The phenomenon of tolerance to CNS depressant drug effects has been extensively studied, but the mechanisms underlying it are poorly understood. Is there a """"""""behavioral tolerance"""""""" (learned adaptation) resembling other conditioning phenomena, but different from the cellular tolerance"""""""", generally associated with physical dependence, on long-term chronic drug treatment? This study will address the hypothesis that the two tolerances are distinct phenomena. We propose that behavioral tolerance (as a learned behavior) requires repeated, concurrent (but not necessarily continuous chronic) exposure to the drug effect and behavior. Cellular tolerance (especially with the general CNS depressant class of drugs) would require chronic drug exposure, but not necessarily experience with a behavior under the drugged state, for response patterns to eventually exhibit less sensitivity to the effects of the drug. Rats will be treated acutely, intermittently, or chronically with ethanol, pentobarbital or oxazepam. Tests of rotarod performance and measurements of body temperature will be done under the drugged state in some rats but temporally separated from drug experiences in other animals. The various treatment groups are calculated to develop subjects that manifest only behavioral tolerance, those showing only metabolic/cellular tolerance, and others showing the combination. Some rats will be killed just after behavioral testing for analysis of serum and brain levels of the drug. The serum half-life of the drug from chronically-treated rats should be shorter than that in controls if metabolic tolerance is induced. Correlating brain levels of drug with the extent of behavioral impairment after a test dose in those groups which have not practiced behavior in the drugged state should define the degree of cellular tolerance that has developed. On stopping chronic drug, this tolerance should fade rather rapidly (within 10 days) even without behavioral extinction trials. Rats that have had extensive behavioral experience in the drugged state, but have not received chronic drug, should demonstrate only behavioral tolerance. This should be maintained for longer periods unless extinction trails are performed. The experimental design should effectively test the hypothesis that behavioral (learned) tolerance is separable from the classical cellular (pharmacodynamic) tolerance obtained with chronic administration of this class of drugs. The solution to this issue would have both theoretical and practical implications for important problems that relate to issues of drug dependence.
| MacKenzie-Taylor, D R; Rech, R H (1993) Cellular and learned tolerances to chlordiazepoxide hypothermia and ataxia. Pharmacol Biochem Behav 44:717-25 |
| MacKenzie-Taylor, D R; Rech, R H (1991) Cellular and learned tolerance to pentobarbital ataxia. Pharmacol Biochem Behav 39:257-64 |
| MacKenzie-Taylor, D R; Rech, R H (1991) Cellular and learned tolerances for pentobarbital hypothermia. Pharmacol Biochem Behav 39:249-56 |
| Mackenzie-Taylor, D; Rech, R H (1991) Cellular and learned tolerances for ethanol hypothermia. Pharmacol Biochem Behav 38:29-36 |
