ANTIAVERSIVE EFFECTS OF 5HT(2C) RECEPTOR AGONISTS AND FLUOXETINE IN AMODEL OF PANIC-LIKE ANXIETY IN RATS

Dose-dependent increases in threshold for operant fear/escape response s of rats submitted to aversive stimulation of the dorsolateral periaq ueductal gray (dPAG) were recorded following intraperitoneal injection of three chemically unrelated but selective 5HT(2C) receptor agonists (Ro 60-0175, Org 12962 and Ro 60-0332) and fluoxetine. The decreased sensitivity of rats to the acute panic-like aversion elicited by stimu lation of this limbic periventricular region was detected at dosages d evoid of impairing effects on the latencies needed for operant brain s timulation interruption. In this paradigm which has been validated as a simulation of acute anxiety with relevance to panic disorder, the se lective activation of 5HT(2C) receptors by Ro 60-0175, Org 12962 or Po 60-0332 induces effects analogous to those observed following benzodi azepine receptor activation by antipanic agents such as clonazepam or alprazolam or following non-selective and indirect 5HT receptor activa tion by fluoxetine. Potency and efficacy of 5HT(2C) receptor agonists were intermediate between those of clonazepam and fluoxetine, indicati ng authentic antiaversive properties and suggesting antipanic potentia l for these 5HT(2C) receptor agonists. In addition, these data suggest that the 5HT(2C) receptor subtype may play a major role in the therap eutic properties of selective serotonin reuptake inhibitors. It is als o speculated that serotonin/benzodiazepine interactions existing in th e brain may functionally involve the 5HT(2C) receptor subtypes and tha t the anxiogenic action reported under certain circumstances for 5HT m imetics are not mediated by 5HT(2C) receptor subtypes. (C) 1998 Elsevi er Science B.V./ECNP.