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.

Public Health Relevance

Benzodiazepines (i.e., Valium-like drugs) are remarkably effective in treating anxiety and sleep disorders, but a major problem with these drugs are side effects, including significant abuse liability. In fact, the abuse of benzodiazepines appears to be on the rise in the US, making the need for improving the side effect profile of these drugs a clear priority. Our research program will examine a novel approach to reducing benzodiazepine abuse: We are exploring a novel combination product, consisting of a benzodiazepine and another type of drug referred to as a neuroactive steroid that in preliminary studies showed enhanced anxiety-reducing effects and virtually no enhancement of abuse potential.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA033795-04
Application #
8637969
Study Section
Special Emphasis Panel (ZRG1-BBBP-J (04))
Program Officer
Singh, Hari
Project Start
2012-06-15
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$422,273
Indirect Cost
$145,373
Name
University of Mississippi Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Huskinson, Sally L; Naylor, Jennifer E; Rowlett, James K et al. (2014) Predicting abuse potential of stimulants and other dopaminergic drugs: overview and recommendations. Neuropharmacology 87:66-80
Shinday, Nina M; Sawyer, Eileen K; Fischer, Bradford D et al. (2013) Reinforcing effects of compounds lacking intrinsic efficacy at *1 subunit-containing GABAA receptor subtypes in midazolam- but not cocaine-experienced rhesus monkeys. Neuropsychopharmacology 38:1006-14
Namjoshi, Ojas A; Wang, Zhi-jian; Rallapalli, Sundari K et al. (2013) Search for *3*ýýý/ýýýýý2 subtype selective ligands that are stable on human liver microsomes. Bioorg Med Chem 21:93-101