Antipsychotic drugs are hypothesized to exert their clinical effects through direct blockade of brain and pituitary dopamine receptors. It is now clear that multiple subtypes of dopamine receptors exist, D1 and D2, which have differential affinities for antipsychotic drugs. Both D1 and D2 dopamine receptors mediate behavioral responses in animals. Dopamine receptors will be characterized in vitro by computer-analyzed radioligand binding techniques with dopaminergic 3H-ligands, and by studies of dopamine-sensitive adenylate cyclases (both stimulatory and inhibitory). The biochemical and pharmacological characteristics of these systems will suggest which populations of dopamine receptors that each may identify. This will be confirmed by lesion studies, functional studies, and response to modification of membrane environment and receptor structure with specific reagents. Such studies will identify potential autoreceptors, pre- and post-synaptic dopamine receptor subtypes and detail some of the molecular mechanisms which differentiate agonist form antagonist receptor interaction and transduction to adenylate cyclase regulation. These receptor parameters will be investigated within postmortem brains from control patients and patients with schizophrenia. Decreased dopamine receptor activity caused by denervation or chronic blockade with antipsychotic drugs results in behavioral supersensitivity accompanied by an increase in receptor number. Such drug-induced increases in dopamine receptors have been hypothesized to be etiologic in tardive dyskinesia. The response of dopamine receptor subtypes to denervation or chronic blockade with subtype-selective and nonselective antipsychotics will be investigated to determine the molecular mechanisms involved in increased receptor binding or changes in regulatory processes. The effects of chronic stimulation with agonists will also be investigated. Dopamine receptor turnover will be evaluated utilizing a novel technique. Receptor autoradiography will be performed to determine the anatomical location of dopamine receptor subtypes and whether they demonstrate differential responses to the above manipulations. The biochemical characterization of distinct populations of brain dopamine receptors holds promise for the development of new classes of dopaminergic agonists and antagonists with more specific therapeutic action and lowered incidence of side-effects.
