At least two distinct dopamine (DA) receptor subtypes (D1 and D2) are present in the brain. Combined treatment with agonists selective for each subtype elicits potentiated behavioral response (i.e. stereotypy) relative to effects produce by each alone. The long term objective of this project is to elucidate the relative influence of striatal D1 and D2 systems in regulating cholinergic and GABAergic neuronal activities which mediate DNA effects.
The specific aims of this project are to provide pharmacological evidence for the following hypotheses: 1) Striatal D1 and D2 receptor systems independently regulate striatonigral efferents, thus activation of both systems leads to convergent functional output and potentiated behavioral response (stereotypy). To test this hypothesis, we will determine whether the behavioral effects of D1 (SKF 38393, fenoldopam) or D2 (quinpirole) agonists are potentiated by intrastriatal (i.s.) and intranigral injection of the GABA antagonist picrotoxin and the GABA agonist muscimol, respectively. Biochemical studies will examine the effects of he DA agonists on GABA turnover and release in substantia nigra. Attempted selective blockade of effects with D1 (SCH 23390) and D2 (sulpiride) antagonists will test whether striatonigral GABA activity is independently regulated by these receptor subtypes. 2) Cholinergic antagonists (e.g. scopolamine; SCOP) in the striatum elicit DA-like behavioral effects by modulating D2 neurotransmission via local or feedback effects rather than by conveying striatal DAergic information to motor output areas. To test this hypothesis, we will determine if DA synthesis inhibition or depletion attenuates the observed potentiating effect of i.s. SCOP plus a D1 agonist fenoldopam), if intact D2 receptors are required for this effect (using the receptor inactivating agent EEDQ) and if the potentiation obtained after combined D1 and D2 agonists is attenuated by i.s. oxotremorine (a cholinergic agonist). 3) Elicitation of different components of stereotypy (sniffing and oral behaviors) require activation of different fractions of D2 receptors. To test this hypothesis, we will measure these responses after inactivation of different proportions of D2 receptors with EEDQ. The insights gained from these basic studies are expected to further our understanding of dopaminergic systems, and therefore of neuropsychiatric disorders putatively involving derangements in activity of this transmitter (e.g. Parkinson's disease and schizophrenia). Furthermore, the results may lead to fruitful new strategies for treatment of these and related disorders.
