The overall long-range objectives of this proposal are to identify CNS neurotransmitter systems that are involved in mediating the rewarding properties of ethanol in order to understand better some of the neurobiological factors underlying excessive alcohol drinking behavior. The hypothesis to be tested is that the ventral tegmental area (VTA) dopamine (DA) neuronal system projecting to the nucleus accumbens (Acb) is a major neuronal pathway involved in initiating and maintaining the rewarding actions of alcohol. Since alcohol drinking behavior can be significantly influenced by genetic factors, experiments will be conducted with the alcohol-preferring P line and the high-alcohol drinking HAD line of rate. Results will be compared with data obtained with the alcohol-nonpreferring NP line and the low-alcohol drinking LAD line as well as with data obtained from stock rate (Wistar, N/Nih). The technique of intracranial self administration(ICSA) will be used to determine if the VTA, Acb or medial prefrontal (MPF) cortex is a potential site for the rewarding actions of alcohol. An electrolytic microinjection transducer (EMIT) system will be used to deliver the alcohol (0-200 mg%/100 nl artificial CSF over 5 seconds) into the 3 brain sites. Animals will be stereotaxically implanted with unilateral guide cannulas in either the VTA, Acb or MPF cortex. Following recovery from surgery, rate will be transferred to 2-lever operant chambers and allowed to self-train for the ICSA of ethanol by pressing an active lever which will deliver the ethanol solution directly into the brain site. These infusions are initially delivered on a FRl schedule of reinforcement and are paired with a red cue-light stimulus. Responses on the active and inactive levers, and the number of reinforcements are recorded throughout the sessions. The dose-response effects of the ICSA of ethanol into the 3 regions will be compared among the selectively bred lines and the stock rats to determine if sites other than the VTA will support ICSA of ethanol and if only the P and HAD lines will significantly self-administer ethanol. Experiments will also establish if the VTA DA system is involved in the ICSA of ethanol into the VTA by determining the effects of (a) D-1 and D-2 receptor antagonists on self-administration; (b) 6-hydroxy dopamine lesions in the VTA on self-administration; and (c) effects of self-administration into VTA on DA release in the Acb or MPF cortex. Finally, experiments will also determine if the GABA-A, 5-HT3 or opioid receptors are involved in mediating the ICSA of ethanol into the VTA. Overall, the information obtained from the proposed studies will hopefully provide a better understanding of some of the neurobiological mechanisms involved in human alcohol addiction.
