Harvard Department Of PsychiatryHarvard Medical School

NONHUMAN PRIMATE MODELS OF ADDICTION AND ANXIETY DISORDERS: PHARMACOLOGICAL BASIS AND MEDICATIONS DEVELOPMENT

New England Regional Primate Research Center

James K. Rowlett, Ph.D., Roger D. Spealman, Ph.D.

Benzodiazepines (BZs) are widely prescribed for the management of anxiety disorders, but their usefulness is constrained by a significant potential for abuse and dependence. Our research is focused on elucidating the mechanisms of action underlying the behavioral effects of BZs and related drugs, with the goal of increasing clinical utility and reducing abuse liability. Our research specifically evaluates the role of BZ receptor selectivity and intrinsic efficacy as determinants of the therapeutic vs. abuse-related effects of this important class of drugs. BZ ligands differing in receptor selectivity and/or agonist efficacy are used as probes to characterize mechanisms of action in nonhuman primate models predictive of anxiolytic activity, subjective effects, and abuse liability. Anxiolytic activity is evaluated in monkeys using conflict procedures in which food-maintained behavior is concurrently suppressed by response-produced presentations of an aversive stimulus. Subjective effects are assessed in monkeys trained to discriminate the convential BZ agonist triazolam or zolpidem, a GABAA/ 1 receptor-preferring agonist, from vehicle. Abuse potential is evaluated using i.v. drug self-administration procedures. Identification of compounds that are effective anxiolytics lacking abuse potential in our studies will provide needed 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.

Key Words: Anxiety disorders, drug addiction, nonhuman primate models, benzodiazepines, medications development, receptor subtypes

Grant Support: NIDA: DA11792, Anxiolytic Effects and Abuse of BZ Receptor Ligands

NIDA: DA13591, Nonhuman Primate Model of Benzodiazepine Relapse

Project Sites: Division of Behavioral Biology, New England Regional Primate Research Center.

Project Director: J. K. Rowlett, Ph.D., Assistant Professor of Psychobiology in the Department of Psychiatry, Division of Behavioral Biology, New England Regional Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough, MA 01772-9102

Contact Person: Margaret Duggan, (508) 624-8034; FAX: (508) 624-8197

Training Opportunities: Three postdoctoral fellows currently receive training in our programs; additional positions are available. The New England Regional Primate Research Center maintains an active seminar training program for prebaccalaureate students.

Representative Publications:

Rowlett, J. K., Spealman, R. D. and Lelas, S.: Discriminative stimulus effects of zolpidem in squirrel monkeys: comparison with conventional benzodiazepines and sedative-hypnotics. Journal of Pharmacology and Experimental Therapeutics, 291: 1233-1241, 1999.

Lelas, S., Spealman, R. D. and Rowlett, J. K.: Using behavior to elucidate receptor mechanisms: a review of the discriminative stimulus effects of benzodiazepines. Exp. Clin. Psychopharmacol., 8: 294-311, 2000.

Rowlett, J. K., Lelas, S. and Spealman, R. D.: Transduction of the discriminative stimulus effects of zolpidem by GABAA/ 1 receptors. Eur. J. Pharmacol., 406:R9-R10, 2000.

Lelas, S., Rowlett, J. K. and Spealman, R.D.: Triazolam discrimination in squirrel monkeys distinguishes high-efficacy agonists from other benzodiazepines and non-benzodiazepine drugs. Psychopharmacology, 154: 96-104, 2001.

Rowlett, J. K., Tornatzky, W., Cook, J. M., Ma C. and Miczek, K. A.: Zolpidem, triazolam, and diazepam decrease distress vocalizations in mouse pups: Differential antagonism by flumazenil and -carboline-3-carboxylate-t-butyl ester ( -CCt). J. Pharmacol. Exp. Ther., 297: 247-253, 2001.

Rowlett, J. K. and Woolverton, W. L.: Discriminative stimulus effects of panadiplon (U-78875), a partial agonist at the benzodiazepine site, in pentobarbital-trained rhesus monkeys. Drug Alcohol Depend., 61: 229-236, 2001.

 

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