Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disease which afflicts 1-2% of the population over 60 years of age. PD arises from premature loss of midbrain dopamine (DA) neurons and is treated symptomatically with drugs which replace DA actions at forebrain DA synapses. Early PD symptoms, which appear when 75-80% of DA neurons have been lost, are easily treated; progression of the disease is complicated by loss of stable and predictable responses to DA-mimetic therapies. The experiments outlined in this proposal will utilize the rat model of preclinical hemiparkinsonism and will explore adaptive synaptic processes which attempt to maintain normal extracellular fluid (e.c.f.) DA levels in basal ganglia. During the current funding period, the techniques of regional brain microdialysis with simultaneous quantitative activity monitoring in awake animals and in situ hybridization have been developed. These techniques will be utilized to address the following questions: 1) What are the roles of D2 DA autoreceptors and NMDA glutamate receptors in controlling DA synthesis and release rates in surviving DA terminals?; 2) Is decreased D2 autoreceptor control of DA synaptic activity associated with decreased synthesis of D2 receptor mRNA in surviving midbrain DA neurons?; 3) Does pharmacologic independence of postsynaptic D1 and D2 receptors after DA loss derive from appearance of D2 receptor synthesis in D1 neurons, and vice-versa?; and 4) What are the synaptic consequences in substantia nigra of intermittent compared to continuous DA replacement?