Neurosteroid-BZ combinations: Strategy for reducing abuse and sedation

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DESCRIPTION (provided by applicant): Benzodiazepines (BZs) are prescribed widely as anxiolytics, hypnotics, muscle relaxants, and anticonvulsants. Although BZs are among the safest psychoactive drugs in modern medicine, their utility is often limited by unwanted side effects such as abuse liability and sedative-motor effects. The overall goal of this application is to determine quantitatively the extent to which combining a BZ with another type of GABAA modulator, a neuroactive steroid, results in enhanced anxiolytic-like effects but not enhanced unwanted side-effects. Specific Aim 1 will evaluate the hypothesis that neuroactive steroids that act at GABAA receptors will enhance the anxiolytic-like effects of BZ-type drugs in a supra-additive manner. Conventional BZs produce characteristic increases in operant behavior that are suppressed by aversive stimuli, i.e., induce "anti-conflict" effects. Using a rhesus monkey conflict procedure, we will evaluate the anxiolytic-like effects of conventional BZs (e.g., clonazepam), alone or in combination with neuroactive steroids (e.g., ganaxolone, pregnanolone). Specific Aim 2 will evaluate the hypothesis that neuroactive steroids that act at GABAA receptors will alter the self-administration of BZ-type drugs in an infra-additive manner. These studies will employ a progressive-ratio (PR) schedule of intravenous drug injection to examine the reinforcing effectiveness of BZs, either alone or in combination with neuroactive steroids. Specific Aim 3 will initiate investigation of the combined effects of neuroactive steroid and BZ-type drugs in a novel observation procedure that distinguishes different levels of sedation and motor function. We will use observational procedures recently developed in our laboratory that dissociate ataxia-like effects, sleep/rest-associated postures, moderate and deep sedation. In all studies, mechanism of action will be assessed by testing receptor subtype-specific GABAA compounds. All combination data will be evaluated with isobolographic/dose-addition analysis in order to determine if effects of drug combinations are additive, supra-additive, or infra-additive. Finally, we will conduct targeted studies with female monkeys to begin to investigate the role of the menstrual cycle in mediating the sedative-motor effects of BZs, based on the observation that endogenous neuroactive steroid levels increase with the progesterone surge during the luteal phase. This pilot study should provide a springboard for evaluating sex as a factor in BZ and neuroactive steroid pharmacology in future applications. The ultimate goal for this research program is to provide critical preclinical information for development of a broadly effective combination product with an improved side effect profile for treating anxiety disorders.