The supersensitivity to dopamine or its agonist drugs is believed to contribute to a variety of clinical phenomena in diseases of the basal ganglia, including abnormal responses to L-dopa medication during treatment of Parkinson's disease as well as tardive dyskinesias. For many years, an u-regulation of striatal dopamine receptor density was though to underlie the behavioral supersensitivity to dopamine agonist drugs that occurs after nigrostriatal injury. However, current evidence refutes this; instead, the major form of supersensitivity that occurs after extensive injury to the nigrostriatal pathway of rats can be attributed to a breakdown in the normal pattern of D1/D2 synergism. The objective of this proposal is to characterize how nigrostriatal injury affects the interaction between D1- and D2-dependent processes within basal ganglia, and several models for these interactions will be tested. The proposed experiments will use the expression of Fos protein, the product of the proto-oncogene, c-fos, within cells of the rat striatum and globus pallidus to determine whether denervation supersensitivity to D1 or D2 agonist drugs is manifested in an altered control of Fos activation within these neurons. In normal animals, the activation of Fos within cells of striatum and globus pallidus depends upon co- activation of D1 and D2 receptor subtypes (D1/D2 synergism). Studies are proposed to determine whether this requirement for D1/D2 co-activation of Fos expression breaks down after nigrostriatal injury. Further studies will elucidate whether, as a consequence of denervation, dopamine agonist-induced Fos activation in striatal neurons occurs in a striatal population (striatonigral, striatopallidal) or compartment (patch, matrix) different from neurologically intact animals exposed to the same treatments. A possible contribution of striatal acetylcholine-containing neurons and GABA-containing axon collaterals to the D1/D2 synergism and its breakdown will also be tested. Finally, experiments will determine whether chronic administration of dopamine D1 or D2 antagonists, which result in only a minor behavior supersensitivity, will lead to a breakdown in the requirement for D1/D2 coactivation of Fos in striatum or globus pallidus.
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