NEUROPHARMACOLOGY OF ETHANOL REINFORCEMENT

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Ethanol has reinforcing properties in man that presumably contribute to alcohol abuse and alcoholism. In rats ethanol is readily self-administered orally when taste factors are minimized by pre-exposing the rats to sweetened solutions. Non-dependent and non-deprived rats will choose ethanol over water in limited access situations and will self-administer sufficient quantities to produce meaningful blood ethanol levels. Work attempting to identify specific neurotransmitters involved in ethanol reinforcement has recently shown that low doses of ethanol can release dopamine in the region of the nucleus accumbens and that dopamine agonists appear to reduce ethanol preference without decreasing water intake. The nucleus accumbens is one of the converging points for a limbic-forebrain- extrapyramidal circuit upon which other reinforcing drugs such as cocaine and heroin may act to produce their reinforcing effects. The purpose of the present proposal is to examine the role of the nucleus accumbens and its afferent and efferent connections in ethanol reinforcement. Non- deprived male Wistar and male Alcohol Preferring (P) rats will be trained to self-administer ethanol in daily 30 min sessions using a saccharin fade out procedure. The role of the mesocorticolimbic dopamine projections to the nucleus accumbens will be tested using 6-hydroxydopamine lesions to the nucleus accumbens. The role of other afferents to the nucleus accumbens will be examined using cell body (ibotenic acid) lesions of the amygdala and hippocampus. The role of neural circuitry efferent to the nucleus accumbens will be examined using cell body (ibotenic acid) lesions of the nucleus accumbens itself, the ventral pallidum, and other efferent connections. The function of specific neurotransmitters hypothesized to modulate this circuitry will be examined by microinjection of agonists and antagonists of opioid peptides, neurotensin, glutamate and cholecystokinin into either the nucleus accumbens or ventral pallidum. These proposed studies parallel published or ongoing studies on the neuropharmacology of psychomotor and opiate reinforcement and as such will provide a means to evaluate the similarities and uniqueness of the substrates for ethanol reinforcement. These results should have important implications not only for our understanding of the neurobiology of ethanol intoxication but may lead to the development of viable pharmacological intervention in alcoholism.