Laboratory animals selectively bred for high and low ethanol preference constitute a powerful experimental model to investigate the neurobiological basis of alcohol abuse and alcoholism. In these animals, a different ratio between the reinforcing and aversive properties of ethanol appears to play a pivotal role in the regulation of ethanol intake, resulting in high ethanol drinking in ethanol-preferring animals and almost complete ethanol avoidance in ethanol-non preferring animals. Both the reinforcing and aversive properties of ethanol are part of the discriminative stimulus (or subjective) effects of ethanol. Thus, identification of possible differences in the pharmacological profile of the discriminative stimulus effects of ethanol between ethanol-preferring and -non preferring animals would be helpful in understanding why ethanol is pleasurable in some individuals and aversive in others. Accumulating experimental evidence indicates that the discriminative stimulus effects of ethanol can be viewed as a mixture of multiple cues, where each cue is the effect of ethanol on the GABA(A) and NMDA receptor complexes, as well as the 5-HT(1) subtype of the serotonin receptor. Moreover, the relative contribution of each component (i.e., the receptor system) is dependent on the training dose of ethanol. Thus, the multi-component frame of the discriminative stimulus effects of low and high doses of ethanol varies both in terms of total size and proportion among the different components. The present research proposal is designed to compare the relative contribution of the GABA(A) and NMDA receptor complexes, as well as the 5-HT(1) receptor subtype, to the discriminative stimulus effects of ethanol in """"""""Sardinian alcohol-preferring"""""""" (sP) and """"""""Sardinian alcohol-non preferring"""""""" (sNP) RATS. These rat lines have been selectively outbred over 35 generations at the University of Cagliari, Italy, for their divergent ethanol preference. Rats will be trained to discriminate either 1.0, 1.5 or 2.0 g/kg ethanol i.g. from water in a T-maze, food-reinforced drug discrimination procedure. Different doses of pentobarbital, diazepam, the uncompetitive NMDA antagonists, phencyclidine and dizocilpine and the 5-HT(1) agonists, TFMPP and CGS 12066B, will be tested for generalization to the ethanol cue in both sP and sNP rats.
