Although benzodiazepines (BZs) are considered to be among the safest prescription drugs in modern medicine, their utility is constrained by a number of side effects, including the liability for abuse, and recent epidemiological research suggests BZ abuse is on the rise in the U.S. The overall goal of this application is to investigate the extent to which GABAA receptor subtypes are differentially involved in self-administration vs. anxiolytic-like effects of BZ ligands, with the goal of developing medications to treat BZ addiction. This renewal application builds on our work from past project periods that has implicated unique roles for α1, α2, and α3 subunit-containing GABAA receptors (α1GABAA, α2GABAA, α3GABAA receptors, respectively) in the anxiolytic-like effects and abuse potential of BZs. The key findings from our work include: (1) compounds lacking efficacy at α1GABAA receptors and relatively low efficacy at α2GABAA/α3GABAA receptors may have reduced abuse potential compared with conventional BZs, but retain robust anxiolytic-like effects; and (2) antagonists that target α1GABAA, α2GABAA, and α3GABAA receptors, but not α5GABAA receptors, can block the reinforcing effects of BZs. In addition, we have obtained enough data and novel ligands to propose the development of pharmacotherapies for BZ addiction, i.e., medication-assisted treatment. Nevertheless, significant knowledge gaps remain before lead compounds can be selected and optimized. Using relevant nonhuman primate models, our proposed studies specifically will evaluate the hypotheses that (1) the anxiolytic-like effects of BZs are mediated by α2GABAA receptor subtypes; (2) intrinsic efficacy at α1GABAA receptor subtypes is a key determinant of the reinforcing effectiveness of BZ-type ligands; and (3) different levels of intrinsic efficacy at GABAA receptor subtypes determine the extent to which subtype-selective ligands alter the reinforcing effects of abused BZs. Anxiolytic activity will be evaluated in rhesus monkeys using conflict procedures in which food- maintained behavior is concurrently suppressed by response-produced presentations of an aversive stimulus. Abuse potential will be assessed using behavioral economics and progressive-ratio schedules, in conjunction with quantitative pharmacological analysis. Our approach to identifying receptor mechanisms and therapeutic strategies may have a profound and long-lasting impact on not just the scientific field, but also the treatment- provider community and, most importantly, the patients struggling with BZ addiction.