Benzodiazepines are among a growing set of compounds that exert many of their effects by actions at the gamma-amino butyric acid (GABA)A receptor complex. Benzodiazepines are widely used for hypnosis and for anxiety-related disorders; however, long term use of these drugs can generate clinically-significant physical dependence. Moreover, there is increasing evidence for the co-abuse of benzodiazepines and other psychoactive drugs especially among individuals with a history of alcohol or sedative/hypnotic abuse. One major goal of this project is to develop a procedure for studying the discriminative stimulus (subjective) effects of benzodiazepine dependence and withdrawal in rhesus monkeys and, during the last period of support, such a procedure was developed. In the continuation of this project, separate groups of diazepam-treated, zolpidem-treated and untreated monkeys will be used to investigate three general issues using measures of drug discrimination, ventilation and neuroendocrine activity. First, GABAA modulators will be used to test hypotheses regarding selectivity of drug action and variations in efficacy. Although much is known about the molecular actions of GABAA modulators in vitro, very little is known about the clinical ramifications of those findings. These studies will provide a bridge from molecular studies to clinical applications by using a non-human primate model of subjective drug effects and physical dependence. Second, these experiments will expand the conditions under which discrimination procedures can be used to study dependence by establishing a flumazenil discrimination in monkeys receiving the novel GABAA modulator zolpidem, a drug that is widely prescribed for hypnosis. Third, """"""""blind' drug evaluations will be conducted under the auspices of the CPDD. Collectively, these studies will provide fundamentally new information on the in vivo pharmacology of GABAA modulators and will help to identify the pharmacologic and behavioral determinants of physical dependence on sedative hypnotics.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-1 (01))
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Schnur, Paul
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University of Texas Health Science Center San Antonio
Schools of Medicine
San Antonio
United States
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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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