Associative control of tolerance to the sedative effects of a short-acting benzodiazepine.
The role of Pavlovian conditioning in tolerance to the depressant effect of a benzodiazepine (midazolam) on the ambulatory activity of rats was examined. The depression of activity by low doses (1.0 and 4.0 mg/kg, ip) of midazolam diminished quickly over repeated doses given at 48-hr intervals (Experiment 1). Equivalent tolerance was observed in groups measured at 2 min and 30 min after drug injection. When challenged with saline, however, drug-tolerant animals tested immediately after injection were hyperactive in comparison with nontolerant controls, whereas equivalent groups tested 30 min after injection were not. A second context was designed, and its discriminability from the original was established by assessing context-specific suppression of activity following exposure to mild electric shock (Experiment 2). In Experiment 3A, although tolerant animals tested in the drug-associated context remained fully tolerant, a second group demonstrated a complete loss of tolerance when given the drug in a saline-associated context. Both groups were fully tolerant when tested again in the drug-associated context after 14 drug-free days. In Experiment 3B, tolerance was significantly reduced by 14 extinction exposures to the drug-associated environment without the drug. These results are uniquely predicted by associative models of drug tolerance and may have implications for the clinical use of this class of drugs.
D000818:Animals; D001143:Arousal / Q000187:drug effects*; D003214:Conditioning, Classical / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012153:Retention, Psychology / Q000187:drug effects
D008874:Midazolam