Pergamon Pharmacology Biochemistry and Ikhavior, Voi. 48, No. 1, pp. 69-76, 1994 Copyright e 1994 ElsevierScience Ltd Printed in the USA. All rights reserved 0091-3057/94 $6.00 + .00 0091.3057(93)E0005-O Acute Effects of Benzodiazepines on Operant Behavior and In Vivo Receptor Binding in Mice TIMOTHY F. BURKE, l LAWRENCE G. MILLER 2 AND JOSEPH M. MOERSCHBAECHER 3 Department of Pharmacology, Louisiana State University Medical Center, New Orleans, LA 70112-1393 Received 28 May 1993 BURKE, T. F., L. G. MILLER AND J. M. MOERSCHBAECHER. Acute effects of benzodiazepines on operant be- havior and in vivo receptor binding in mice. PHARMACOL BIOCHEM BEHAV 48(1) 69-76, 1994.-Lorazepam and alprazolam produced dose-dependent decreases in the rate of fixed-ratio (FR) 20 schedules of food presentation in which either a nose-poke or a lever-press defined the operant and under a fixed-interval (FI) 2-min lever-press schedule of food presentation. In contrast, under FI 2-min and differential reinforcement of low response rate (DRL) 20-s schedules of nose-poke responding for food, intermediate doses of alprazolam produced increases in response rate. Lorazepam, however, only decreased overall response rates under the FI schedule and produced some increases in responding under the DRL schedule. Acute in vivo benzodiazepine receptor binding experiments showed that low to intermediate doses of alprazolam produced significant increases in the binding of [3H]flumazenil in all brain areas tested, while lorazepam produced increases in the brain stem only. The acute effects on binding produced by both drugs were positively and significantlycorrelated with their acute effects on response rate only under the FR lever-press procedure. These results indicate that the effects of benzodiazepines on in vivo binding may be related to their effects on FR lever-pressresponding. Alprazolam Benzodiazepines Differential reinforcement of low response rate Fixed-interval Flumazenil GABAA-benzodiazepine receptor complex In vivo binding Lorazepam Mice Operant behavior Fixed-ratio THE benzodiazepines represent one of the most frequently prescribed drug classes in the world. This widespread use is due in large part to their broad range of properties, which include anxiolytic, anticonvulsant, sedative, and muscle relax- ant effects 05). These effects are presumed to be mediated primarily by a specific central benzodiazepine receptor which is associated in a macromolecular complex with the recogni- tion site for 3,-aminobutyric acid (GABA) and a chloride ion channel. Benzodiazepines also have well-characterized effects on schedule-controlled behavior. In rats, it has been found that benzodiazepines produce dose-dependent decreases in re- sponse rates under schedules of reinforcement controlling high rates of responding, such as fLxed-ratio (FR) schedules (27). However, under schedules that engender relatively low re- sponse rates, such as fixed-interval (FI) or differential rein- forcement of low response rate (DRL) schedules, benzodiaze- pines often produce either no change or increases in response rate at lower doses and then decrease response rates at higher doses (2,27). These results indicate that benzodiazepines exert rate-dependent effects upon schedule-controlled behavior in a manner similar to those previously described for stimulants such as amphetamine (6). One goal of the present study was to begin to extend the characterization of the effects of benzo- diazepines on schedule-controlled behavior to the mouse. A number of studies have attempted to correlate the behav- Present address: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48209-0626. 2 Present address: Division of Clinical Pharmacology, Departments of Psychiatry and Pharmacology, Tufts University School of Medicine and New England Medical Center, Boston, MA 02111. 3 To whom requests for reprints should be addressed. 69