New Insights Into The Regulation Of Dopamine Receptor Subtypes And Their Roles In Behavior

Abstract

Previous research has demonstrated the existence of two distinct dopamine receptor subtypes (Kebabian & Calne, 1979; Creese et al. 1983), possessing unique pharmacologic and biochemical properties. D₁ dopamine receptors stimulate adenylate cyclase activity, while D₂ dopamine receptors inhibit this enzyme and may well have other second messenger systems. However both receptor subtypes co-exist in many tissues making the determination of their respective physiological and behavioral roles difficult. All neuroleptics, commonly used drugs in the treatment of schizophrenia, have been shown to be either mixed D₁/D₂ receptor antagonists or selective D₂ receptor antagonists. These drugs, when administered to animals, induce profound motoric effects, termed catalepsy, which are characterized by the inability to initiate movement. This drug-induced behavioral syndrome is similar to some of the symptoms of Parkinson’s disease. Indeed, when administered to man, a similar spectrum of “extrapyramidal motor effects” are induced — which are ameliorated by anti-par-kinsonian drugs such as anticholinergics. Thus the behavioral effects of neuroleptics mimic some of the symptoms of Parkinson’s disease which are probably mediated by identical underlying biochemical substrates. D₂ receptors have been implicated as the site mediating both the antipsychotic and the antidopaminergic, extrapyramidal motoric effects of neuroleptics (Creese et al., 1976; Seeman et al., 1976). By inference, D₂ receptors have been considered to be the mediators of dopaminergic agonists’ behavioral effects. These behavioral effects are also motoric — agonists such as L-DOPA, apomorphine or amphetamine stimulating motor activity at low doses, while dyskinesias and stereotyped motor responses occur at higher doses in both animals and man. However, all of these agonists activate both D₂ and D₁ receptors.