Dopamine receptors and the dopamine hypothesis of schizophrenia
Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3H]‐dopamine or [3h]‐haloperidol.
Abstract
The discovery of neuroleptic drugs in 1952 provided a new strategy for seeking a biological basis of schizophrenia. This entailed a search for a primary site of neuroleptic action. The Parkinsonian effects caused by neuroleptics suggested that dopamine transmission may be disrupted by these drugs. In 1963 it was proposed that neuroleptics blocked “monoamine receptors” or impeded the release of monoamine metabolites. The neuroleptic concentration in plasma water or cerebrospinal fluid was of the order of 2 nM for haloperidol in clinical therapy. A systematic research was made between 1963 and 1974 for a primary site of neuroleptic action which would be sensitive to 2 nM haloperidol and stereoselective for (+)‐butaclamol. Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3H]‐dopamine or [3H]‐haloperidol. These binding sites, now termed D2 dopamine receptors (which inhibit adenylate cyclase), are blocked by neuroleptics in direct relation to the antipsychotic potencies of the neuroleptics. No such correlation exists for D1 receptors (which stimulate adenylate cyclase).