Behavioral tolerance to the force differentiation effects of diazepam and midazolam in rats

Rationale: Several benzodiazepines (BZs) have been shown to increase the pe ak force of operant responses at doses that increased, decreased, or had no effect on response rate, suggesting that operant response force may be a s ensitive index of BZs' effects rather than solely a correlate of rate-depen dent effects. In addition, contingent tolerance to the rate-dependent effec ts of BZs has been reported, but the degree of contingent tolerance that de velops when the critical variable of the task is force of the response has not been explored. Objectives: These experiments examined the effects of ac ute and repeated oral administration of diazepam (DZ) and midazolam (MZ) on a force-differentiation task to explore the importance of task requirement s on the development of contingent tolerance. Methods: Two groups of rats w ere trained to press a force-sensing operandum, and responses having peak f orces falling within fixed lower and upper limits [low force (8-10 g) or hi gh force (40-50 g)] were reinforced with water. Acute effects of the oral a dministration of DZ (0.3, 1.0, 3.0, 10.0, 30.0 mg/kg) and MZ (same doses) w ere determined for the discriminated-force task before and after a repeated -administration procedure. Results: When administered acutely, both drugs i ncreased the peak force of responses in a dose-related manner and concomita ntly reduced the proportion of reinforced responses, with MZ exhibiting gre ater potency. For the next 36 days, one group received drug before experime ntal sessions and the other group received drug after the experimental sess ion. A second dose-effect determination demonstrated that rats chronically dosed with DZ or MZ pre-session displayed more contingent tolerance to alte rations in peak force than rats that had received 36 drug injections postse ssion, where there was no opportunity to practice the force-discrimination response while under the drug state. Conclusions: These results suggest tha t perceptual motor difficulty of the task rather than effort may be an impo rtant variable in predicting the degree of contingent tolerance that develo ps. Additionally, these results suggest that both behavioral and pharmacolo gical mechanisms are involved in the development of drug tolerance to the B Zs.