Should either target ultimately prove to be untenable to pursue human studies, other systems under study by the TSRI-ARC may be viable, such as specific glutamate, serotonin, or hypocretin targets. Drugs selected for human study will either be FDA-approved for other indications or available for study under an IND. Mifepristone, a mixed GR/progesterone antagonist, showed efficacy in TSRI-ARC animal and human laboratory models of protracted abstinence, but mifepristone’s progesterone antagonism causes abortion and does not contribute to AUD efficacy. CORT122928, a “next generation” selective GR antagonist, has been proposed as the first drug for human study based on its performance in TSRI-ARC animal models and its superior side effect profile relative to the parent compound (i.e., no risk of abortion). MAP4343 is our lead compound to test microtubule assembly as a novel therapeutic strategy for AUD and has shown efficacy in TSRI-ARC models of AUD, as well as in animal models of depression and anxiety.(1) A highly standardized, reliable, and valid human laboratory model informing the three stages of the addiction cycle—withdrawal/negative affect, preoccupation/anticipation, and binge/intoxication—will serve as a screen of novel drugs for treating AUD.(2, 3) The predictive validity of our human lab model has been supported in studies of approved drugs (acamprosate, naltrexone) and novel drugs (gabapentin, mifepristone, pregabalin, and duloxetine), with human laboratory results converging with drinking outcomes of double-blind, placebo-controlled clinical trials ranging from 2 weeks to 1 year in duration.(4-9) Of particular relevance to this proposal, gabapentin was identified by TSRI-ARC electrophysiological studies and animal models(10) as having therapeutic potential for AUD, which was also found in our human lab model(5) and randomized controlled trial,(9) lending support to the translational methods proposed across TSRI-ARC components.​
 

Subjects for each study will be 50 non-treatment-seeking male and female paid volunteers meeting DSM-5 criteria for AUD of ≥ moderate severity (AUD-MS). Studies are randomized, double-blind, and placebocontrolled. The dosing duration is subchronic, at least 1 week, and based on drug pharmacokinetics, with 1 month of post-treatment follow-up. The primary endpoint is craving severity in response to in vivo alcohol cues presented in the laboratory, with secondary naturalistic measures of drinking, negative affect, craving, sleep, and executive function at baseline, during treatment, and 1-month post-treatment follow-up.