Cholecystokinin octapeptide (CCK-8) is present within midbrain dopamine (DA)-containing neurons and appears to act as a cotransmitter. The importance of these DA neurons in current hypotheses of the etiology and treatment of several neurological and psychiatric disorders requires that their physiology and their pharmacological responsiveness be well understood. In recent years, much has been learned about the receptor subtypes which mediate the effects of CCK-8 on DA neurons, but much remains to be learned about the scope and sites of CCK-8 actions In the midbrain. The studies proposed in this application are intended to evaluate possible sites of action for modulatory effects of CCK-8 on the electrophysiological activity of DA neurons in anesthetized rats. The serotonergic input to the midbrain from the dorsal raphe nucleus Influences the electrophysiological activity of DA neurons. In the first set of proposed experiments, Interactions of CCK-8 with the effects of dorsal raphe nucleus stimulation (and with serotonin itself on nigrostriatal and mesoaccumbal DA neuronal activity will be evaluated. Non-DA interneurons in the substantia nigra pars reticulata (SNr). Influence the activity of nigral DA neurons and may be accessible to locally released CCK-8. The SNr is also the source of non-DA nigrothalamic and nigrotectal neurons which are important links in the extrapyramidal motor system. Thus, the effects of CCK-8 on the activity of SNr interneurons and antidromically identified nigrothalamic and nigrotectal neurons will be determined. The neurotoxin 6-OHDA causes the degeneration of DA neurons and is used to produce an animal model of Parkinson's disease. The pharmacological responsiveness of the remaining DA neurons has been shown to be greatly altered. Because of the intimate relationship between CCK-8 and DA, it is possible that the responsiveness of remaining DA neurons to CCK-8 is changed in the 6-OHDA-lesioned rat. Such a change In responsiveness would have important implications for the regulation of DA neuronal function in the lesioned rat and, by inference, certain disease states. In the last set of experiments, the effects of CCK-8 on remaining DA neurons in the 6-OHDA-lesioned rat will be tested. The effects of the lesions on DA levels and CCK-8 levels in the midbrain DA cell body region and in DA cell projection sites will also be determined.

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