Drug and Alcohol Dependence 63 (2001) 39–49 Behavioral effects of flunitrazepam: reinforcing and discriminative stimulus effects in rhesus monkeys and prevention of withdrawal signs in pentobarbital-dependent rats Lisa R. Gerak a , William L. Woolverton b , Michael A. Nader c , Graham A. Patrick d , Louis S. Harris d , Gail Winger e , James H. Woods e , Charles P. France a, * a Department of Pharmacology, Louisiana State Uniersity Health Sciences Center, New Orleans, LA 70112, USA b Department of Psychiatry and Human Behaior, Uniersity of Mississippi Medical Center, Jackson, MS 39216, USA c Department of Physiology and Pharmacology, Wake Forest Uniersity School of Medicine, Winston -Salem, NC 27157, USA d Department of Pharmacology and Toxicology, Virginia Commonwealth Uniersity, Medical College of Virginia, Richmond, VA 23298, USA e Departments of Pharmacology and Psychology, Uniersity of Michigan, Ann Arbor, MI 48109, USA Received 13 September 1999; received in revised form 18 July 2000; accepted 25 July 2000 Abstract Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABA A modulators. One group of monkeys (n =3) responded to receive injections of methohexital or saline (i.v.) while other groups (n =2–4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n =2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n =3–6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Flunitrazepam; Drug discrimination; Self-administration; Rhesus monkey; Pentobarbital-dependent rats www.elsevier.com/locate/drugalcdep 1. Introduction In many countries, flunitrazepam is widely used to treat sleep disorders, although it has never been mar- keted in the United States. It appears to be a potent, highly efficacious positive modulator of -aminobu- tyric acid (GABA) at the GABA A receptor complex with a pharmacology similar to other benzodiazepines (Woods and Winger, 1997). Except for pharmacoki- netic variations, few differences have been observed between flunitrazepam and other benzodiazepines (Woods and Winger, 1997). However, in spite of the similarities in the pharmacologic profile among benzo- diazepines, their abuse liability appears to vary markedly at least in some populations, such as those with a history of drug abuse. For example, reports from several countries suggest that many opioid abusers also use benzodiazepines illicitly and often prefer flunitrazepam to other benzodiazepines (Barnas et al., 1992; Darke et al., 1995; Gelkopf et al., 1999; San et al., 1993). In addition, other studies have sug- gested a difference between flunitrazepam and triazo- lam. For example, in patients maintained on the long-acting opioid methadone, flunitrazepam produces * Corresponding author. Department of Pharmacology. University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. Tel.: +1-210-5676969; fax: +1-210-5670104. E-mail address: france@uthscsa.edu (C.P. France). 0376-8716/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0376-8716(00)00189-7