Dopamine

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Dopamine

Definition

Dopamine, identified as a central nervous system agent in 1959, is a neurotransmitter (nerve-signaling molecule) the body makes from the amino acid tyrosine. Dopamine in turn serves as the molecule the body uses to make adrenaline and noradrenaline. In addition to operating in nervous system signaling, it also acts as a hormone in an area of the brain called the hypothalamus, regulating release of the hormone prolactin, which is involved in parenting behavior and milk production. The body regulates dopamine’ activity in the brain in part by using proteins called dopamine transporters, which can take up dopamine and dump it back into a cell, preventing the signaling molecule from exerting its activity. The body also has five types of proteins, called dopamine receptors, responsible for recognizing the dopamine molecule, binding to it, and transmitting its signal to the cell. Dopamine is at the center of the development of a number of psychiatric disorders, including addiction and schizophrenia , and it also plays a prominent role in the manifestations of Parkinson’s disease.

Description

The brain produces dopamine in three primary areas: the substantia nigra, the ventral tegmental area, and the arcuate nucleus. The first two are of particular interest in terms of psychiatric disorders; the arcuate nucleus is associated with dopamine’s role as a neurohormone in prolactin regulation.

Disorders associated with dopamine signaling have a biological basis in the brain that appears to be site-specific. The brain has four major dopamine-signaling pathways.

The mesocortical pathway connects the ventral tegmental area to the cortex, the part of the brain involved in cognition and that may play a role in motivation. This pathway features in hypotheses of dopamine’s association with schizophrenia.
The mesolimbic pathway also begins in the ventral tegmental area, which is linked to the nucleus accumbens, the largest component of the ventral striatum. Much research has associated the nucleus accumbens and the mesolimbic pathway with brain reward processes and addiction and also with different aspects of schizophrenia.
The nigrostriatal pathway connects the dopamine-producing nigrostriatal area with the striatum and plays a high-profile role in the development of Park-sinon’s symptoms.
The tuberoinfundibular pathway involves the hypothalamus and dopamine as a neurohormone.

In terms of neuropsychiatric disorders, dopamine is probably best known as the neurotransmitter underlying the development and persistence of addiction as part of the mesolimbic reward pathway. In brief, experiences we find rewarding, such as food or sex, can become associated with increased dopamine, as can some pathological behaviors, such as compulsive gambling. Some drugs also directly elicit an increase in dopamine, setting off the reward pathway and leading more use of the drug. Ultimately, some people become addicted to substances or behaviors because of the dopamine release they trigger and the feelings of euphoria or tension relief that can follow the release.

Anatomically, these distinct dopamine-signaling pathways, variously involved in specific pathologies, may overlap with one another. For example, there is some comorbidity among schizophrenia, depression , and drug dependence and some anatomical overlap in the dopamine-signaling areas of the brain underlies this.

Dopamine receptors

The dopamine receptors, the five proteins responsible for receiving the dopamine signal for a cell, are divided into two general classes: those that are D1-like, and those that are D2-like. Of the five, the D1A through D1D and D5 receptors are all D1-like, and the D2, D3, and D4 receptors fall into the D2-like category. The distribution of these receptors differs in different dopamine-related areas of the brain. For example, the ventral striatum and limbic cortex of the mesolimbic pathway have more D2-like receptors, and D2 and D4 receptors are more closely associated with people with substance abuse problems. The dorsal striatum, involved in dopamine-related disorders such as Parkinson’s, has more also D2- than D1-like receptors. But in the prefrontal cortex, where dopamine-signaling dysfunction is associated with schizophrenia, the ratio of D1-like receptors to D2-like receptors is higher. The two general classes of receptors have opposite effects at the molecular level, but they act together in complex ways.

Dopamine and schizophrenia

A much-discussed proposed explanation for the manifestations of schizophrenia is the “dopamine hypothesis of schizophrenia.” This hypothesis implicates dopamine-signaling dysfunction along different dopamine pathways in the symptoms associated with schizophrenia. The hypothesis finds its origins in the fact that antipsychotic medications (also called “neuroleptics”) exert their effects by blocking or inhibiting D2 receptors. The mesolimbic pathway may be involved, a conclusion based on studies showing a link between dysfunction of this system and the delusions and hallucinations of schizophrenia, with an

increase in striatal dopamine in association with these occurrences. On the other hand, the mesocortical pathway is also probably involved because of its role in working memory, memorization, and manipulation of spatial information, all of which are affected in schizophrenia. A decrease in dopamine in the prefrontal area, which is linked to the ventral tegmental area in the mesocortical pathway, appears to lead to the cognitive deficits of schizophrenia. In addition, the nigrostriatal pathway may be involved: there is an increase in dopamine transmission from the substantia nigra to the striatum in people with schizophrenia.

Dopamine, the brain reward system, and addiction

The nucleus accumbens (in the ventral striatum and part of the mesolimbic pathway) is the focal point of dopamine’s involvement in the brain’s reward pathway and addiction. There is an increase in dopamine release in the nucleus accumbens in addiction, and activity in this area is a target of models exploring the mechanisms of behavioral or substance addictions. Human imaging studies , which have become quite revelatory in terms of the biological underpinnings of psychiatric disorders, show that endogenous release of dopamine in the striatum is correlated with drug-induced feelings of pleasure. For example, a dose of amphetamine or of alcohol will promote dopamine release in the ventral striatum. Dopamine also is associated with the cravings of addiction and may play a role in the significance an addicted person may assign to cues that others perceive as neutral (known as salience). This system has also been implicated in process or behavioral addiction.

Dopamine and movement and repetitive disorders

Dopamine’s role in the extrapyramidal (movement and coordination) symptoms of Parkinson’s is seated in a shortage of the neurotransmitter in the nigrostriatal pathway, specifically involving the putamen and caudate nucleus. Tourette’s, a syndrome characterized by onset in childhood, involuntary tics, stereotypic behaviors, and repetitive thoughts and rituals, is also seated in the dorsal striatum. This syndrome can occur as a comorbidity with obsessive-compulsive disorder and/or attention deficit/hyperactivity disorder (ADHD), which some studies also have associated with dopamine-signaling dysfunction.

Dopamine and mood disorders

Changes in dopamine signaling may contribute to symptoms of depression, such as an inability to experience

KEY TERMS

D1, D2, etc. —Dopamine receptor proteins.

Dopamine —A neurotransmitter and neurohormone.

Mesolimbic pathway —The “reward pathway” of the brain.

Nucleus accumbens —A part of the brain involved in the mesolimbic reward pathway, which receives dopamine signaling from the ventral tegmental area.

Ventral tegmental area —Produces dopamine and signals to the nucleus accumbens the rest of the striatum.

pleasure or loss of motivation. Although low levels of dopamine binding to the D2 receptor are associated with social anxiety , an increase in dopamine can be associated with the hypersocial behavior of someone experiencing the manic aspects of bipolar disorder.

Drugs related to dopamine/dopamine receptor regulation

Drugs may act at any point along a dopamine-signaling pathway. L-dopa, used in treating Parkinson’s, is a dopamine precursor that is synthesized into dopamine in the brain and ameliorates the effects of low dopamine levels in the dorsal striatum. Monoamine oxidase inhibitors (MAOIs) block the activity of the enzyme that breaks down dopamine; these may be used as antidepressants and can affect dopamine-related pathways. Antipsychotics are divided into two classes, the typical and atypical antipsychotics, and can target different types of dopamine receptors. Atypical antipsychotics, including clozapine , may target the D4 receptor more strongly than the D2. Bromocriptine targets D2 and is a partial inhibitor of D1. The recently approved aripirprazole is a partial dopamine agonist (mimic), and amantadine is also a dopamine agonist.

Resources

BOOKS

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text revision. Washington, D.C.: American Psychiatric Association, 2000.

PERIODICALS

Franken, Ingmar H.A., Jan Booij, and Wim van den Brink. “The Role of Dopamine in Human Addiction: From Reward to Motivated Attention.” European Journal of Pharmacology 526 (2005): 199–206.

Grant, Jon E., J.D., M.D., M.P.H., Judson A. Brewer, M.D., Ph.D., and Marc N. Potenza, M.D., Ph.D. “The Neurobiology of Substance and Behavioral Addictions.” CNS Spectrum 11 (2006): 924–930.

Greene, James G. “Gene Expression Profiles of Brain Dopamine Neurons and Relevance to Neuropsychiatric Disease.” Journal of Physiology 575 (2006): 411–416.

Kienast, T., and A. Heinz. “Dopamine and the Diseased Brain.” CNS and Neurological Disorders-Drug Targets 5 (2006): 109–131.

Totterdell, Susan. “The Anatomy of Comorbid Neuropsychiatric Disorders Based on Cortico-limbic Synaptic Interactions.” Neurotoxicity Research 10 (2006): 65–86.