dopamine hypothesis, however, many studies support the evidence that imbalances in the brain concerning dopamine are related to psychotic and negative symptoms. More research is needed to identify what causes schizophrenia.

Frequently Asked Questions about The Dopamine Hypothesis

--> what is the dopamine hypothesis of schizophrenia in psychology.

The dopamine hypothesis, first proposed by Van Rossum in 1967, is the theory that high or low levels of dopamine may cause schizophrenic symptoms.

--> What is the role of dopamine in schizophrenia?

The dopamine hypothesis suggests dopamine level imbalances and too many dopamine receptors play a role in the development of symptoms of schizophrenia. However, the dopamine hypothesis does not fully explain how the disorder develops. Newer antipsychotics that are generally more effective than previous drug treatments target more neurotransmitters than just dopamine, suggesting that it may not exclusively be dopamine that causes schizophrenia.

--> What is the original dopamine hypothesis of schizophrenia?

The original dopamine hypothesis states that too much dopamine within an individual's brain causes the onset of schizophrenic symptoms, such as hallucinations.

--> Do people with schizophrenia have low levels of dopamine?

Schizophrenic people may have low levels of dopamine. The dopamine hypothesis suggests both low and high levels of dopamine in certain areas of the brain may be responsible for schizophrenic symptoms. Low levels of dopamine, for instance, may result in negative symptoms. 

Test your knowledge with multiple choice flashcards

What did Farde et al. (1990) find in their study into the dopamine hypothesis?

True or False: The dopamine hypothesis was later revised as research revealed schizophrenic patients may also have too many dopamine receptors, which can also contribute to the disorder.

Excess dopamine in the mesolimbic pathway (ventral tegmental area and nucleus accumbens) contributes to ________ symptoms of schizophrenia.

Your score:

Join the StudySmarter App and learn efficiently with millions of flashcards and more!

Learn with 13 the dopamine hypothesis flashcards in the free studysmarter app.

Already have an account? Log in

What is dopamine?

 A neurotransmitter associated with the rewards system of our brains.

What is a synapse?

A small gap between neurons across which messages are fired through neurotransmitters.

Issues with dopamine production in the ________ nigra contributes to symptoms of schizophrenia.

substantia.

No difference in dopamine (D2) receptor levels between schizophrenic and non-schizophrenic participants.

The dopamine hypothesis is a deterministic theory. Why is this a limitation?

Deterministic theories have their limitations, as they are not compatible with societal notions of responsibility and self-control, on which many of our legal and moral norms are based.

How does Parkinson's treatment, L-Dopa, support the dopamine hypothesis?

Some patients are given levodopa (L-Dopa) when treating Parkinson’s disease, a drug that increases dopamine levels in the brain. These patients are reported to experience psychotic side effects similar to schizophrenia symptoms. This supports the role that dopamine plays in the development of schizophrenic symptoms.

of the users don't pass the The Dopamine Hypothesis quiz! Will you pass the quiz?

How would you like to learn this content?

Free psychology cheat sheet!

Everything you need to know on . A perfect summary so you can easily remember everything.

Join over 22 million students in learning with our StudySmarter App

The first learning app that truly has everything you need to ace your exams in one place

• Flashcards & Quizzes
• AI Study Assistant
• Study Planner
• Smart Note-Taking

Sign up to highlight and take notes. It’s 100% free.

This is still free to read, it's not a paywall.

You need to register to keep reading, create a free account to save this explanation..

Save explanations to your personalised space and access them anytime, anywhere!

By signing up, you agree to the Terms and Conditions and the Privacy Policy of StudySmarter.

Entdecke Lernmaterial in der StudySmarter-App

Final dates! Join the tutor2u subject teams in London for a day of exam technique and revision at the cinema. Learn more →

Reference Library

Collections

• See what's new
• All Resources
• Student Resources
• Assessment Resources
• Teaching Resources
• CPD Courses
• Livestreams

Study notes, videos, interactive activities and more!

Psychology news, insights and enrichment

Currated collections of free resources

Browse resources by topic

• All Psychology Resources

Resource Selections

Currated lists of resources

• Exam Support

Example Answers for Section C Schizophrenia Topic Paper 3 June 2018 (AQA)

Last updated 13 Aug 2018

• Share on Facebook
• Share on Twitter
• Share by Email

Here are a series of suggested answers for the Schizophrenia topic questions in AQA A Level Psychology Paper 3 (Section B) in June 2018.

Question 22 : (2 marks)

Comorbidity is when the same person has two or more disorders at the same time. For example, about 50% of people with schizophrenia are also diagnosed with depression.

- - - - - - - - -

Question 23 : (2 marks)

System overlap refers to the way that disorders have shared symptoms. For example hallucinations are a symptom of both schizophrenia and bipolar disorder. This can lead to problems with reliability of diagnosis as one doctor might diagnose the person as having schizophrenia while another might diagnose bipolar disorder.

Question 24: (4 marks)

Group A’s scores suggest a normal distributed as the mean, median and mode are all almost the same (22). However, group B’s scores suggest a positively skewed distribution as the mean (26) is higher than both the median (22.5) and the mode (16).

Question 25 : (16 marks)

One biological explanation for schizophrenia is that it is passed on through the genes. Gottesman reports that while the rate of schizophrenia in the general population is 1%, if one parent has schizophrenia there is a 12% likelihood their child will develop it and if both parents have schizophrenia, it increases to 40%. Schizophrenia seems to be polygenic, as a number of genes have been implicated. It also seems to be aetiologically heterogeneous as different studies have identified different candidate genes. For example, Ripke et al. found 108 separate genetic variations were associated with increased risk of schizophrenia.

Evidence to support the genetic explanation comes from Gottesman and Shields, who found a concordance rate of 42% for MZ and 9% for DZ. MZ twins share 100% of their genes, compared to DZ twins who only share 50% of their genes, so this suggests that genes must have some influence on the development of schizophrenia. However, the concordance rate for MZ twins is not 100% which suggests that other factors must also be involved. It is also important to note that two-thirds of people with schizophrenia have no relative with a similar diagnosis and therefore have no one to inherit it from. However, one explanation for this is mutation in parental DNA.

The dopamine hypothesis is another biological explanation for schizophrenia. The original version suggested it was due to high levels or activity of dopamine in the subcortex (hyperdopaminergia). For example, an excess of dopamine receptors in Broca’s area might be responsible for poverty of speech and auditory hallucinations. More recent versions have included hypodopaminergia, where low levels of dopamine in the prefrontal cortex are believed to be responsible for some of the negative symptoms of schizophrenia.

Research evidence from autopsies has shown that schizophrenia sufferers have more dopamine receptors, which may lead to more neural firing and therefore an over production of messages. Further support comes from the fact that dopamine agonists (e.g. amphetamines) can produce-schizophrenia like symptoms in non-sufferers. Conversely, antipsychotic drugs work by binding to dopamine receptors and reduce symptoms. However, the newer antipsychotic drugs affect other neurotransmitters such as serotonin and glutamate as well as dopamine. Therefore it appears that several neurotransmitters may be involved in the development of schizophrenia, meaning the dopamine hypothesis is too simplistic. Biological explanations for schizophrenia can be criticised for being biologically reductionist. By oversimplifying schizophrenia in terms of genes and neurotransmitters, the social context within which it develops has not been considered. In order to explain schizophrenia effectively it would be better to take an interactionist approach, such as the diathesis stress model. This suggests that biological factors predispose someone to schizophrenia, but this has to be ‘triggered’ by some sort of experience or stressor. Evidence to support this view comes from the prospective adoption study by Tienari et al. Although this study showed that children with a biological parent were still at greater risk even if they had been adopted into families with no history of schizophrenia, all reported cases of schizophrenia occurred in families rated as ‘disturbed’. When the families were rated as ‘healthy’, the likelihood of developing schizophrenia for those with a biological mother with schizophrenia fell to below 1%. However, biological factors must have had a role to play as none of the adoptees with no family history of schizophrenia from ‘disturbed’ families developed schizophrenia

• Schizophrenia

You might also like

Schizophrenia: comorbidity.

Study Notes

Schizophrenia: Culture

Schizophrenia: gender bias, schizophrenia: symptom overlap, new findings show dopamine’s complex role in schizophrenia.

5th January 2017

Schizophrenia and Type 2 Diabetes

19th January 2017

Q&A from AQA: 16 Mark Questions for Psychological Treatments of Schizophrenia

2nd February 2017

Video: Smoking Cannabis Damages Brain for LIFE

7th February 2017

Our subjects

• › Criminology
• › Economics
• › Geography
• › Health & Social Care
• › Psychology
• › Sociology
• › Teaching & learning resources
• › Student revision workshops
• › Online student courses
• › CPD for teachers
• › Livestreams
• › Teaching jobs

Boston House, 214 High Street, Boston Spa, West Yorkshire, LS23 6AD Tel: 01937 848885

• › Contact us
• › Terms of use
• › Privacy & cookies

© 2002-2024 Tutor2u Limited. Company Reg no: 04489574. VAT reg no 816865400.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• HHS Author Manuscripts

Dopamine overdose hypothesis: Evidence and clinical implications

David e. vaillancourt.

1 Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA

2 Department of Neurology, University of Florida, Gainesville, FL, USA

3 Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA

Daniel Schonfeld

Youngbin kwak.

4 Center for Cognitive Neuroscience, Duke University, Durham, NC, USA

Nicolaas I. Bohnen

5 Neurology Service and GRECC, VA Ann Arbor Healthcare system

6 Department of Neurology, University of Michigan, Ann Arbor, MI, USA

7 Department of Radiology, University of Michigan, Ann Arbor, MI, USA

Rachael Seidler

8 Department of Neuroscience, University of Michigan, Ann Arbor, MI, USA

9 Department of Psychology, University of Michigan, Ann Arbor, MI, USA

10 School of Kinesiology, University of Michigan, Ann Arbor, MI, USA

About a half a century has passed since dopamine was identified as a neurotransmitter, and it has been several decades since it was established that people with Parkinson’s disease receive motor symptom relief from oral levodopa. Despite the evidence that levodopa can reduce motor symptoms, there has been a developing body of literature that dopaminergic therapy can improve cognitive functions in some patients but make them worse in others. Over the past two decades, several laboratories have shown that dopaminergic medications can impair the action of intact neural structures and impair the behaviors associated with these structures. In this review we consider the evidence that has accumulated in the areas of reversal learning, motor sequence learning, and other cognitive tasks. The purported inverted-U shaped relationship between dopamine levels and performance is complex and includes many contributory factors. The regional striatal topography of nigrostriatal denervation is a critical factor as supported by multimodal neuroimaging studies. A patient's individual genotype will determine the relative baseline position on this inverted-U curve. Dopaminergic pharmacotherapy and individual gene polymorphisms can affect the mesolimbic and prefrontal cortical dopaminergic functions in a comparable inverted-U dose-response relationship. Depending on these factors, a patient can respond positively or negatively to levodopa when performing reversal learning and motor sequence learning tasks. These tasks may continue to be relevant as our society moves to increased technological demands of a digital world that requires newly learned motor sequences and adaptive behaviors to manage daily life activities.

Introduction

A little over half a century has passed since dopamine was identified as a neurotransmitter and it was recognized that depleting monoamines in the brain through the administration of reserpine caused hunched immobility in rodents 1 . This finding led to the hypothesis of a dopaminergic depletion disorder as the pathophysiological basis of Parkinson’s disease. Since then, dopamine substitution using levodopa (L-3,4-dihydroxyphenylalanine) has been the most widely used pharmacotherapy for Parkinson’s disease. Despite reducing symptom manifestation, a majority of patients chronically exposed to dopamine therapy will eventually develop motor complications, including response fluctuations and drug-induced dyskinesias (abnormal involuntary movements) such as choreic and dystonic limb or truncal movements 2 . In addition, while restoring cognitive functions associated with dopamine depleted brain regions, dopamine substitution can also impair certain cognitive functions, such as probabilistic reversal learning, motor sequence learning and other cognitive tasks, that are associated with intact dopamine-dependent brain regions 3 – 5 . Dopamine overstimulation has been studied for over a decade since the work of Gotham and colleagues 6 , with papers by Swainson and colleagues 7 and Cools and colleagues 3 initially proposing the dopamine overdose hypothesis.

Fronto-executive cognitive deficits can be observed even in early Parkinson’s disease in the areas including executive function, learning, memory, motor inhibition, impulse control, and visuospatial processing 8 . These cognitive deficits may be related to mesocortical, mesolimbic, and nigrostriatal dopaminergic pathways, as well as other pathways associated with acetylcholine and norepinephrine 8 . Cognitive deterioration following dopaminergic therapy can occur in several tasks. In this review of the dopamine overdose hypothesis, we characterize the specific evidence supporting this hypothesis by reviewing the relevant literature in the areas of reversal learning, motor sequence learning, and other cognitive tasks. Issues related to impulsivity and reward processing are not addressed in this review, since these issues have been addressed previously 9 , 10 . First, we discuss the physiology of the dopamine overdose hypothesis. Next, we discuss evidence for the negative effects of dopaminergic medication on probabilistic reversal learning, followed by the evidence for the negative effects of dopaminergic medication on motor sequence learning. We then discuss the evidence that other cognitive tasks can be negatively affected by levodopa when patients with Parkinson’s disease carry specific genetic polymorphisms. Finally, we discuss the clinical implications of the hypothesis as they apply to treatment and management of Parkinson’s disease patients.

Physiological Basis for the Dopamine Overdose Hypothesis

There are two major subtypes of dopaminergic neurons in the brain: the neurons of the substantia nigra pars compacta [A9 neurons] 11 , which give rise to the nigrostriatal pathway; and the A10 neurons of the ventral tegmental area (VTA), which give rise to the mesolimbic and mesocortical pathways that innervate parts of the limbic system and the neocortex 12 . The regional pattern of degeneration within the substantia nigra in patients with Parkinson’s disease appears to be specific such that a loss of pigmented neurons is greatest in the ventral lateral tier, followed by the dorsal tier, which is different to the patterns identified with healthy aging 13 . In vivo diffusion magnetic resonance imaging has provided evidence in support of this selective pattern of degeneration by showing that measures of structural integrity within the ventral and lateral substantia nigra are most affected in early Parkinson’s disease compared with control subjects 14 , 15 , whereas the dorsal substantia nigra is more affected in older adults compared with young adults 16 .

The ventral lateral tier of the substantia nigra sends dopaminergic projections primarily to the dorsal putamen, whereas the dorsal tier of the substantia nigra sends dopaminergic projections primarily to the ventral striatum. The ventral striatum receives also projections from the VTA 11 . Studies using 18 F-dopa positron emission tomography (PET) have shown that patients with unilateral Parkinson’s disease who are Hoehn and Yahr Stage 1 have reduced dopamine storage primarily within the dorsal putamen contralateral to motor symptoms 17 . In a cross-sectional study, it was shown that in early Parkinson’s disease, 18 F-dopa metabolism was reduced by almost 50% in the dorsal rostral putamen and dorsal caudal putamen, whereas the ventral putamen was unaffected 18 . With the progression of disease symptoms, there is a loss of 18 F-dopa metabolism in the ventral putamen. Longitudinal multi-tracer PET studies show that the posterior-dorsal to anterior-ventral striatal gradient of nigrostriatal denervation is maintained while the asymmetry gradient becomes less prominent with progressive Parkinson's disease 19 . Figure 1A shows the posterior-dorsal to anterior-ventral gradient of nigrostriatal denervation in Parkinson's disease across different stages of severity of disease (from mild to severe, left to right). Early and most severe loss of nerve terminals is in the dorsal and posterior putamen. Anterior and ventral striatal regions are relatively spared, at least in the early stage of disease. This pattern of striatal degeneration from dorsal to ventral segments with the progression of Parkinson’s disease provides a fundamental basis for the dopamine overdose hypothesis. That is, regions that are less affected early in the disease could be over stimulated by exogenous dopamine administration.

A, shows the posterior-dorsal to anterior-ventral gradient of nigrostriatal denervation in Parkinson's disease across different stages of severity of disease (from mild to severe, left to right). Early and most severe loss of nerve terminals is in the dorsal and posterior putamen. Anterior and ventral striatal regions are relatively spared, at least in early stage of disease. Abbreviations: P=putamen, C=Caudate. B, individual patients can experience differing performance effects in response to levodopa administration due to a combination of factors including stage of disease, striatal structure used in the task, and genotype for genetic polymorphisms that play a role in dopaminergic metabolism in striatum and prefrontal cortex (Cools, 2006). These factors collectively determine each patient’s starting location on the inverted-U shaped function describing the association between dopamine and performance, which in turn determines whether performance will worsen, improve, or show no change with dopaminergic medications.

It has been several decades since Cotzias and colleagues 20 demonstrated the striking efficacy of oral levodopa for relieving motor symptoms of Parkinson’s disease. Since that time, levodopa has remained the gold standard for antiparkinsonian therapy. Nonetheless, since the dorsal putamen is mostly affected in early Parkinson’s disease whereas the ventral striatum remains relatively intact 18 , a given dose of levodopa that has beneficial effects for most motor tasks that rely upon dorsal putamen, can also have deleterious effects on specific cognitive and motor tasks that specifically rely upon ventral striatum 5 . The administration of levodopa is thought to decarboxylase in remaining dopaminergic neurons, and thus the lack of specificity of dopamine therapy can lead to a possible over stimulation of ventral striatal areas that remain intact. Figure 1B illustrates the many factors which can modulate the effects of dopaminergic medication on performance, including disease stage, striatal structure engaged by the task, and genotype for genes that regulate endogenous dopamine availability. The dopamine overdose hypothesis proposes that when patients with Parkinson’s disease are off levodopa or other dopaminergic medications, their performance on tasks such as probabilistic reversal learning is optimal, whereas their performance on cognitive tasks such as set-switching is impaired. Since reversal learning and set-switching implicate ventral and dorsal striatum respectively 21 , 22 , these tasks have provided excellent paradigms to investigate dopaminergic effects on different striatal regions. Further, when levodopa or other dopaminergic medications are given to the patient the proposal is that performance on probabilistic reversal learning will worsen, whereas set-switching performance improves. While set-switching requires flexible swapping or switching between tasks, reversal learning requires an adaptation to a previously learned stimulus-reward contingency. The central tenet of the dopamine overdose hypothesis is that tasks that rely on the ventral striatum will be impaired by dopaminergic medications in early Parkinson’s disease because of over stimulation of the structure.

In addition to the effects of dopamine on the ventral and dorsal striatum, there is also evidence that dopamine overdose effects can occur in prefrontal cortex 8 . The mesocortical dopaminergic pathway projects from VTA to frontal cortex, and this pathway regulates numerous cognitive functions including set-shifting, working memory, and planning. As reviewed in subsequent sections, the studies in the literature collectively point to a cortical and subcortical role for dopamine overdose effects. In the next sections, we will review the specific evidence in support of the dopamine overdose hypothesis in several domains of learning and cognitive performance.

Reversal Learning and Dopamine in Parkinson’s Disease

Table 1 shows a summary of the studies in which reversal learning paradigms have been investigated in patients with Parkinson’s disease off and on levodopa. The consistent empirical finding has been that when on levodopa reversal learning performance is impaired compared with the performance off levodopa. Initial evidence in support of this finding was from a study by Swainson and colleagues 7 . The authors studied three groups of patients with Parkinson’s disease, including mild/unmedicated, mild/medicated, and severe/medicated. The reversal learning task required subjects to choose between a red pattern and a green pattern, with one pattern rewarded over the other on a probabilistic schedule. The subjects were asked to learn the task and figure out which pattern was correct, and after a series of trials the correct pattern was reversed. This was not immediately detectable given that rewards were assigned probabilistically (e.g. 80-20 ratio). When the reversal occurred, patients in the mild/medicated and severe/medicated group had difficulty adapting to the new pattern. The patients in the mild/unmedicated group had no difficulty adapting in the reversal learning task. In a subsequent study by the same laboratory 3 , set-switching performance and reversal learning were compared in two groups of subjects with Parkinson’s disease while either off or on dopaminergic therapy. The set-switch task required that subjects identify the correct letter or number in a well-learned sequence and did not require that subjects adapt to a new condition as in the reversal learning task. The authors identified that reaction time during the set-switch task was reduced with dopaminergic medication. During the reversal learning task, subjects with Parkinson’s disease in the off and on medication groups made more errors than control subjects at the reversal learning stage, but the patients with Parkinson’s disease off medication were able to adapt to the reversal. Patients on dopaminergic medication had more difficulty shifting their performance when the reward stimuli reversed. While the between group design utilized in these studies may make interpretations difficult, they did provide a critical advance in identifying which type(s) of task is detrimentally affected by dopaminergic medication in mild to moderate Parkinson’s disease.

Summary of studies in which probabilistic learning and motor sequence learning paradigms have been investigated in patients with Parkinson’s disease off and on levodopa

Subsequent studies by the same laboratory and others have used within-subjects designs to test subjects with Parkinson’s disease off and on levodopa. Fifteen subjects with Parkinson’s were tested off and on levodopa monotherapy using an instrumental learning task with constant stimulus-reward assocations, and a reversal learning task with changing reward contingencies. The study counterbalanced whether patients were tested in the on or off state first. A simple instrumental learning task was used since it has been linked mainly with dorsal striatum and frontal circuits 23 , 24 , whereas the reversal learning task has been linked with ventral striatum and frontal circuits 21 , 25 , 26 . The prediction was that dopaminergic medication would have opposite effects on performance during these two tasks. Figure 2 shows experimental findings from the study during the instrumental learning task and the reversal learning task 27 . During the instrumental learning task ( Figure 2A ), which had constant reward contingencies, subjects on levodopa produced a greater percentage of correct choices compared to when off levodopa. Figure 2B shows the opposite pattern for the reversal learning task. Here, subjects on levodopa produced fewer reversal errors than when the subjects were off medication. These findings controlled for the testing order and tested the same subjects, and provide compelling evidence that reversal learning is impaired when subjects with Parkinson’s disease are on medication.

Figure adapted from Graef and colleagues (2010). A, performance of On-beginner (“On first”) and Off-beginner (“Off first”) subgroups across sessions on the reversal learning task. Covariate-corrected estimated means of the number of reversals achieved are shown in boxes. B, performance of On-beginner (“On first”) and Off-beginner subgroups (“Off first”) across sessions on the instrumental learning task. Covariate-corrected estimated means of percentage of correct choices are shown in boxes.

Another probabilistic learning task, developed by Gluck and colleagues, is the Weather Prediction Task 28 . In this task, four “cards” have independent and probabilistic relationships to two possible outcomes, “sun” and “rain”. Patients with Parkinson’s disease exhibit impaired learning on this task when they are on dopaminergic medication, but learn at a rate similar to that of controls when off medication 29 , 30 . In a similar paradigm, Parkinson’s patients and controls were asked to learn which of two stimuli was associated with a reward 31 . The stimuli varied in shape and color, with only dimension predicting reward. Parkinson’s patients were impaired at learning the initial association when on medications, but not when they were off medications. In the next phase of the study, the relevant dimension of each stimulus was held constant whereas the irrelevant feature changed. Control subjects, Parkinson’s patients on medication, and patients off medication all performed equally well during this transfer phase. Given that the weather prediction task has been shown to rely on the head caudate nucleus 32 , a more anterior striatal structure which exhibits dopaminergic denervation later in Parkinson’s disease than the putamen, these findings provide additional support for the dopamine overdose hypothesis playing a role in the behavior of patients with Parkinson’s disease when on levodopa.

Dopamine stimulates receptors in the basal ganglia and prefrontal cortex, and there is an important distinction for D1 and D2 receptors in these brain regions. The dopamine overdose hypothesis is also supported from studies of dopamine synthesis in animals and pharmacological studies in healthy adults. In animal models, stimulating D1 receptors with dopaminergic medication in the prefrontal cortex has revealed changes in the firing of neurons during the delay period of delayed-response tasks 33 – 35 . Computational models have provided insight into how dopamine enhances D1 receptor stimulation such that dopamine can increase the resistance to distracting stimuli 36 , 37 . D2 receptors are more abundant in the basal ganglia than in the prefrontal cortex, and it has been suggested that the basal ganglia may serve as a gating mechanism for updating the prefrontal cortex 38 . D2 receptor stimulation has been tested in healthy adults using the D2 receptor agonist bromocriptine relative to their baseline dopamine synthesis capacity as determined by 18 F-fluoro-L-meta-tyrosine PET tracer 39 . Subjects performed a reward-based reversal learning task with deterministic stimulus-outcome contingencies that required a button press to predict if the face or scene stimulus would lead to a reward or punishment. The authors found that during the placebo drug, striatal dopamine synthesis was positively related to reversal learning performance. Subjects with low striatal dopamine synthesis performed poorly on the reversal learning task, whereas high striatal dopamine synthesis was associated with high reversal learning performance. Subjects with low striatal dopamine synthesis responded positively to bromocriptine. In contrast, subjects with high baseline striatal dopamine synthesis were over-stimulated by bromocriptine, and exhibited impaired reversal learning performance when on drug.

In a study using event-related functional magnetic resonance imaging (fMRI), it was found that in healthy adults performing a probabilistic reversal learning task the ventral striatum and ventrolateral prefrontal cortex were specifically activated when subjects committed reversal errors 21 . A recent study evaluated the effects of bromocriptine versus sulpiride (a D2 receptor antagonist), and the combination of both drugs on reward and punishment reversal learning 40 . It was found that improved reward relative to punishment reversal learning performance occurred with the administration of sulpiride compared with bromocriptine. These findings provide additional insight into the specificity of the D1 and D2 receptors related to reward and punishment during reversal learning 40 . Next, we discuss the pertinent findings for the dopamine overdose hypothesis for motor sequence learning.

Motor Sequence Learning and Dopamine in Parkinson’s Disease

Both probabilistic reversal learning and category learning rely on more ventral subcortical structures such as the nucleus accumbens and caudate nucleus, which remain relatively intact in mild to moderate Parkinson’s disease. Thus, the dopamine overdose hypothesis provides a plausible framework from which to interpret the finding that patients perform these tasks better when off medication. There is a gradient of dopaminergic denervation within the caudate and putamen as well, with the more ventral and anterior portions of these structures affected later in the disease 41 , 42 . The Seidler laboratory has conducted a series of experiments to investigate interactions between this gradient of denervation and anti-parkinsonian medications, working with a motor sequence learning task 4 , 43 , 44 .

Motor sequence learning refers to the capacity to combine individual elements of action into one smooth, cohesive movement. For example, patients moving into an assisted living facility may need to learn an action sequence to navigate their new surroundings. Sequential behavior is also important for skills such as driving and playing a musical instrument and motor sequence learning plays an important role in many physical rehabilitation protocols. In healthy individuals, the process of motor sequence learning is known to rely on the striatum 45 – 47 . In particular, it has been demonstrated that early in sequence learning, the more ventral and anterior portions of the striatum (i.e. associative striatum) are engaged 47 , whereas once a sequence becomes well learned it is represented in the more dorsal and posterior aspects of the striatum (i.e. sensorimotor striatum). Previous studies investigating the effects of medication on sequence learning in Parkinson’s patients have yielded mixed results. Table 1 shows the study by Carbon et al. 48 which references the data from two prior studies from the same laboratory indicating that motor sequence learning was impaired by levodopa. The initial paper by Feigin and colleagues 49 found that levodopa reduced sequence learning in Parkinson’s patients for a subjective measure of self-reported learning. When comparing objective measures, the investigators reported non-significant differences in sequence learning for patients on versus off levodopa 50 , 51 . Although not significant for objective measures of learning, the direction of change was that levodopa may be impairing sequencing learning for some of the subjects, and that was opposite to the effects of DBS which improved sequencing learning 48 , 49 . This line of work averaged performance across time rather than examining performance changes in the context of learning. Based on the purported inverted-U shaped relationship between dopamine levels and performance and established changes in associative and sensorimotor striatum with learning, it could be that Parkinson’s patients learn new motor sequences faster in the early stages of learning when they were off medication in comparison to on medication. In contrast, once sequences become well learned, patients could be able to perform them better when on medication as opposed to off medication.

In an initial experiment 4 , 14 patients with mild to moderate Parkinson’s disease and 11 healthy controls were evaluated within the same age range for their ability to learn a sequence of finger movements. Patients were tested on two separate occasions, once on their anti-parkinsonian medications, which included varying combinations of medications across the participants of L-dopa and/or dopamine agonists. On the second occasion, patients were tested in the functional off state, 12–18 hours after taking their last dose of dopaminergic medications. Testing occurred in a counterbalanced fashion across medication states. As predicted by the dopamine overdose hypothesis, patients off medication exhibited early learning improvements that were equivalent to those of control subjects for the early phase of learning (see Figure 3A ). As learning progressed, performance of the patients on medication began to catch up to that of their off medication performance.

Panel A (from Kwak et al. 2010) illustrates that patients off their medication learn new sequences of action at the same rate as healthy controls, while patients on medication are impaired. For trials 1 – 16 and 49 – 64 participants pressed buttons in response to randomly cued stimuli; trials 17 – 48 were sequence practice trials. Panel B (from Kwak et al. 2012) illustrates a region in the right ventral putamen that is more active when patients learn a motor sequence off medication than when they are on medication. This differential activation is correlated with off-medication improvements in sequence learning.

In a follow up study 44 , new cohorts of 17 Parkinson’s patients and 21 healthy control subjects were studied in order to evaluate brain networks recruited during sequence learning with fMRI. Again, patients were tested across two different days. For this study a single blind placebo controlled medication design was used, with patients being given either levodopa plus carbidopa or placebo plus carbidopa after arriving to the study in the functional off state. The order of drug versus placebo testing was counterbalanced across testing days. It was found that levodopa was associated with decreased recruitment of the ventral putamen during early phase of sequence learning. Moreover, the difference in activation levels in this structure between on and off medication testing days was correlated with differences in sequence learning performance between on and off days across individual patients. That is, patients that showed the largest decrease in ventral putamen activation when on medication versus off medication exhibited the largest decrease in sequence learning abilities when on medication versus off medication, as illustrated in Figure 3B . A PET investigation by another group reported reduced brain deactivation when Parkinson’s patients were learning a sequence of actions on levodopa versus off 52 . Taken together, these findings suggest that both task-relevant and default network activation can be negatively impacted by administration of levodopa in mild to moderate stage Parkinson’s disease.

Another study measured dopaminergic denervation in 18 Parkinson’s patients using 11 C-dihydrotetrabenazine PET scans 53 . Patients acquired new motor sequences on two testing days in a counterbalanced within subjects design, either on placebo or levodopa plus carbidopa. The ratio of denervation in the anterior putamen versus the posterior dorsal putamen predicted the level of levodopa-associated impairments in motor sequence learning. That is, patients with relatively less denervation in the anterior putamen showed greater on-medication sequence learning decrements. Thus, individual differences in the magnitude of motor sequence learning dopamine overdose effects can be predicted by the spatial pattern of dopaminergic denervation across the striatum.

Genotype and Dopaminergic Medication Interact to Influence Cognitive Function

Another set of studies indicates that dopaminergic medication may lead to deleterious performance on specific cognitive tasks depending on the genotype of the patient ( Figure 1B ). A common polymorphism in the catechol O-methyltransferase (COMT) gene has a strong influence on performance on tests of working memory, attention, and planning 54 – 56 . COMT is an important regulator of dopamine levels, and its activity is thought to primarily influence dopamine levels in the prefrontal cortex 57 , 58 . In healthy individuals 59 , low-activity COMT genotypes are associated with improved performance on the Wisconsin Card Sorting Test, and fMRI studies have confirmed that the prefrontal cortex activity is influenced by the COMT genotype. However in Parkinson’s disease, performance on a Tower of London cognitive test in a large cohort of 288 patients with PD found that low COMT activity was associated with impaired performance, and the effect was more pronounced in those patients taking dopaminergic medications 54 . Using fMRI, it was found that patients with Parkinson’s disease who were homozygous for valine (val/val; high COMT activity) performed better and had greater activity in the frontal-parietal cortex compared with patients with Parkinson’s disease who were homozygous for methionine (met/met; low COMT activity) 56 . The authors did not find clear fMRI differences in the putamen and caudate nucleus.

In a task of attention control 55 , people with Parkinson’s disease who tested for the high COMT genotype (val/val) adopted a more optimal attention shifting strategy compared with the Parkinson’s disease group that had the low COMT genotype (met/met). The low COMT genotype group failed to adopt the attention shifting strategy. The authors also found that the fronto-parietal network typically associated with attention was less active in the low COMT genotype compared with the high COMT genotype. There were no differences observed in the putamen and caudate nucleus.

Another gene that may interact with medication effects in Parkinson’s patients is the DRD2 gene, which codes for dopamine D2 receptors in the striatum. A recent study 43 evaluated whether a particular DRD2 polymorphism (rs 1076560, G > T) is associated with the on versus off medication sequence learning effects that were previously reported in patients with Parkinson’s disease. DRD2 T allele carriers of this polymorphism have reduced D2S expression (short isoform of the D2 receptor); thus in comparison G allele carriers have higher D2 receptor availability. It was predicted that Parkinson’s patients who are minor T allele carriers would exhibit a greater benefit of levodopa on early stage sequence learning. This hypothesis was evaluated in a behavioral study with 45 Parkinson’s patients; 1 patient was TT genotype (grouped together with GT patients), 10 were GT, and 34 were GG. Patients were tested on two days following a single blind placebo controlled design. Levodopa improved early sequence learning over the level of placebo pill for only the TT and GT patients, whereas GG patients did not learn better on levodopa. In contrast, levodopa improved performance on the grooved pegboard test, a simple motor execution test that should rely predominately on the sensorimotor striatum, for all patients regardless of genotype.

These findings suggest that endogenous dopamine modulating factors and exogenous dopamine interact to result in dopamine overdose effects in patients with Parkinson’s disease. That is, disease, genetics, and medication status can all influence an individual’s location on the inverted-U shaped function relating dopamine to performance. Moreover, these studies suggest that the viewpoint for the dopamine overdose hypothesis to occur only because of the ventral and dorsal striatum is too narrow and that other factors including the prefrontal cortex and parietal cortex also play a role. Also, these findings further demonstrate that the genotype of the patient is an important factor to consider when interpreting effects of dopamine on cognitive functions.

Clinical Implications and Conclusions

The clear consensus of a large body of literature is that dopaminergic therapy can improve cognitive functions in some patients but make them worse in others (see 5 for an in-depth review). The dopamine overdose hypothesis provides a conceptual framework to better understand patients' individual cognitive responses to dopaminergic pharmacotherapy in Parkinson's disease. The purported inverted-U shaped relationship between dopamine levels and performance is complex and includes many contributory factors. As discussed in this review, the regional striatal topography of nigrostriatal denervation is a critical factor as supported by fMRI and dopaminergic PET studies. Second, a patient's individual genotype will determine the relative baseline position on this inverted-U curve. Third, dopaminergic pharmacotherapy and individual gene polymorphisms, such as COMT, can also affect the mesolimbic and prefrontal cortical dopaminergic functions in a comparable inverted-U dose-response relationship similar as proposed for the striatum. Therefore, at present a patient's individual cognitive response to dopaminergic pharmacotherapy cannot be predicted by a simple formula. However, a number of clinical implications may be inferred based on the available literature and experience in clinical movement disorders practice.

Striatal dopamine overdose effects have been identified for probabilistic reversal learning and motor sequence learning tasks. Implications for instrumental activities of daily living are clearly apparent. Current technological advances in society will affect persons living with Parkinson's disease. Exposure to new electronic gadgets for daily communication, financial management, bill paying, receiving healthcare, and even medication management are essentially unavoidable and will challenge patients' learning skill abilities. This will include sequential motor behaviors that include fine and precise finger movements when using these new gadgets. Navigation in new environments, whether it is driving a car in new surroundings or moving into a new place to live will be equally challenging.

A key predictor for adverse cognitive learning effects of dopaminergic therapy is the presence of early stage and/or mild severity of disease, where overdose effects of dopaminergic medications are predicted to be most prominent. Practical implications of the dopamine overdose hypothesis in the management of the individual patient with Parkinson's disease will first depend on identification of a dopaminergic dose-related cognitive or behavioral problem. If present, a simple pointer will be to implement a new motor learning challenge, such as using a new device, when in a relative medication 'off' state (assuming preservation of critical motor abilities). Apart from learning new motor behaviors in an 'off' state, a rational pharmacological therapy approach based on the principle of the lowest effective dose may also help to prevent or ameliorate dopaminergic 'on' overdose cognitive adverse effects. Most of all, clinicians need to consider a broader range of symptoms and individual patient priorities in adjusting medication dosages by suggesting medication strategies that strike a better balance between motor and cognitive symptoms 60 . It is also important to consider premorbid personality and psychiatric history when making clinical decisions. Future clinical treatment algorithms may include information about specific gene polymorphisms that affects the dopamine system (so-called 'personalized medicine'). It may also be prudent to consider exercise as an adjunct to dopamine therapy to reduce motor symptoms to also minimize the overdose, as recent studies have shown promise using balance training over six months 61 and progressive resistance exercise over two years 62 .

Cognitive functions, including reward based learning, have been the major focus of research of the dopamine overdose hypothesis 60 . However, much is less is known into the neurobehavioral correlates of these impairments and how it affects instrumental activities of daily living. Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system in patients with Parkinson's disease who are on dopaminergic drugs, in particular dopamine agonists. Patients with DDS show evidence of impulse control disorders 63 . Further research is needed to determine whether an excess of exogenous dopamine release within the anteroventral striatum and related cortical projections may be a mechanistic factor underlying impulsive and/or risk taking behaviors in susceptible patients.

Acknowledgements

This review was funded in part by NIH grants (R01 NS075012, R01 NS052318, P01 NS015655 and R01 NS070856), Bachman-Strauss Foundation, Tyler’s Hope Foundation, NASA NNX11AR02G, NSBRI, Department of Veterans Affairs, and the Michael J. Fox Foundation.

Dr. Vaillancourt receives grant support from NIH, Bachmann-Straus Foundation, Tyler’s Hope Foundation, and consults for projects at UT Southwestern Medical Center, University of Illinois, and Great Lakes NeuroTechnologies. Dr. Bohnen has research support from the NIH, Department of Veteran Affairs, and the Michael J. Fox Foundation. Dr. Seidler receives grant support from NIH, NASA, NSBRI, and the Michigan Parkinson’s Foundation.

Financial Disclosure Statement: Daniel Schonfeld has no financial disclosures. Dr. Kwak has no financial disclosures.

Author Contributions

Mr. Schonfeld – review design, collecting articles, and writing

Dr. Kwak – review design and writing

Dr. Bohnen - review design, obtaining funding, collecting articles, and writing

Dr. Seidler - review design, obtaining funding, collecting articles, and writing