CELLULAR AND LEARNED TOLERANCES TO CHLORDIAZEPOXIDE HYPOTHERMIA AND ATAXIA

Four groups of rats received chlordiazepoxide (CDP): a) intermittently, experiencing hypothermia and rotarod performance (RR) deficit after test doses (contingency); b) chronically, experiencing hypothermia and RR deficit after test doses; c) intermittently, RR preceding test doses and with protection against hypothermia afforded by exposure to heat lamps (nonexperienced, noncontingency); and d) chronically, RR preceding test doses and with protection against hypothermia. After 36 days of chronic CDP (groups 2 and 4) or vehicle (groups 1 and 3), all groups experienced RR and body temperature (BT) drug deficits after test doses of CDP at the postwithdrawal test. Group 1 but not group 3 was tolerant to peak hypothermia of the drug. Both chronic groups (2 and 4) showed marked tolerance to hypothermia. At the postwithdrawal test, after discontinuing chronic CDP or vehicle for 9 days, only groups 2 and 4 lost drug tolerance to hypothermia. After extinction training (daily testing of RR and BT after injecting vehicle over 9 days), group 2 but not group 4 was again less sensitive to CDP-induced hypothermia at the postextinction test. Regarding CDP-induced RR ataxia, group 1 was more tolerant than group 3 at the postchronic test, while group 4 but not group 2 also showed tolerance to ataxia. At the postwithdrawal test, only group 4 lost tolerance to peak RR ataxic effects of CDP. At the postextinction test, only group 1 lost tolerance for ataxia relative to postchronic test results. These findings differ from those of previous studies with alcohol and pentobarbital that matched learned tolerance [contingent tolerance (CT)] with contingent drug behavior presentation and cellular and/or dispositional tolerances [noncontingent tolerance (NCT)] with chronic drug treatment, but without need of drug-behavior contingency. In the present study, chronic CDP administration, while promoting cellular/dispositional tolerances (NCT), appeared to interfere with development of learned or behavioral tolerance (CT) even when contingent drug behavior training was done (in group 2). That this interference related to chronic CDP is assured because intermittent CDP at 4-day intervals with contingent drug behavior training (group 1) caused prominent CT whereas there was little evidence of CT in rats receiving intermittent CDP but not tested contingently (group 3). Therefore, CT does develop with spaced doses of CDP, and NCT develops dramatically with chronic CDP. But, chronic dosing may somehow nullify development of CT when these subjects (group 2) are also exposed to the contingent training procedure.