Alcohol addiction is a chronic disorder involving neuroplastic changes in the brain that contribute both to the maintenance of ongoing drug use and relapse to drug seeking after periods of abstinence. Although substantial progress has been made in identifying neurobiological mechanisms that mediate excessive alcohol seeking and consumption, enduring susceptibility to relapse remains a major obstacle in the treatment of alcohol addiction. A key factor known to maintain drug taking and to precipitate relapse are learned responses elicited by sensory stimuli that have been repeatedly paired with drug administration and thus become salient cues predictive of impending drug reinforcement. Given its oral route of administration, the chemosensory cues accompanying alcohol consumption are among the most intimate and consistent stimuli immediately predictive of the drug's postabsorptive effects. Ethanol chemosensory stimuli induce urges to drink and corresponding physiologic changes in alcoholics and promote relapse to ethanol seeking in rodent models, yet the underlying neural substrates mediating learned responses to ethanol sensory cues in chronically exposed organisms are not well established. The present proposal aims to investigate alterations in the neural processing of ethanol orosensory signals within the insular cortex following chronic experience with the drug and the effects of inactivation of candidate subregions of the insula in reducing learned reactivity to ethanol chemosensory cues and their ability to induce ethanol-seeking responses. Experiments under Specific Aim 1 will measure alterations in central neural response to ethanol chemosensory signals within the insula in chronically ethanol- exposed animals and the effects of direct pharmacological silencing of primary gustatory and visceral subregions of the insular cortex in suppressing heightened behavioral reactivity to ethanol chemosensory cues. Experiments under Aim 2 will measure neural response within the insula elicited by re-exposure to ethanol chemosensory cues following extinction of self-administration and the ability of inactivation of gustatory and interoceptive regions of the insula to disrupt cue-induced reinstatement of ethanol seeking. At the conclusion of this project, we will have produced valuable data regarding neural mechanisms underlying established alcohol- seeking responses elicited by exposure alcohol sensory cues, essential to identifying targets for treatment to reduce compulsive drug seeking and persistent vulnerability to relapse. More broadly, these studies will continue to enhance our understanding of the central nervous system processing of alcohol sensory information, an understudied but important area of research.
Sensory stimuli that are repeatedly associated with drug administration result in memory traces in the brain for cues that predict drug reward. Exposure to these stimuli can produce unconscious or conscious urges for the drug that maintain ongoing drug use and/or promote vulnerability to relapse. The studies proposed in this project aim to understand brain mechanisms that underlie learned responses to alcohol-related sensory stimuli in order to identify targets to reduce alcohol seeking elicited by these cues.
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