Benzodiazepines and related gamma-amino butyric acid (GABA)A modulators are used widely for their anxiolytic, hypnotic and anti- convulsant effects. These same compounds are also abused, both alone and in combination with other classes of drugs (e.g., opioids), and long- term use of benzodiazepines can lead to clinically significant physical dependence. The GABAA receptor complex is the site of action of other drugs of abuse (e.g., ethanol) and GABAergic systems, in general, are thought to indirectly modulate the effects of still other drugs of abuse (e.g., cocaine). Much has been learned over the past 10 years from molecular studies on GABA receptors, yet little of this knowledge has been applied to studies in behaving organisms, particularly with regard to GABA neurobiology and substance abuse. Procedures have been developed under this grant for studying discriminative stimulus effects of GABAA modulators in rhesus monkeys and studies proposed in this application will use those procedures to investigate the neurobiology of drugs that vary in their actions on GABAergic systems. Studies under Aim 1ill will compare GABAergic and other drugs for their ability to prevent and reverse benzodiazepine withdrawal and also to mimic the subjective (discriminative) effects of benzodiazepine in normal subjects. A parallel study (Aim II) will establish a discrimination with flumazenil in monkeys treated daily with the a1-s3lective positive modulator zolpidem to test whether this widely-prescribed sedative/hypnotic produces dependence that can be differentiated from that produced by diazepam.Neuroactive steroids will be studied under Aim III to see whether th eye modify the behavioral effects of other compounds that act at the GABAA receptor complex. This study is founded on positive preliminary data with pregnanolone and a literature showing that neuroactive steroids uncouple benzodiazepine receptors from the GABAA receptor complex in vitro. Blind evaluation of compounds will continue the auspices of the Drug Evaluation Committee of the College on Drug Dependence under Aim IV. Collectively, these studies will provide important quantitative information on the nature of drug/receptor and drug/drug interactions for GABAA modulators and related drugs. These data will promote an understanding of GABAergic neurotransmission and abuse liability for a variety of clinically relevant compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009157-12
Application #
7027082
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (03))
Program Officer
Aigner, Thomas G
Project Start
1995-03-15
Project End
2008-01-31
Budget Start
2006-04-01
Budget End
2008-01-31
Support Year
12
Fiscal Year
2006
Total Cost
$285,138
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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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