Pharmacology Biochemistry & Behavior, Vol. 24, pp. 93-98, 1986. :~'Ankho International Inc. Printed in the U.S.A. 0091-3057/86 $3.00 + .00 Tolerance to and Cross-Tolerance Among Ethanol, Pentobarbital and Chlordiazepoxide A. D. LI~, 1 J. M. KHANNA, H. KALANT AND F. GROSSI Department of Pharmacology, University of Toronto, Toronto, Canada M5S IA8 and Addiction Research Foundation of Ontario, Toronto, Canada M5S 2S1 Received 6 March 1985 LI~, A. D., J. M. KHANNA, H. KALANT AND F. GROSSI. Tolerance to and cross-tolerance among, ethanol, pentobar- bital and chlordiazepoxide. PHARMACOL BIOCHEM BEHAV 24(1) 93-98, 1986.--The acute administration of ethanol, pentobarbital and chlordiazepoxide impaired, in a dose-dependent manner, the performance of rats on the moving-belt and two-way shuttle-box avoidance tests. Administration of these drugs for three weeks resulted in tolerance to their motor-impairing effects. Tolerance to ethanol or pentobarbital was characterized by a parallel shift of the dose- response curve to the right. Tolerance to chlordiazepoxide, however, was of greater extent and was accompanied by an apparent flattening of the dose-response curve. Symmetrical cross-tolerance developed between ethanol and pentobarbital. On the other hand, while chlordiazepoxide treatment conferred full cross-tolerance to ethanol and pentobarbital, only partial cross-tolerance to chlordiazepoxide was observed following treatment with ethanol or pentobarbital. These results suggest that at least part of the tolerance to chlordiazepoxide depends on changes in specific benzodiazepine receptors and is independent of the tolerance associated with non-specific changes in the cell membrane. Tolerance Ethanol Pentobarbital Chlordiazepoxide THE acute administration of benzodiazepines produces a general depressant effect on the central nervous system [13], and tolerance to this effect has been reported to occur fol- lowing chronic administration [14,34]. Clinical observations have indicated that the drowsiness occurring during the ini- tiation of diazepam treatment disappears after a few days of chronic treatment, despite a higher blood level of diazepam and its metabolite as a consequence of accumulation in the body [14]. Animal studies have revealed a similar phenom- enon. In a conflict behavior paradigm which employs the unpunished bar-pressing response as the dependent measure for the depressant effect, tolerance to a variety of ben- zodiazepines has been demonstrated following chronic treatment [3, 27, 29, 40]. In addition, tolerance has also been shown to occur to the depression of locomotor activity by these drugs [6, 7, 11] and to their ataxic effect [4, 35, 36]. Despite these demonstrations of tolerance to the depressant effect of benzodiazepines, it is still difficult to draw any gen- eral conclusion regarding the nature or extent of the tolerance, since limited doses and test systems were em- ployed in the studies cited. Besides their use in the treatment of anxiety, ben- zodiazepines, particularly diazepam and chlordiazepoxide, have been used quite extensively in the management of ethanol withdrawal reactions [39,46] and are known to be co-abused with other drugs [34]. Nevertheless, it is clear that benzodiazepines differ from ethanol and other central de- pressants with respect to their spectra of effects on human psychomotor performance [45]. While clinical observations have suggested a potential cross-tolerance among the ben- zodiazepines [46], few experimental studies have been done to assess the development of cross-tolerance between ben- zodiazepines and other central depressants.Changes in benzodiazepine receptor binding have been observed fol- lowing chronic ethanol or barbiturate administration, but it was not actually demonstrated that cross-tolerance to benzodazepines existed after such treatment [9, 21, 30]. Recent work by Rosenberg et al. [36] has shown that while chronic treatment with flurazepam produced a high degree of tolerance to diazepam-induced ataxia, little or no cross- tolerance to ethanol and pentobarbital was observed. The possibility of cross-tolerance to benzodiazepines following ethanol or pentobarbital treatment was not examined. In the present study, we report the development of tolerance to ethanol, pentobarbital and chlordiazepoxide, and cross-tolerance between them, as measured by changes in dose-response (D-R) curve for each drug, on two different test systems: shuttle box avoidance [1,44] and the moving belt [25]. METHOD Male Wistar rats weighing 200-220 g were purchased from Charles River (Montreal, Quebec). They were housed IRequests for reprints should be addressed to Dr. A. D. L6, Biobehavioral Studies Department, Addiction Research Foundation, 33 Russell Street, Toronto, Canada, M5S 2SI. 93