The physical dependence potential of benzodiazepines is well established and continues to be an important undesirable effect of this class of therapeutics. Because benzodiazepines and related compounds continue to be used widely in medicine, there is a considerable need for preclinical evaluation of the dependence and abuse potential of these compounds. The current application proposes to study the discriminative stimulus effects of benzodiazepine dependence and withdrawal in rhesus monkeys treated daily with chlordiazepoxide (CDP) while responding under a multiple schedule of food presentation and stimulus-shock termination (SST) and discriminating between i.m. injections of vehicle and the benzodiazepine antagonist flumazenil. The primary goal of the proposed studies is to develop a drug discrimination model of benzodiazepine dependence in non-human primates and the use this procedure to evaluate basic issues regarding receptor mediation and efficacy of benzodiazepines and related compounds. After stimulus control is established between flumazenil and vehicle in CDP- treated monkeys, the subjects will be divided in to two groups of four: one group will be used to study the discriminative stimulus effects of terminating CDP treatment (e.g., withdrawal) as well as the ability of compounds to reverse any effects observed upon termination of CDP treatment; a second group will be used to characterize in detail the discriminative stimulus effects of flumazenil and other compounds in CDP-treated monkeys. In both groups, compounds will be assessed not only for their behavioral effects when administered alone, but also in studies where two compounds are administered together; the latter studies will address issues regarding the nature of drug action at receptors (e.g., is the interaction simple, competitive antagonism?) as well as differences in efficacy among compounds. In a collaborative project with Dr. T. Cicero, endocrine function will also be monitored in rhesus monkeys that are receiving CDP daily and in monkeys undergoing acute episodes of abstinence- or antagonist-induced withdrawal. A third group of four monkeys will be trained to discriminate between flumazenil and vehicle under conditions that are identical to conditions that are used in the CDP-treated monkeys, although this group will not be treated chronically with drug. A second and smaller component of the proposed studies involves utilization of the flumazenil discrimination in CDP-treated monkeys as a drug evaluation assay, under the auspices of the College on Problems of Drug Dependence and as part of a larger collaborative effort designed to characterize the dependence and abuse potential of benzodiazepines and pharmacologically-related compounds. These studies will develop the first non-human primate model of benzodiazepine dependence that utilizes drug discrimination procedures and, thereby, will serve as a pharmacological bridge to provide fundamental information on the mechanism of action of anxiolytics.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (SRCD (29))
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Schnur, Paul
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Louisiana State University Hsc New Orleans
Schools of Medicine
New Orleans
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Gerak, Lisa R; France, Charles P (2014) Discriminative stimulus effects of pregnanolone in rhesus monkeys. Psychopharmacology (Berl) 231:181-90
Zanettini, Claudio; France, Charles P; Gerak, Lisa R (2014) Quantitative pharmacological analyses of the interaction between flumazenil and midazolam in monkeys discriminating midazolam: Determination of the functional half life of flumazenil. Eur J Pharmacol 723:405-9
Zanettini, Claudio; Yoon, Seong Shoon; France, Charles P et al. (2013) Acute tolerance to chlordiazepoxide qualitatively changes the interaction between flumazenil and pregnanolone and not the interaction between flumazenil and midazolam in rhesus monkeys discriminating midazolam. Eur J Pharmacol 700:159-64
Gerak, Lisa R; France, Charles P (2012) Quantitative analyses of antagonism: combinations of midazolam and either flunitrazepam or pregnanolone in rhesus monkeys discriminating midazolam. J Pharmacol Exp Ther 340:742-9
Gerak, Lisa R; France, Charles P (2011) Chronic benzodiazepine treatment does not alter interactions between positive GABA(A) modulators and flumazenil or pentylenetetrazole in monkeys. Behav Pharmacol 22:49-57
Bai, Xiang; France, Charles P; Gerak, Lisa R (2011) The discriminative stimulus effects of midazolam are resistant to modulation by morphine, amphetamine, dizocilpine, and ýý-butyrolactone in rhesus monkeys. Psychopharmacology (Berl) 217:495-504
Li, Jun-Xu; McMahon, Lance R; Gerak, Lisa R et al. (2008) Interactions between Delta(9)-tetrahydrocannabinol and mu opioid receptor agonists in rhesus monkeys: discrimination and antinociception. Psychopharmacology (Berl) 199:199-208
Gerak, Lisa R; McMahon, Lance R; France, Charles P (2008) Acute cross tolerance to midazolam, and not pentobarbital and pregnanolone, after a single dose of chlordiazepoxide in monkeys discriminating midazolam. Behav Pharmacol 19:796-804
McMahon, Lance R; Javors, Martin A; France, Charles P (2007) Changes in relative potency among positive GABA(A) receptor modulators upon discontinuation of chronic benzodiazepine treatment in rhesus monkeys. Psychopharmacology (Berl) 192:135-45
McMahon, Lance R; Gerak, Lisa R; France, Charles P (2006) Efficacy and the discriminative stimulus effects of negative GABAA modulators, or inverse agonists, in diazepam-treated rhesus monkeys. J Pharmacol Exp Ther 318:907-13

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