Dopamine plays an important role in controlling movement, emotion and cognition. Dopaminergic dysfunction has been implicated in the pathophysiology of schizophrenia, mood disorders, attention-deficit disorder, Tourette's syndrome, substance dependency, tardive dyskinesia, Parkinson's disease and other disorders.
In 1952, Delay and Deniker reported the use of chlorpromazine (Thorazine) to treat psychosis. They initiated an important advance in the treatment of schizophrenia without a clear understanding of the mechanisms underlying the drug's therapeutic effect. In 1963, Carlsson first postulated that the effects of neuroleptics were secondary to dopamine receptor blockade. Also at this time researchers discovered that dopamine depletion in the striatum played a role in Parkinson's disease. In 1979, Kebabian and Calne determined that at least two dopamine receptors mediated this system, and for the next decade the actions of dopamine were viewed as being mediated by two dopamine receptors, D1 and D2.
There has been an explosion of interest and information regarding dopamine receptors in the human brain. Recent advances in molecular genetics have revealed the two-receptor model to be a gross oversimplification. In the last three years, seven distinct dopamine receptors have been identified.
For clinicians to make effective use of the new drugs that will emerge from this active research area, they will need to understand how dopamine affects behavior and keep abreast of the developments in dopamine pharmacology. This article is intended as the clinician's practical guide to the current understanding of dopamine receptors and their role in neuropsychiatric illness. (For a comprehensive review of dopamine receptors, see Niznik and Van Tol, and Gingrich and Caron.)
The Dopaminergic System
In the brain, the principal dopamine systems arise from cells in the midbrain and the hypothalamus. The cells in the midbrain can be divided into three groups: A8 in the retro-rubral field, A9 in the substantia nigra, and A10 in the ventral tegmental area. The neurons arising from A8 and A9 ascend to the striatum, forming part of the extrapyramidal system, and are involved in initiating and coordinating movement. The neurons of the A10 area project to the limbic and cortical areas and are referred to as the mesolimbic and mesocortical tracts, respectively. Researchers believe that these neurons are involved in emotional expression and cognitive function, and this system may be involved in the pathophysiology of mood disorders, schizophrenia and substance abuse.
The dopamine cells of the hypothalamus project via the tuberoinfundibular tract to the infundibulum and anterior pituitary. In this area, dopamine acts directly to inhibit the release of prolactin.
When a neurotransmitter binds to a receptor, an extracellular signal is transduced into an intracellular one, causing a functional change inside target neurons. The nervous system contains two basic types of receptors. Fast receptor systems, such as the GABAA receptor and the nicotinic receptor at the neuromuscular junction, involve the direct binding of a neurotransmitter to a ligand-gated channel, which opens or closes the channel. Slower G-protein-linked receptor systems, as seen in the dopaminergic system, work through second-messenger systems, such as cyclic adenosine monophosphate (cAMP), and have a longer duration of action. (G-proteins derive their name from the conformational change induced in guanine nucleotides by the neurotransmitter-receptor complex.)
All of the dopamine receptors are similar in structure, and they mediate their effects through G-proteins. The prototypic makeup of all dopamine receptors consists of a protein composed of approximately 400 amino acids. These receptor proteins span the cell membrane and have extracellular, intramembrane and intracellular components. Each receptor contains seven hydrophobic, membrane-spanning segments.
Small changes in the primary amino acid sequence of the protein-receptors results in secondary structural changes that differentiate the dopamine subtypes.
Intracellularly, dopamine receptors interact with either stimulatory or inhibitory G-proteins. This interaction stimulates or inhibits adenylate cyclase, an enzyme that can catalyze the production of cAMP, one of the most important second messengers in the cell. The cAMP then exerts several biochemical changes such as activating genes and influencing the opening and closing of calcium and potassium channels .
D1 or D1A. The D1 receptor is the most abundant dopamine receptor in the brain. This receptor is linked to stimulatory G-proteins that activate adenylate cyclase. The D1 receptors are found in high concentration in the substantia nigra pars reticulata, caudate, putamen, nucleus accumbens, olfactory tubercle, and frontal and temporal cortex. To date, the role of the D1-like receptors in psychiatric disorders is unclear.
Some evidence suggests that these receptors affect behavior indirectly through their regulatory effects on the D2-like receptors. Recent research suggests that the stimulation of D1 receptors has a synergistic effect on the D2 receptor motor response to dopamine. This information has led to the development of D1 and D2 agonists, such as pergolide (Permax) for the treatment of Parkinson's disease.
The unique pharmacological profile of clozapine (Clozaril) may, in part, be secondary to clozapine's mild affinity for the D1 receptor, which is not found in many of the classical neuroleptics.
D1B or D5. The D5 receptors also are linked to stimulatory G-proteins and activate the enzyme adenylate cyclase. Their agonist/antagonist profile is similar to that of D1 receptors, except that D5 receptors have been found to have a 10-fold higher affinity for dopamine D1 receptors. The higher affinity for dopamine suggests that D5 receptors may be involved in maintaining dopaminergic tone and arousal. The D5 receptor has been anatomically localized to the cortex, hippocampus and limbic system.
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