The Interactions Of 5-HT1A Agonists And Benzodiazepines In Models Of Physical Dependence

Abstract

U-93385E is a high intrinsic activity 5-HT1A agonist with potent antianxiety effects in animal models. In the course of evaluating this compound, we sought to determine whether it shared with the benzodiazepine anxiolytics any similar physical dependence-inducing properties. Not surprisingly, in an acute (3-day dosing) dependence assay which utilizes flumazenil to precipitate abstinence, and in a diazepam cross dependence paradigm, U-93385E was inactive. Other 5-HT1A agonists (8-OH-DPAT, buspirone and ipsapirone) were similarly inactive. However, we found that U-93385E was capable of blocking precipitated abstinence hyperexcitability in diazepam-dependent mice as measured by electroshock seizure thresholds. This observation caused us to more closely investigate the interactions of the 5-HT1A agonists and flumazenil on electroshock-induced seizures. The results revealed that U-93385E, though having little effect on seizure thresholds, raised them when combined with flumazenil. In contrast, both ipsapirone and 8-OH-DPAT raised thresholds. However, the effect of ipsapirone, but not that of 8-OH-DPAT, was blocked by flumazenil. The diversity of these interactions indicates that they are not due strictly to 5-HT1A mechanisms, and that caution must be exercised in the interpretation of the results of physical dependence experiments based on withdrawal hyperexcitability.