This proposal continues to be directed at identifying and characterizing the behavioral, neurochemical, and neuropharmacological mechanisms involved in ethanol-seeking behavior and dependence. Studies conducted during the previous funding period have characterized neuropharmacological mechanisms involved in the anti-punishment effects of ethanol and the motivational effects of ethanol withdrawal. The present proposal extends these efforts by shifting emphasis to the investigation of relapse. Specifically, the objective of this proposal is to employ the alcohol deprivation effect (ADE) as a model of excessive drinking or """"""""loss of control"""""""" and to study its neurochemical and neuropharmacological basis. The hypothesis is that alcohol deprivation after a period of chronic ethanol self-administration leads to changes in the functional activity and/or sensitivity to alcohol of the same brain neurotransmitter systems that have previously been implicated in the reinforcing effects of ethanol, the genetic basis of alcohol preference, or the motivational effects of ethanol withdrawal. This hypothesis will be tested by focusing on both pre synaptic and post synaptic changes associated with the ADE using in vivo neurochemical as well as behavioral pharmacological approaches.
Specific Aim 1 will examine changes in basal neurotransmitter profiles after alcohol deprivation as well as changes in neurotransmitter sensitivity to systemically injected and self-administered ethanol. Target brain sites will include the shell of the nucleus accumbens and the central nucleus of the amygdala. The neurochemical systems of interest are gamma-aminobutyric acid (GABA), dopamine (DA), endogenous opioids, and corticotropin-releasing factor (CRF). These studies will be complemented by investigations of the behavioral effects of pharmacological agents on deprivation-enhanced ethanol intake in Specific Aim 2.
Specific Aim 3 will study the neurobiological basis of the enhancement of the ADE associated with protracted abstinence in previously ethanol-dependent rats. These experiments are designed to determine whether the ADE in post-dependent rats involves identical, but more pronounced changes in neurotransmitter function compared to non-dependent rats, or involves additional or different neurochemical mechanisms. Finally, Specific Aim 4 will begin to explore sex differences and their neurobiological basis in the susceptibility to the ADE. The results of these studies are expected to reveal adaptive processes that lead to enhanced alcohol intake after deprivation and, thereby, may provide novel insights into brain mechanisms that underlie processes such as alcohol craving, loss of control, and relapse.
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