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.
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