Human alcoholics undergo major periods of relapse and compulsive alcohol seeking, where alcohol intake persists despite adverse economic, social, and physical consequences. Although compulsion represents a major clinical hurdle to treatment of alcoholism by promoting relapse and continued alcohol intake, virtually nothing is known about molecular and neuronal mechanisms that drive compulsive aspects of alcohol intake. Human studies suggest that compulsive behavior may be regulated by frontal cortical areas that send glutamatergic inputs to the nucleus accumbens core (NAcore), and NAcore glutamate receptor signaling is critical for the expression of many motivated, addictive, and perhaps habitual behaviors. The Insular cortex in particular is implicated in generating strong drives that promote addiction, at least for nicotine. Here, the major goal of this proposal is an exploratory set of rat experiments addressing whether a common molecular circuit (Insula inputs to the NAcore and activation of NAcore NMDA receptors) drives different forms of aversion-resistant ethanol intake, which may model some aspects of human compulsive alcohol intake. We hypothesize, based in part on extensive preliminary data, that this common molecular circuit promotes aversion-resistant ethanol intake regardless of intake model (drinking ethanol from a bottle, operant lever pressing for ethanol) or the sensory modality of the aversive stimulus paired with ethanol (taste for quinine, somatosensory for footshock). Thus, Specific Aim 1 uses state-of-the- art optogenetic techniques in vivo to examine whether inhibiting Insula-to-NAcore inputs similarly reduces ethanol intake during the different forms of aversion-resistant ethanol intake. In particular, we use halorhodopsin, a light-activated inhibitory protein than can be viraly expressed within a particular brain region to selectively modulate axon terminals. Also, our in vitro electrophysiology experiments find enhanced NMDAR function under Insula-to-NAcore inputs, and thus Specific Aim 2 examines whether pharmacological block of NMDARs within the NAcore also inhibits aversion-resistant ethanol intake with different intake models and different aversive stimuli paired with ethanol. We also examine whether Insula-NAcore inputs and NAcore NMDARs mediate intake when ethanol is not overtly paired with an aversive stimuli. Glutamatergic inputs to the NAcore likely play a central role in the expression of aversion-resistant alcohol intake, and our use of optogenetics in combination with intracranial pharmacology is likely to provide critical and therapeutically relevant information about molecular mechanisms underlying compulsive alcohol intake.

Public Health Relevance

The results of these experiments in animal models will provide critical new information about the brain regions and molecules that drive compulsive ethanol intake, where intake continues despite aversive consequences. Since compulsive intake is a major clinical hurdle in the treatment of alcoholism, our experiments investigating the molecular bases of aversion-resistant, compulsive ethanol intake will help identify novel therapeutic targets for the treatment of human alcoholism and other human diseases involving compulsion.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Biomedical Research Review Subcommittee (AA)
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Cui, Changhai
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Hopf, F W (2016) Do specific NMDA receptor subunits act as gateways for addictive behaviors? Genes Brain Behav :
Seif, Taban; Simms, Jeffrey A; Lei, Kelly et al. (2015) D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats. Neuropsychopharmacology 40:2357-67
Hopf, F Woodward; Lesscher, Heidi M B (2014) Rodent models for compulsive alcohol intake. Alcohol 48:253-64