Exposure to specific environments that have been associated with past alcohol use is thought to contribute to propensity to relapse in human alcoholics. We employ an animal model for relapse triggered by ethanol-associated environments. In this model, subjects acquire an ethanol self-administration habit in a distinctive context, and then undergo a period of extinction in a second distinctive context during which ethanol is no longer available and ethanol seeking by the subjects diminishes. However, when the subjects are placed once again into the ethanol-associated context, ethanol-seeking is robustly renewed, indicating that the context has acquired the ability to motivate responding due to its predictive relationship with ethanol self-administration. The studies within this proposal will begin to define the underlying neural circuit for this context-dependent reinstatement. Studies in the first aim will test whether context-dependent reinstatement for ethanol seeking depends upon DAergic transmission. Studies within the second aim will use reversible inactivation to determine whether the expression of context-dependent reinstatement for ethanol depends upon the hippocampus (HIPP), and will further define the importance of the hippocampal projection to the nucleus accumbens (NAC) in the behavior, by reversibly inactivating the two brain regions in opposite hemispheres (a disconnection). Next in vivo electrophysiology in awake rats will be used to test the hypothesis that neural activity within the NAC and HIPP is context-specific by comparing responses of individual neurons when subjects are exposed to the context previously associated with ethanol, and to the extinction context in which instrumental responding was not reinforced by ethanol. Hence this aim will test whether distinct contextual representations exist in either one or both of these two regions, defining a possible neurophysiological basis for context-dependent reinstatement. Taken together this set of studies will begin to define the neurochemical, neuroanatomical, and neurophysiological basis for context-dependent reinstatement of ethanol seeking. These results will provide new understanding of the possible biological mechanisms that underlie context-dependent relapse in humans, and may lead to new treatment strategies.
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