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Studies in Nonhuman Primates and Clinical Implications

Thomas R. Insel, MD; Philip T. Ninan, MD; Joseph Aloi; David C. Jimerson, MD; Phil Skolnick, PhD; Steven M. Paul, MD

Arch Gen Psychiatry. 1984;41(8):741-750.

Abstract
• β-Carboline-3-carboxylic acid ethyl ester (β-CCE) binds with high affinity to brain benzodiazepine receptors and has potent behavioral and physiologic effects in primates. Doserelated increases in behavioral agitation, plasma cortisol level, BP, and heart rate were observed after administration of doses between 50 and 500 µg/kg of β-CCE to rhesus monkeys. All of these effects were blocked by pretreatment with diazepam. Pretreatment with clonidine hydrochloride and propranolol hydrochloride, both of which have been reported to have anxiolytic actions in man, attenuated only selective aspects of the response to β-CCE. The behavioral, endocrine, and physiologic effects of low doses of β-CCE in monkeys are similar to those observed in anxious patients or normal subjects under anxiety-provoking or stressful situations. Administration of benzodiazepine receptor active antagonists such as β-CCE to primates may, therefore, provide a valid and reproducible model of human anxiety that could be used to investigate specific biologic aspects of anxiety disorders.

Author Affiliations
From the Clinical Neuropharmacology Branch (Dr Insel and Mr Aloi), the Laboratory of Clinical Science (Dr Jimerson), and the Clinical Neuroscience Branch (Dr Paul), National Institute of Mental Health; the Laboratory of Biorganic Chemistry (Dr Skolnick), National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, Bethesda, Md; and the Department of Psychiatry (Dr Ninan), Emory University and Veterans Administration Hospital, Atlanta.

Footnotes
Accepted for publication Dec 26, 1983.

Reprint requests to Clinical Neuropharmacology Branch, National Institutes of Health Clinical Center 10-3D 41, Bethesda, MD 20205 (Dr Insel).

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