Dopamine Receptors in the Human Brain

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