In animal models, striatal dopamine (DA) appears to mediate a number of behavioral phenomena, including stereotypy, rotation and catalepsy. At least two distinct DA receptor subtypes (D1 and D2) appear to exist in the mammalian central nervous system. The objective is to gain an understanding of the underlying mechanism(s) involved in the apparent functional interaction between thee receptor subtypes.
The specific aims are to provide evidence for the following hypothesis: 1) both D1 and D2 receptors mediate certain behaviors under control by DA; 2) activation of striatonigral systems controlled by these receptors results in convergent functional output, i.e., the response elicited from simultaneous activation of both systems is greater than from either one singly; and 3) these receptors act independently of each other in controlling these functional outputs. Both behavioral and biochemical methods will be utilized to achieve these goals. Advantage will be taken of newer agents possessing demonstrated selectivity of action at these receptor subtypes, e.g.: SKF 38393, LY 171555 (selective D1 and D2 agonists, respectively), SCH 23390 and sulpiride (selective D1 and D2 antagonists, respectively). The hypothesis of convergent D1 and D2 receptor mediation of function will be tested by examining the effects elicited by selective agents singly and in combination on stereotypy (after systemic administration) and on rotation in intact animals (after unilateral intrastriatal application). The hypothesis that separate striatonigral neural systems are under independent control of D1 and D2 receptors will be tested by examining drug/receptor specificity with regard to the effects of intrastriatally applied drugs on GABA turnover in substantia nigra. In ancillary studies selective lesion of D1 or D2 receptors in vivo with the inactivating agent EEDQ will be evaluated for its potential as a new model to assess the functional relationship between D1 and D2 receptors. The insights gained from these basic studies are expected to further our understanding of dopaminergic systems, and therefore of neuropsychiatric disorders in which this neurotransmitter is either demonstrably or putatively involved (e.g. Parkinson's disease and schizophrenia, respectively). Furthermore, the results may lead to fruitful new strategies for treatment of these and related disorders.
