Preliminary studies have shown that dopamine, applied by iontophoresis or released from dendrites within the substantia nigra, has a dual effect on non-dopaminergic output neurons of the substantia nigra pars reticulata. Specifically, dopamine was found to increase the firing rates of many parse reticulata neurons. More consistently and significantly, however, dopamine behaved as a """"""""neuromodulator"""""""" which lessened the ability of applied GABA to inhibit these cells, and diminished the GABA-mediated inhibition of these neurons evoked by stimulation of the striatonigral pathway. The objectives of the proposed studies are to: 1) Distinguish mechanistically the rate-increasing and GABA-attenuating effects of dopamine on pars reticulata neurons. This goal will involve efforts to separate the two effects of dopamine, and in dissociating them, to determine their individual sites and mechanisms of action. 2) Establish the pharmacologic specificity of the effects of dopamine on pars reticulata neurons. This goal will be accomplished by using several newly introduced dopamine agonist and antagonist drugs with selectivities for D-1 and D-2 dopamine receptor subtypes. Specifically, the D-1 agonist, SK&F-38393, and the D-2 agonist, LY-171555, will be substituted for dopamine in testing for the dopamine-mediated responses. Similarly, the D-1 antagonist, SCH-23390, and the D-2 antagonists, (-)sulpiride, YM-09151-2, and zetidoline will be tested for their relative abilities to block the GABA modulating and rate-increasing effects of iontophoretically applied dopamine. If studies with the above drugs produce any electrophysiological effects consistent with a D-1 profile, then iontophoresis studies with cyclic AMP analogues and forskolin, an activator of adenylate cyclase, will be carried out to assess whether stimulation of the cyclase might underlie the D-1-associated response(s). 3) Determine the overall contribution that nigral actions of dopamine make toward basal ganglia output function. This final phase of studies will assess how, and to what degree, the intranigral effects of dopamine influence pars reticulata output function during generalized dopamine system activation elicited by i.v. administration of apomorphine, a dopamine agonist. These studies will advance our understanding of normal basal ganglia output function and should facilitate design of new strategies for therapeutic intervention in certain neurological disorders, such as Parkinson's disease, Huntington's disease, tardive dyskinesia, in which basal ganglia output funciton is believed to be disrupted.
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