KETOTIFEN AND ITS ANALOGS REDUCE AVERSIVE RESPONDING IN THE RODENT

The abilities of ketotifen and other 4-piperidylidene derivatives (HF200-184, HE36-953, SDZ209-321 and SDZ206-703) to inhibit aversive responding were compared in the mouse light/dark test box and in the rat social interaction test. Ketotifen and HF200-184 reduced aversive responding of the mouse to the brightly illuminated area of the test box and facilitated rat social interaction; HF200-184 was approximately 100 times more potent than ketotifen. The chronic administration and withdrawal from treatment with diazepam, ethanol, nicotine and cocaine in the mouse was associated with increased behavioural suppression which was prevented by the administration of ketotifen and HF200-184 during the period of withdrawal. HE36-953 also prevented the behavioural consequences of withdrawal from diazepam and cocaine. The relative potencies of ketotifen and its analogues to inhibit aversive responding did not correlate with their affinities for the 5-HT3 recognition site. It is concluded that compounds within the 4-piperidylidene series can reduce behavioural suppression in rodent models of anxiety and attenuate the behavioural consequences of withdrawing from treatment with drugs of abuse.