Parkinson's disease (PD) is a common disorder characterized by the selective loss of midbrain dopamine (DA) neurons; DA replacement in the form of the precursor L-dopa mediates neurological improvement. With long-term treatment, however, most patients develop fluctuations in response to L-dopa (""""""""on-off"""""""" swings and drug-induced dyskinesias) which present a major clinical management problem. Experimental animals with DA depletion, like patients with PD, have enhanced responses to DAergic stimulation; the mechanisms which underlie this """"""""denervation supersensitivity"""""""" remain unknown. In DA-depletion D1/D2 function changes profoundly such that D1 agonists become full motor stimulants and selective D1 and D2 agonist effects are no longer blocked by antagonists of the other receptor subtype. The overall objective of this proposal is to clarify the mechanism of this shift in D1/D2 function and thereby improve our understanding of the mechanism of DAergic drug action in PD. Evidence is presented which suggests that this shift in D1/D2 function is present within 12-24 hours of acute DA depletion. A working hypothesis is proposed in which striatal neurons expressing D1 receptors and neurons expressing D2 receptors are functionally coupled through the actions of DA. It is suggested that DA depletion results in the breakdown of this functional linkage and the relative independence of D1 and D2 mediated striatal output systems. Six hypotheses based on this model will be tested using rat models of DA depletion. Hypothesis #1: Enhanced metabolic responses to DA agonists occur within 24 hours of DA depletion. Hypothesis #2: Acute DA depletion is able to reversibly convert a normosensitive turning model into a supersensitive turning model. Hypothesis #3: Lack of stimulation at either D1 or D2 receptor is sufficient to result in enhanced metabolic responses to either D1 or D2 agonist. Hypothesis #4: Supersensitive responses to DA agonists in acute DA depletion are not mediated by an increased number of D1 and D2 receptors or increased receptor mRNA levels. Hypothesis #5: Supersensitive metabolic responses to D1 agonist stimulation correlate temporally with a fall in extracellular [DA]. Hypothesis #6: Continuous stimulation of both D1 and D2 receptors restores normosensitivity to a DA-denervated system. The results should provide fundamental data on the functional consequences of D1 and D2 receptor stimulation relevant to the pathogenesis and management of response fluctuations in patients with advanced PD.
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