Tardive dyskinesia is a condition produced by long-term antipsychotic drug use, and affects millions of people world-wide. Though the problems has been termed a """"""""dopamine supersensitivity syndrome,"""""""" this undoubtedly describes only part of the underlying pathophysiology. Recent clinical evidence, in fact, suggests that calcium channel inhibitors may be useful for reducing the symptoms of tardive dyskinesia, as well as the symptoms of some other neuropsychiatric disorders. The goal of this proposal, therefore, is to further the understanding of dopamine and calcium related processes in animal models of human neuro- and psychopathology. Within a three year period, the experiments described in this proposal will examine the hypothesis that calcium channel inhibitors exert direct effects on dopamine receptor regulation and (or) function. Thus, this project will characterize: (1) the effects of chronic administration of calcium channel inhibitors on the development and the maintenance of neuroleptic induced changes in dopamine receptor characteristics and activity, (2) the interaction in vitro between calcium channel inhibitors, adenylate cyclase activity, and dopamine receptor characteristics, and (3) the role of dopamine (lesions) in the effects of calcium channel inhibitors on dopamine receptor regulation and function. The experiments will characterize i) changes in D1 ((3H)SCH23390) and D2 ((3H)spiroperidol) receptor recognition site density and affinity for ligand, ii) agonist displacement of the respective radioligand in the presence and absence of guanine nucleotide and iii) changes in D1 receptor mediated activation and D2 receptor mediated inhibition of adenylate cyclase activity in rat brain striatum.
