ASSESSMENT OF THE DEPENDENCE POTENTIAL OF THE POTENT HIGH-EFFICACY 5-HT1A AGONIST S-14506 IN RATS

This study assessed the dependence potential of S-14506 -(4-fluorobenz oylamino)ethyl]-4-(7-methoxynapthyl) piperazine], a novel, potent 5-HT 1A full agonist with anxiolytic and antidepressant actions in animal m odels. The dependence potential of S-14506 was compared with that of t he benzodiazepine (BZ) chlordiazepoxide (CDP). BZ withdrawal caused we ight loss, aphagia and hyperthermia after chronic b.i.d. treatment for 21 days. None of these withdrawal effects were seen after similar b.i .d. S-14506 treatment at high doses. However, the acute pharmacologica l actions of CDP and S-14506 differed on a number of indices. Specific ally, CDP increased food intake and body weight, whilst S-14506 decrea sed these measures, possibly due to the induction of the serotonin syn drome. Of particular interest was the observation that S-14506 induced marked hypothermia, to which complete tolerance developed very rapidl y (after only 1 day). The observation of marked, rapid tolerance to S- 14506-induced hypothermia, in conjunction with the absence of withdraw al hyperthermia after prolonged chronic treatment at high doses, sugge sts that tolerance to this effect of S-14506 can be dissociated from d ependence. Collectively, the data reported suggest that the full 5-HT1 A agonist S-14506 is devoid of dependence potential, other human and a nimal studies having previously suggested that partial 5-HT1A agonists typically induce no, or minimal, dependence.