Endocannabinoid modulation of affective signs of cannabinoid withdrawal

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DESCRIPTION (provided by applicant): Cannabis is universally the most commonly abused illicit drug. Recent legal changes reflect a societal acceptance of cannabis as a "soft drug" with relatively mild withdrawal symptoms, as compared with opioids and other drugs of abuse. However, as recently recognized by the DSM-V, Cannabis Use Disorder and Cannabis Withdrawal Syndrome affect many users, the primary symptoms being increased anxiety, agitation, and cravings for cannabis. Not surprisingly, alleviating the aversive symptoms brought about by abstinence is common cause of relapse. Thus, there is a need to develop new treatments for cannabis dependence. The goal of the proposed studies is to inform clinical treatments for cannabinoid dependence in humans. Current preclinical research on cannabis dependence uses somatic outcomes to quantify cannabis withdrawal. Although these models have been very useful, they do not explore the emotional aspects of cannabis withdrawal that are most salient in humans and contribute directly to relapse. Our preliminary data indicate that withdrawal from �tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, increases preference for the dark portion of the light/dark box and decreases marble burying, a proxy measure of digging. The goal of Aim 1 is to fully characterize these changes in emotionality. We will treat mice repeatedly with THC, and then precipitate withdrawal with the cannabinoid receptor antagonist rimonabant, to elicit and quantify withdrawal behaviors in a battery of tests well known to respond to anti-anxiety drugs. In addition to behavioral interventions, adjuvant therapies have been used with much success to reduce drug dependence. The goal of Aim 2 of the proposed studies is to normalize THC withdrawal-induced behavioral changes by blocking the metabolism of endogenous cannabinoids. The two endocannabinoids are anandamide, which is primarily metabolized in vivo by fatty acid amide hydrolase (FAAH) and 2-arachidonoylethanolamine, which is mainly metabolized by the enzyme monoacylglycerol lipase (MAGL). We propose to selective inhibit FAAH or MAGL in mice undergoing THC withdrawal, and to test alterations in behavioral assays that our unpublished preliminary data indicate are altered by THC withdrawal. It is expected that inhibition of FAAH or MAGL will attenuate THC-withdrawal induced behavioral changes, without any effect on general activity. The successful completion of the proposed project is expected to yield preliminary data for larger scale neural/behavioral project, the goal of which will be to inform cannabinoid dependence research in humans.