Alcohol dependence is a chronic relapsing disorder characterized by compulsive alcohol use. Significant effort has been dedicated to reveal neurobehavioral factors responsible for promoting relapse. Despite such effort, effective interventions to prevent alcohol relapse have yet to be established. An alternative research strategy may thus prove beneficial. For this premise, an omission cue-induced suppression (OCIS) paradigm was developed to investigate the relapse-suppressing potential of cues that signal alcohol omission (unavailability). Preliminary results indicate that omission cues suppress alcohol seeking triggered by all major modes of relapse-promotion: alcohol cues, stress and alcohol itself. Remarkably, omission cues suppress alcohol seeking in alcohol dependent subjections undergoing acute or protracted withdrawal - conditions linked to high risk of relapse. Additional preliminary results indicate that OCIS is controlled by 1) a discrete subpopulation of omission cue-activated neurons in the medial prefrontal cortex (mPFC) - a region implicated in cognitive control of drug craving in addicts. Given that the neural activation is a product of loca excitatory neurotransmission, OCIS is likely controlled by 2) omission cue-activated excitatory transmission in mPFC, as well as 3) omission cue-activated excitatory afferent innervations to mPFC - brain substrates known to provide the drive to induce neural activation in mPFC. Considering the above, this project will test the overarching hypothesis that OCIS of alcohol seeking is controlled by omission cue-activated excitatory neurotransmission and afferents driving distinct neural activation in mPFC.
Three Aims are proposed.
Aim 1 will focus on omission cue-activated neurons in mPFC.
Aim 2 will focus on omission cue-activated excitatory neurotransmission in mPFC.
Aim 3 will focus on omission cue-activated excitatory afferent inputs to mPFC. Collectively, the expected results will establish brain mechanisms that actively suppress - rather than promote - alcohol relapse, and therefore present new insights for blocking relapse.

Public Health Relevance

Alcohol dependence is a chronic relapsing disorder characterized by compulsive alcohol use. The purpose of this grant is to combine a novel behavioral paradigm and advanced molecular, neurochemical, neuropharmacological, as well as neuroanatomical techniques to determine brain mechanisms that actively suppress (as opposed to promote) alcohol relapse in dependent subjects (rats) undergoing withdrawal - conditions linked to a high relapse risk. Since the majority of drug addiction research has focused on factors that promote relapse, the expected results could provide novel insights into alcohol craving and relapse, and aid to improve relapse-suppression strategy.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Cui, Changhai
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Scripps Research Institute
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La Jolla
United States
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