At present, five dopamine receptors have been described, consisting of two separate families, the D1-like (D1, D5) and D2-like (D2, D3, D4) receptor groups. The D1 receptor is coded by a gene on chromosome 5, increases cAMP by Gs-coupled activation of adenylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle and cortex. The other member of this family, D5, is coded by a gene on chromosome 4, also increases cAMP, and is found in the hippocampus and hypothalamus. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the D1 receptor (Figure 29–3, top) nor did a selective D1 antagonist prove to be an effective antipsychotic in patients with schizophrenia.
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FIGURE 29–3 Correlations between the therapeutic potency of antipsychotic drugs and their affinity for binding to dopamine D1 (top) or D2 receptors (bottom). Potency is indicated on the horizontal axes; it decreases to the right. Binding affinity for D1 receptors was measured by displacing the selective D1 ligand SCH 23390; affinity for D2 receptors was similarly measured by displacing the selective D2 ligand haloperidol. Binding affinity decreases upward. (Reprinted, with permission, of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc., from Seeman P: Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1987;1:133.)
The D2 receptor is coded on chromosome 11, decreases cAMP (by Gi-coupled inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both preand postsynaptically on neurons in the caudate-putamen, nucleus accumbens, and olfactory tubercle. A second member of this family, the D3 receptor, also coded by a gene on chromosome 11, is thought to also decrease cAMP and is located in the frontal cortex, medulla, and midbrain. D4 receptors also decrease cAMP and are concentrated in the cortex.
The first-generation antipsychotic agents block D2 receptors stereoselectively for the most part, and their binding affinity is very strongly correlated with clinical antipsychotic and extrapyramidal potency (Figure 29–3, bottom). In vivo imaging studies of D2-receptor occupancy indicate that for antipsychotic efficacy, the typical antipsychotic drugs must be given in sufficient doses to achieve at least 60% occupancy of striatal D2 receptors. This is not required for some second-generation antipsychotic drugs such as clozapine and olanzapine, which are effective at lower occupancy levels of 30–50%, most likely because of their concurrent high occupancy of 5-HT2A receptors. The first-generation antipsychotic drugs produce EPS when the occupancy of striatal D2 receptors reaches 80% or higher.
Positron emission tomography (PET) studies with aripiprazole show very high occupancy of D2 receptors, but this drug does not cause EPS because it is a partial D2-receptor agonist. Aripiprazole also gains therapeutic efficacy through its 5-HT2A antagonism and possibly 5-HT1A partial agonism.
These findings have been incorporated into the dopamine hypothesis of schizophrenia. However, additional factors complicate interpretation of dopamine receptor data. For example, dopamine receptors exist in both highand low-affinity forms, and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms.