The overall goal of the projects in this proposal is to identify CNS sites and receptors involved in mediating ethanol (E) drinking behavior. The primary focus will be on the mesocorticolimbic dopamine (DA) system, emanating from cell bodies in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAC) shell, medial prefrontal cortex (MPC), and ventral pallidum (VP). The dorsal raphe nucleus (DRN) will also be investigated, which sends serotonin (5-HT) projections to the DA system. A general working hypothesis is that the mesocorticolimbic DA system mediates the reinforcing properties of E, and activity within this DA system is regulated by various autoreceptors, and pre- and post-synaptic receptors. It is assumed that hereditary influences can predispose high E drinking behavior through genetic effects on neurobiological substrates within the neurotransmitter systems and receptors being investigated. Thus, to accomplish the overall goal, rats selectively bred for high alcohol intake, the P, HAD1 and HAD2 lines, will be used as models. The strategy will be to conduct experiments in rats of the P line, and then to confirm key findings in the HAD replicate lines. Three experimental techniques will be used. First, the effects on E drinking in a limited access paradigm will be assessed after CNS site-specific microinjections of receptor agents for DA, 5-HT and GABAA receptors. Selected receptor agents for subtypes will be tested at each CNS site; the VTA, NAc, VP, MPC and DRN. Second, microdialysis will be utilized to assess the extracellular levels of DA in the VTA, NAc, VP, and MPC during ongoing E self administration in an operant paradigm. Third, the reinforcing actions of E at three prospective sites, the NAc, VP and MPC, will be investigated by utilizing an intracranial self administration (ICSA) procedure. The findings will further knowledge regarding the role of the mesocorticolimbic DA system in the reinforcing consequences of E ingestion, and should delineate the importance of certain neurotransmitter receptor subtypes regulating this DA system and mediating ethanol self administration.
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