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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011792-14
Application #
8266447
Study Section
Special Emphasis Panel (ZRG1-BBBP-C (02))
Program Officer
Thomas, David A
Project Start
1998-06-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
14
Fiscal Year
2012
Total Cost
$333,224
Indirect Cost
$141,164
Name
Harvard University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Duke, Angela N; Meng, Zhiqiang; Platt, Donna M et al. (2018) Evidence That Sedative Effects of Benzodiazepines Involve Unexpected GABAA Receptor Subtypes: Quantitative Observation Studies in Rhesus Monkeys. J Pharmacol Exp Ther 366:145-157
Huskinson, S L; Naylor, J E; Townsend, E A et al. (2017) Self-administration and behavioral economics of second-generation synthetic cathinones in male rats. Psychopharmacology (Berl) 234:589-598
Townsend, E Andrew; Platt, Donna M; Rowlett, James K et al. (2017) Reinforcing effectiveness of midazolam, ethanol, and sucrose: behavioral economic comparison of a mixture relative to its component solutions. Behav Pharmacol 28:386-393
Huskinson, S L; Freeman, K B; Petry, N M et al. (2017) Choice between variable and fixed cocaine injections in male rhesus monkeys. Psychopharmacology (Berl) 234:2353-2364
Chandler, Cassie M; Follett, Meagan E; Porter, Nicholas J et al. (2017) Persistent negative effects of alcohol drinking on aspects of novelty-directed behavior in male rhesus macaques. Alcohol 63:19-26
Gunter, Barak W; Jones, Sherman A; Paul, Ian A et al. (2016) Benzodiazepine and neuroactive steroid combinations in rats: anxiolytic-like and discriminative stimulus effects. Psychopharmacology (Berl) 233:3237-47
Meng, Zhiqiang; Rowlett, James K (2016) Self-administration of progesterone and synthetic neuroactive steroids by male rhesus monkeys. Drug Alcohol Depend 165:265-9
Fischer, Bradford D; Platt, Donna M; Rallapalli, Sundari K et al. (2016) Antagonism of triazolam self-administration in rhesus monkeys responding under a progressive-ratio schedule: In vivo apparent pA2 analysis. Drug Alcohol Depend 158:22-9
Gunter, Barak W; Platt, Donna M; Rowlett, James K (2015) Differential interactions engendered by benzodiazepine and neuroactive steroid combinations on schedule-controlled responding in rats. Pharmacol Biochem Behav 137:53-9
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

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