Evaluation of the dependence liability of quinolizinones acting as partial agonists at the benzodiazepine receptor

Abstract

AbstractThe quinolizinones Ro 19‐5663, Ro 19‐5686 and Ro 41‐3696 bind with high affinity to the benzodiazepine receptor (BZR) in vitro in the rat brain. These compounds exhibit anxiolytic‐like effects in an operant punishment task in mice and rats and anticonvulsant effects by fully protecting against pentylenetetrazol‐induced tonic seizures in mice and rats and fully protecting against audiogenic seizures in genetically susceptible mice. However, they produced at most only minimal motor impairment in the rotarod task in rodents. These compounds attenuated flunitrazepaminduced sleep in squirrel monkeys, thus antagonizing the effects of a BZR full agonist. In a precipitated withdrawal paradigm, chronic oral treatment in seizure‐prone young DBA/2J mice or adult squirrel monkeys was followed by iv challenge with the BZR antagonist sarmazenil. Following the completion of a chronic treatment regiment with high doses of these quinolizinones, no signs of precipitated withdrawal were observed in mice and only weak signs of sarmazenil‐induced withdrawal were observed in monkeys. In contrast, sarmazenil challenge after chronic treatment with the BZR full agonists triazolam and alprazolam elicited marked withdrawal reactions in mice and monkeys, respectively. In sum, these quinolizinones are BZR partial agonists which offer potential anxiolytic and anticonvulsant efficacy concomitant to reduced adverse effects, including a clear reduction of dependence liability, in comparison to BZR full agonists. © 1995 Wiley‐Liss, Inc.