ALCOHOL REWARD AND BRAIN DOPAMINE--PHARMACO-MODULATIONS

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The objective of this research is to gain further insight into alcohol's action on brain reward circuits and on dopamine (DA) and enkephalinergic mechanisms involved in direct brain reward. This work derives from the hypothesis that abusable substances, including ethanol, derive part of their abuse liability from neuropharmacological facilitation of brain reward circuits. Some workers report that exogenous ethanol robustly lowers brain-stimulation reward thresholds, while others report that experiential factors are additive to ethanol's pharmacological facilitation of brain-reward. We and others have recently found that self-administration of ethanol in laboratory rats more robustly enhances brain reward than exogenous administration. It is also well-established that significant genetic differences exist among rat strains regarding alcohol preference. One alcohol-preferring strain, the Lewis rat, is also unusually sensitive to morphine and cocaine, and shows significantly higher preferences for morphine and cocaine than other rat strains. We have shown that the Lewis rat is also uniquely sensitive to the brain-reward enhancing effects of delta(9)-tetrahydrocannabinol (delta(9)-THC), the psychoactive ingredient in marijuana, and that this unique sensitivity to brain-reward facilitation correlates highly with a unique sensitivity of Lewis rats to facilitation of extracellular DA in reward-relevant loci in the nucleus accumbens, a crucial forebrain limbic convergence of reward-related DA circuitry. The general aim of the presently proposed work is to carry forward and extend all these previous findings, with the hope of identifying forebrain DA mechanisms that may correlate with high ethanol preference, and determine whether it is possible to modulate those mechanisms pharmacologically - thus hopefully opening up new possibilities of pharmacotherapy for alcohol addiction and abuse. The specific aims are to 1) study the effect of exogenously-administered versus self-administered ethanol on extracellular DA efflux (as measured by in vivo brain microdialysis and in vivo voltammetry) in three reward-relevant DA forebrain loci - nucleus accumbens, medial prefrontal cortex, and neostriatum; 2) study the effect of strain differences (alcohol-preferring Lewis rats versus non-preferring F344 rats) on exogenously-administered and self-administered ethanol-induced extracellular DA efflux in these three reward-relevant DA forebrain loci; 3) study effects seen in 1) and 2) in both normal animals and protracted-abstinence animals; and 4) study possible pharmacological modulations (by serotonergic, DAergic, and enkephalinergic manipulations) of effects seen in 1), 2), and 3). This application addresses specific research needs stipulated in NIAAA Request for Applications RFA-AA-92-01 [Research on Pharmacologic Treatments for Alcoholism] and NIAAA Program Announcement PA-91-97 [Exploratory/Developmental Grants (R21) for Research on the Etiology of Alcoholism] ("..Goals include clarifying the basis for alcohol craving so that more effective therapeutic agents, such as dopaminergic agonists and serotonin uptake inhibitors, can be tested.. ..Research is required to specifically delineate the potential of agents that alter dopaminergic function..and..to identify the precise mechanisms by which the opioid system alters drinking behavior..").