RC1 PHARMACOTHERAPY AND MECHANISMS OF ETHANOL DEPENDENCE AND RELAPSE DRINKING

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Alcoholism is a chronic relapsing disorder that continues to be a serious medical and social problem in the U.S. and enhanced efforts are needed to treat it. Advances in our understanding about mechanisms underlying motivation to drink and, in particular, mechanisms that drive transition from moderate drinking to more excessive and uncontrolled drinking are key to developing new and more effective treatment strategies. A contemporary view of alcohol addiction is that adaptations in glutamate (GLU) and dopamine (DA) transmission within regions of the striatum (key components of neurocircuitry that mediate motivated behavior) play a significant role in regulation of ethanol drinking behavior. While our current research efforts have focused on neurochemical adaptations in the ventral striatum (i.e., nucleus accumbens; NAc), recent evidence suggests that adaptations in GLU and DA transmission in the dorsolateral striatum (DLS) may play a prominent role in mediating the transition from controlled drinking to uncontrolled compulsive drinking that is characteristic of ethanol dependence. Accordingly, the overall objective of this proposal is to examine adaptations in GLU and DA transmission in dorsal striatum that may qualitatively or quantitatively differ from those in ventral striatum, as well as evaluate the influence of pharmacotherapeutics on voluntary ethanol drinking and neurochemical alterations that may underlie motivation to drink in dependent compared to nondependent animals. A guiding principle of the proposal is that ethanol dependence is associated with adaptations in GLU and DA transmission within dorsolateral striatum and that play an integral role in driving transition from moderate controlled drinking to uncontrolled excessive drinking. The research plan entails use of an established mouse model of ethanol dependence and relapse drinking along with in vivo microdialysis procedures to characterize changes in extracellular levels of GLU and DA in dorsal compared to ventral regions of the striatum that are associated with escalation of voluntary ethanol drinking in dependent mice compared to stable intake exhibited by nondependent mice. Additionally, these studies will provide new information on potential neuroanatomical sites and neurochemical mechanisms underlying the ability of pharmacological treatments to reduce excessive ethanol drinking associated with dependence, which could lead to new insights and approaches in the development of more effective pharmacotherapies for the treatment of alcoholism.