This proposal represents one of eight interactive R01s which are investigating hereditary influences on the biological determinants of abnormal ethanol-seeking behavior. The overall goal of the experiments in this proposal (IRG 7) is to study athe relationship between ethanol (EtOH) drinking behavior and genetically- determined differences in central nervous system (CNS) neurobiological substrates postulated to regulate the pharmacological effects of EtOH. To accomplish this goal, the experiments will require lines of rats selectively bred for divergent EtOH drinking behavior. Two sets of selected lines to be used throughout all experiments are the alcohol-preferring (P) and the -nonpreferring (NP) rats, and the hi - (HAD) and low-alcohol drinking (LAD) rats. The experiments will focus on CNS sites, and on neurotransmitter receptors and receptor subtypes at those sites, which are thought to mediate the actions EtOH. It is hypothesized that, when compared with the NP and lAD rats, rats selected for high EtOH intake (P and HAD) will exhibit innate differences at CNS sites that mediate the pharmacological consequences of EtOH. The CNS pharmacological actions of EtOH are presumed to include at least two general psychoactive effects; reinforcement and aversion. It is further hypothesized that rats innately predisposed to high EtOH intake will exhibit enhanced reinforcing effects of EtOH (euphoric and/or anxiolytic effects) and a higher threshold for the aversive consequences of EtOH ingestion. One set of experiments will examine the alterations of the reinforcing effects of EtoH drinking with CNS site-specific microdialysis of EtOH and microinjections of receptor agents. The site-specific actions of EtOH are proposed to yield behavioral consequences which reflect the pharmacological actions of EtOH at the site. Microinjections of receptor agents will provide a test of the neurotransmitter pathways involved in the reinforcing pharmacological effects of EtOH. In another set of experiments, the threshold for electrical brain stimulation reinforcement (BSR) and the effects of EtOH on BSR will be compared in rats from the selected lines. EtOH is expected to have a greater effect on BSR threshold in P and HAD than in NP and lAD rats. Sites that are found to alter EtOH drinking will subsequently be investigated with microinjections of receptor antagonists in an operant reinforcement paradigm. Sites that are found to alter EtOH drinking will also be investigated with site-specific EtOH microdialysis for CNS sites mediating aversion (conditioned taste aversion) and anxiety (plus maze). A shared resource in this IRPG (Shared Resource IV: Behavioral Testing) will provide this IRPG and others within the group (IRPGs 1,2, 3, 5 and 8) with behavioral assessment for preference for EtOH and other solutions, t ests of aversion, anxiety, reinforcement and tolerance.
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