The long term objective of the current proposal is the attainment of a greater understanding of the functional organization of the basal ganglia. Substantial evidence suggests that many neurological and psychiatric disorders, including Parkinson's disease, Huntington's Disease, Sydenham's chorea, torsion distoma, Tourette's syndrome and schizophrenia, may result from abnormal basal ganglia functioning and progress in understanding the etiology of these disorders, and in developing treatment for them, is largely dependent on advances in understanding the basic mechanisms of basal ganglia function. The proposed experiments are designed to examine basal ganglia organization using the immunocytochemical detection of the transcription factor Fos as a marker for neurons affected by various behavioral or pharmacological manipulations. The first group of experiments will study the influence of D2 dopamine receptors and muscarinic acetylcholine receptors on the induction of Fos like immunoreactivity (FLI) produced by administration of the selective, full, D1 dopamine agonist A77636 in intact animals. The possibility that D2 receptor stimulation is necessary for A77636 to elicit striatal Fos expression will be studied by examining the effect of a selective D2 antagonist of A77636-induced FLI in anatomically identified striatonigral cells. The alterations in A77636-induced FLI produced by coadministration of a selective D2 agonist will then be studied. Statistical techniques will be used to examine changes in the pattering of FLI produced by the D2 agonist and the relative effects of this compound in the striosomal and matrix compartments of the striatum will be accessed. Similar methods will be used to examine the potentiation of A77636-induced striatal FLI produced by the muscarinic antagonist scopolamine. The possibility that coadministration of a D1 and a D2 agonist, or of a D1 agonist and a cholinergic antagonist, will produce interactive effects of Fos expression in several basal ganglia output structures will also be examined. Since certain behaviors are associated with striatal dopamine release, the second group of experiments will examine the extent to which the striatal Fos expression induced by one of these behaviors, mating in male rats, resembles that produced by administration of dopamine agonists. These studies will examine the statistical patterning the regional and compartmental distribution of sex-induced striatal FLI, and the anatomical connections of the labeled cells. The next group of studies will examine the internal circuitry of the basal ganglia. Some experiments will examine the distribution of extrastriatal FLI induced by injections of the GABA agonist muscimol into the globus pallidus, the entopeduncular nucleus of the pars reticulate of the substantia nigra, while other experiments will examine the effects of lesions of the subthalamic nucleus, or systemic administration of an excitatory amino acid antagonist, on neuroleptic- induced FLI in the substantia nigra and entopeduncular nucleus. The final group of studies will attempt to characterize the circuity activated by stimulation or blockade of dopamine receptors by using retrograde tracing in combination with Fos immunocytochemistry to study the connections of immunoreactive cells in the nigra and entopeduncular nucleus following neuroleptic treatment, or in the """"""""midbrain extrapyramidal region"""""""" following amphetamine treatment.
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