Benzodiazepines (BZs) are prescribed widely for the treatment of anxiety and sleep disorders. Although 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 dependence, 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 the anxiolytic effects, self-administration, and physical dependence associated with BZ ligands, using relevant nonhuman primate models. Ligands with selectivity for different BZ-sensitive receptors (i.e., 11GABAA, 12GABAA, 13GABAA, and 15GABAA subtypes) will be used as pharmacological probes to determine the role of these receptors in the behavioral effects of 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. Reinforcing effects will be evaluated using progressive-ratio schedules of i.v. drug self-administration. Physical dependence and tolerance following chronic BZ treatment will be measured using quantitative observation techniques. For all procedures, systematic antagonism studies will be used to dissociate effects due to specific GABAA receptor subtypes. Identification of compounds that are effective anxiolytics lacking abuse and dependence potential in our studies will provide fundamental information for developing safer and more broadly effective anti-anxiety medications, as well as compounds that may be beneficial in the pharmacological management of BZ dependence.

Public Health Relevance

Valium and related drugs, referred to as benzodiazepines are prescribed widely for the treatment of anxiety and sleep disorders, two of the most common psychiatric disorders in the U.S. Benzodiazepines are considered to be among the safest prescription drugs in modern medicine, but they unfortunately are also drugs of abuse. The overall goal of this application is to uncover brain mechanisms that control the beneficial effects as well as the abuse of benzodiazepines, with the hope of developing safer drugs for treating anxiety and sleep disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BBBP-C (02))
Program Officer
Lynch, Minda
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Medicine
United States
Zip Code
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
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
Makaron, Leah; Moran, Casey A; Namjoshi, Ojas et al. (2013) Cognition-impairing effects of benzodiazepine-type drugs: role of GABAA receptor subtypes in an executive function task in rhesus monkeys. Pharmacol Biochem Behav 104:62-8
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
Ruedi-Bettschen, Daniela; Rowlett, James K; Rallapalli, Sundari et al. (2013) Modulation of *5 subunit-containing GABAA receptors alters alcohol drinking by rhesus monkeys. Alcohol Clin Exp Res 37:624-34
Fischer, Bradford D; Teixeira, Laura P; van Linn, Michael L et al. (2013) Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation. Psychopharmacology (Berl) 227:347-54
Fischer, Bradford D; Atack, John R; Platt, Donna M et al. (2011) Contribution of GABA(A) receptors containing ýý3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys. Psychopharmacology (Berl) 215:311-9
Licata, Stephanie C; Rowlett, James K (2011) Self-administration of bretazenil under progressive-ratio schedules: behavioral economic analysis of the role intrinsic efficacy plays in the reinforcing effects of benzodiazepines. Drug Alcohol Depend 113:157-64
Rowlett, James K; Kehne, John H; Sprenger, Ken J et al. (2011) Emergence of anti-conflict effects of zolpidem in rhesus monkeys following extended post-injection intervals. Psychopharmacology (Berl) 214:855-62
Fischer, Bradford D; Rowlett, James K (2011) Anticonflict and reinforcing effects of triazolam + pregnanolone combinations in rhesus monkeys. J Pharmacol Exp Ther 337:805-11

Showing the most recent 10 out of 38 publications