Dopaminergic 3H-agonist receptors in rat brain. New evidence on localization and pharmacology.

Recent methodological advances have allowed the reliable assay of specific dopaminergic 3H-agonist binding sites in rat striatum. Successful assay depends on preincubation of tissue homogenates at 37 degrees C; this results in a guanyl nucleotide-sensitive and dopamine (DA)-dependent increase in the density (Bmax) of 3H-agonist binding. Lesions of DA terminals or drugs which deplete DA levels prevent the preincubation-induced increase in binding, and this effect is completely reversible by preincubation with added DA. In contrast, kainic acid lesions irreversibly reduce 3H-agonist binding. It is concluded that the evidence supporting the existence of presynaptic "D-3" sites is artefactual and that 3H-DA binding sites are more likely related to post-synaptic receptors. 3H-DA binding involves two sites, one of which has pharmacologic properties similar to D-1 receptors, whereas the other resembles D-2 receptors. The affinity of 15 antipsychotic drugs for 3H-haloperidol binding sites was highly correlated (R = 0.94) with their inhibitory potency at a subset of 3H-DA binding sites. However, the inhibition of 3H-DA binding by antipsychotic drugs was noncompetitive. These findings can be explained by an allosteric model, whereby antagonists bind to a site different from but allosterically linked to a high-affinity 3H-DA binding site.