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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Dopamine Receptors

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Multiple dopamine receptor subtypes exist

Two subtypes of DA receptor were initially identified on the basis of pharmacological and biochemical criteria. D1 receptors were shown to couple to stimulation of adenylyl cyclase activity, while D2 receptors inhibited enzyme activity (Fig. 12-6). More recently, multiple D1-like and D2-like receptors have been identified (Table 12-3) [21,22] and amino acid sequences determined. The known subtypes of DA receptor are members of the G protein-linked receptor family with seven hydrophobic domains, an extracellular N terminus and an intracellular C terminus (Fig. 12-4). Consensus sequences for phosphorylation are found in the second (i2) and third intracellular (i3) loops and the C-terminal tail. The D1-like receptors have relatively small i3 loops and long C-terminal tails, while the D2-like receptors have large i3 loops and short C-terminal tails.

Figure 12-6. Effect of dopamine on intracellular signaling pathways.

Figure 12-6

Effect of dopamine on intracellular signaling pathways. Stimulation of receptors by agonists can change enzyme activities as well as gene expression. Five subtypes of dopamine receptor have been identified. The D1 and D5 receptors are coupled to adenylyl (more...)

The D1-like receptors include the D1 and D5 receptors [21,22]. The D1-like receptors have a high affinity for benzazepines like SCH-23390 and a low affinity for benzamides and are coupled to stimulation of adenylyl cyclase activity. The most striking pharmacological difference among them is the high affinity of D5 receptors for DA.

Molecular genetic studies have demonstrated the presence of two forms of mRNA coding for D2 receptors, designated D2L and D2S. These two forms differ by 87 bases, corresponding to a 29-amino-acid insert in the i3 loop of the receptor (Fig. 12-4). The two species of D2 receptor mRNA appear to arise through alternative splicing. Both D2L and D2S receptors are coupled to inhibition of adenylyl cyclase activity, although D2S stimulation causes a greater inhibition. The D3 receptor, a second member of the D2-like receptor family, has been cloned and expressed in COS-7 cells. D3 receptor mRNA is found in limbic areas of the brain, including the nucleus accumbens. Comparison of the properties of D2 and D3 receptors shows that the D3 receptor has a relatively high affinity for atypical neuroleptics and for DA autoreceptor inhibitors, including (+)-UH232 and (+)-AJ76. Cloning of the D4 receptor has introduced an additional level of complexity to the study of DA receptors. Of particular interest is the high affinity of D4 receptors for the atypical neuroleptic clozapine. D4 receptor mRNA has been detected in the frontal cortex, midbrain, amygdala and medulla, with lower concentrations detected in the basal ganglia. The use of molecular approaches in the study of the D4 receptor has been hampered by the high G/C content of its coding sequences. D3 and D4 receptors inhibit adenylyl cyclase, and D4 receptors are positively coupled to K+ channels.

The number of D1 and D2 receptors can be modulated by antagonists or neurotoxins

The density of D2 receptors in rat striatum is increased following lesions with the neurotoxin 6-hydroxydopamine or by administration of antagonists. Similar results for D1 receptors were obtained following chronic administration of the D1-selective antagonist SCH-23390. Subtypes of DA receptor may be coregulated since the D2 antagonist sulpiride attenuated the ability of SCH-23390 to increase the density of D1 receptors. The increase in the density of D2 receptors following chronic administration of antagonists may be responsible for the development of a movement disorder called tardive dyskinesia (see Chap. 45).

Available behavioral data suggest that either acute or repeated administration of agonists acting at DA receptors results in augmentation of the behavioral effects of the drugs. This phenomenon, known as reverse tolerance or sensitization, is characterized by a selective increase in the intensity or duration or a shift to an earlier time of onset of stereotypical behaviors such as locomotion, sniffing, rearing, licking and gnawing. Sensitization to indirect DA agonists like amphetamine or cocaine also occurs. The mechanisms underlying behavioral sensitization are likely to be complex. It is known, for example, that stereotypical behavior and locomotor hyperactivity are critically dependent on activation of both D1 and D2 receptors.

Direct and indirect agonists at dopamine receptors, including amphetamine, bromocriptine and lisuride, have been shown to induce psychotic episodes

A strong correlation exists between the clinical doses of neuroleptics and their affinity for brain D2 receptors. This has led to the hypothesis that psychotic disorders result from overstimulation of D2 receptors. Long-term administration of neuroleptics to humans or experimental animals can result in an increase in the density of striatal D2 receptors and in the appearance of extrapyramidal side effects, including parkinsonian movement disorders and tardive dyskinesia. A panel of antipsychotic drugs referred to as atypical neuroleptics, including clozapine, melperone and fluperlapine, have been reported to produce fewer extrapyramidal side effects and have been useful in the treatment of patients with schizophrenia who respond poorly to typical antipsychotics such as haloperidol. The relative affinities of D2, D3 and D4 receptors for typical and atypical neuroleptics together with the selective expression of D3 receptor mRNA in limbic areas of the brain have led to the hypothesis that the clinical utility of neuroleptics in the treatment of psychiatric illness may be due, at least in part, to their ability to antagonize stimulation of D3 or D4 receptors, while the motor dysfunction observed following chronic treatment with typical neuroleptics could be due to alterations in the density of D2 receptors in the striatum.

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Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK27980


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