The overall objective is to provide an understanding of the neurobiological/neurochemical basis for the disparate alcohol drinking behaviors of the genetically bred alcohol-preferring (P line) and alcohol-nonpreferring (NP line) rats. Since the alcohol intake of the NP line resembles that of the majority of a general population of rats, the overall hypothesis to be tested is the following: in the P line, there is an innate imbalance in certain neuronal systems which mediate the reinforcing and aversive effects of ethanol, and exposure to alcohol alters these systems in favor of alcohol drinking. Using quantitative autoradiography techniques for (3H)-ligand binding, the densities of recognition sites for serotonin (5-HT), dopamine (DA), gamma-aminobutyric acid-benzodiazepine (GABA-BDZ) and N-methyl-D-aspartate (NMDA) will be determined (a) for alcohol-naive P and NP rats and (b) following free-choice alcohol drinking in the P rat. The (14C) 2-deoxyglucose technique coupled with quantitative autoradiography will be used to determine local cerebral glucose utilization (a) in alcohol-naive P and NP rats and (b) following contingent and noncontingent alcohol administration. Microdialysis procedures will be used to measure in vivo release of DA, 5-HT, GABA and glutamate in the nucleus accumbens and medial prefrontal cortex of P and NP rats following alcohol administration. The synaptoneurosome membrane preparation from the cerebral cortex will be used to study any differences between the P and NP rats in the response to muscimol, pentobarbital and ethanol on (36)Cl- influx at the GABA-BDZ-Cl- complex. CNS regions and associated transmitter systems involved in mediating alcohol drinking behavior will be established with two experimental approaches: (a) microinfusion of 5-HT, DA, GABA and glutamate agonists and antagonists into selected CNS sites, and (b) neurotoxin lesioning of specific 5-HT and DA pathways. These studies should contribute toward understanding the neuronal systems involved in maintaining high alcohol intake in a rat population which is genetically vulnerable to the addictive properties of alcohol. Such findings would provide a foundation for developing treatment strategies to combat certain forms of human alcoholism.
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