The ventral tegmental area (VTA) dopamine (DA) and dorsal raphe nucleus (DRN) serotonin (5-HT) pathways to the nucleus accumbens (ACC) have been implicated in mediating the reinforcing properties of alcohol. The ACC and VTA receive 5-HT innervations from the DRN and there is evidence that 5-HT can influence DA release in the VTA and ACC. Data also indicate that ethanol-induced DA release in the ACC may be mediated by 5-HT3 receptors. The hypotheses to be tested are that (1) the VTA DA neurons to the ACC are regulated by the DRN 5-HT system via 5-HT3 receptors, and (2) this 5-HT system is involved in mediating the actions of alcohol on the mesolimbic DA system. The neurochemical experimental approach will utilize a microdialysis technique coupled with a small-bore HPLC-EC procedure to collect and measure extracellular levels of DA and 5-HT in the ACC of unanesthetized, freely moving, adult male Wistar rats as a measure for determining changes in neuronal activity. The experimental design will establish if (1) local application of 5-HT3 agonists into the VTA and ACC stimulates the release of DA in the ACC; (2) local application of 5-HT3 antagonists into the VTA and ACC inhibits DA release induced by activation of the DRN 5-HT neurons; (3) local administration of 5-HT3 antagonists into the VTA and ACC attenuates the alcohol-stimulated release of DA in the ACC following i.p. ethanol administration; and (4) the activity of the DRN 5-HT neuronal system alters the effects of i.p. alcohol on the VTA DA pathway to the ACC. The data from this proposal will provide valuable information on the involvement of the DRN 5-HT system in regulating the activity of VTA DA neurons projecting to the ACC and mediating the actions of alcohol on this DA pathway. Such knowledge may aid in the development of specific pharmacological agents for treatment of alcoholism and alcohol abuse.
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