Evidence indicates that the dorsal (DR) and median (MR) raphe nuclei may play important roles in the control of behavior. Although these two nuclei are the major sources of forebrain serotonin (5-HT), recent evidence suggests that many of the behavioral effects of raphe lesions, such as hyperactivity, are not secondary to 5-HT depletion. Therefore, it cannot be assumed, a priori, that the behavioral effects of midbrain raphe lesions reflect 5-HT depletion, since both the DR and MR contain large numbers of non-serotonergic cells and fibers of passage. The results of some studies suggest that the MR and DR interact with the dopaminergic (DA) system, although it is not known whether these interactions reflect involvement of serotonergic elements within the raphe nuclei. The studies proposed in this application are principally concerned with investigating behavioral and biochemical interactions between the midbrain raphe nuclei and the DA system. These interactions will be studied in rats with electrolytic, 5,7-dihydroxytryptamine, or ibotenic acid lesions of either the MR or DR and in controls. Additional studies will be conducted in behaving animals receiving microinjections into the MR. Manipulations of the DA system will be conducted using intracerebral or systemic administration of haloperidol or 6-hydroxydopamine lesions of the basal forebrain. Tests for behavioral interactions between the raphe and DA will include neuroleptic-induced catalepsy, suppression of locomotor activity and avoidance deficits. Evidence for biochemical interactions will be gathered using high performance liquid chromatography and brain microdissection techniques. Determinations of 5-HT, DA and their metabolites will be made in a number of brain regions following manipulations of the MR and DR. Correlation coefficients will be calculated between changes in forebrain DA or 5-HT mechanisms and spontaneous locomotor activity in control and lesioned rats. The effects of MR lesions on non-DA mediated behaviors will also be evaluated to determine whether the effects of raphe lesions are specific to behaviors relying on DA mechanisms. Finally, we will examine whether the hyperactivity produced by intra-MR injections of muscimol is reliant on serotonergic and/or dopaminergic systems. Since 5-HT and DA have been implicated in the pathogenesis of some psychiatric disorders, our studies may prove to be useful in understanding the aetiology of these conditions.
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