Guanine nucleotides distinguish between two dopamine receptors [28]

BEHAVIOURAL¹ and neurophysiological² data suggest the existence of more than one dopamine receptor in the brain3. Differences in drug specificity of the dopamine-sensitive adenylate cyclase and dopamine receptors labelled by the butyrophenones, ³H-haloperidol or ³H-spiroperidol, indicate that the cyclase and the binding sites may, in part, involve distinct receptors^4,5. Lesion studies directly demonstrate the existence of physically distinct dopamine receptors in the corpus striatum⁶. Kainic acid microinjections, which selectively destroy intrinsic neurones in the corpus striatum, almost totally deplete the dopamine-sensitive adenylate cyclase while producing only a 40-50% decline in ³H-haloperidol or ³H-spiroperidol binding. Most of the remaining ³H-haloperidol or ³H-spiroperidol binding is lost following cerebral cortex ablation, which removes a major neuronal input to the corpus striatum, indicating that these binding sites are localised to axons and terminals of the cortico-striate projection⁶. As the dopamine-sensitive adenylate cyclase is not reduced by cerebral cortex ablation, the cortico-striate dopamine receptors do not seem to be linked to adenylate cyclase. Whether or not the ³H-butyrophenone binding sites destroyed by kainic acid represent the same dopamine receptors as those linked to adenylate cyclase has not been clear. Guanine nucleotides regulate binding at several hormone and neurotransmitter receptors, especially those associated with adenylate cyclase^7-13. Previously, we^14-16 and others¹⁷ showed that dopamine receptor binding of ³H-agonists and ³H-antagonists can be regulated by guanine nucleotides. We now report that kainic acid lesions abolish the sensitivity of dopamine receptor binding to guanine nucleotides. Thus, ³H- spiroperidol and ³H-apomorphine binding sites involve two dopamine receptors, only one of which is regulated by guanine nucleotides.