Pharmacology Biochemistry and Behavior, Vol. 59, No. 4, pp. 925–934, 1998 © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/98 $19.00 + .00 PII S0091-3057(97)00539-X 925 Benzodiazepine Dependence: From Neural Circuits to Gene Expression JUDITH A. PRATT, ROS R. BRETT 1 AND DAVID J. LAURIE 2 Department of Physiology and Pharmacology, University of Strathclyde, Glasgow G1 1XW, Scotland, UK Received 17 July 1997; Revised 9 October 1997; Accepted 9 October 1997 PRATT, J. A., R. R. BRETT AND D. J. LAURIE. Benzodiazepine dependence: From neural circuits to gene expres- sion. PHARMACOL BIOCHEM BEHAV 59(4) 925–934, 1998.—The neural mechanisms underlying benzodiazepine de- pendence remain equivocal. The present studies tested the hypothesis that similar neural systems are recruited during diaz- epam tolerance and withdrawal, and that these are associated with changes in GABA A receptor properties. 2-Deoxyglucose quantitative autoradiography was employed to map the brain structures affected during chronic treatment and withdrawal from diazepam (5 mg/kg IP daily) in rats. Acute administration of diazepam evoked widespread reductions in local rates of cerebral glucose (LCGU) utilization throughout the brain. Brain structures associated with sensory processing developed tol- erance to these depressant effects of diazepam after 3 days of treatment, whereas tolerance occurred in the Papez circuit of emotion after 28 days of treatment. These data suggest that adaptive changes in different neuroanatomical circuits may un- derlie tolerance to the various effects of diazepam. During flumazenil-precipitated withdrawal from diazepam there were marked increases in glucose use in structures of the Papez circuit, the nucleus accumbens, and the basolateral amygdala. These data suggest that the Papez circuit features strongly in diazepam tolerance and withdrawal and supports a common adaptive process being involved in these phenomena. While GABA enhancement of benzodiazepine binding was reduced in the nucleus accumbens after repeated diazepam treatment, there was little evidence to support adapative changes in GABA A receptors or GABA A subunit gene expression ( 2 ,  1 , or  4 ) as underlying the functional changes in the identified circuits. Al- ternative neurochemical mechanisms, such as changes in glutamatergic function should be considered. © 1998 Elsevier Sci- ence Inc. Benzodiazepine Tolerance Withdrawal Dependence Diazepam Rat GABA A receptor Autoradiography 2-Deoxyglucose autoradiography Gene expression Papez circuit Requests for reprints should be addressed to Dr. J. A. Pratt, Department of Physiology and Pharmacology, University of Strathclyde, Glasgow Gl lXW, Scotland. 1 Present address: Department of Biological Sciences, University of Paisley, Paisley, PA1 2BE. 2 Present address: Sandoz AG, CH 4002, Basle 61, Switzerland. BENZODIAZEPINES are commonly prescribed for the treatment of anxiety and sleep disorders. However, prolonged treatment can lead to dependence with a recognized with- drawal syndrome (17). In addition, tolerance occurs at differ- ent rates to different aspects of benzodiazepine action. Toler- ance to the sedative effects occurs rapidly, followed by tolerance to the anticonvulsant actions, and last, but less clearly, tolerance to anxiolysis (4,24). One hypothesis to explain the processes underlying diaz- epam tolerance and withdrawal is that chronic drug treatment leads to adaptive processes that counter the effects of the drug at the GABA A receptor and that these processes persist after the drug has been cleared from the brain, thereby leaving the opposing processes unopposed and the resultant emergence of withdrawal symptoms. Indeed, many studies have focussed on investigating changes at the level of the GABA A receptor after chronic benzodiazepine treatment. Results from in vitro approaches have in general found support for the view that changes in the GABA A receptor occur after continuous drug exposure to cells in culture (5). However, the results from ex vivo ap- proaches have been less convincing. For example, radioligand binding studies have shown no change, downregulation, or even upregulation of benzodiazepine binding (7). In general, downregulation appears to occur when large doses of benzo- diazepines are administered chronically (28). There is some