Long-term effects of clomipramine and fluoxetine on dorsal periaqueductal grey-evoked innate defensive behaviours of the rat

Rationale: The defensive responses induced by electrical stimulation of dor sal periaqueductal grey (DPAG) of the rat have been proposed as a model of panic attacks in humans. Objective: The present experiments were carried ou t to evaluate the long-term effects of clinically effective panicolytics on these responses. Methods. Rats that had electrodes implanted into the DPAG were treated for 21 days with clomipramine (CLM; 5, 10 and 20 mg/kg), fluo xetine (FLX; I and 5 mg/kg) or saline. Long-term effects were assessed prio r to the treatment to avoid acute drug effects. Threshold logistic function s of defensive responses were compared by likelihood ratio coincidence test s. Results: CLM attenuated DPAG-evoked defensive behaviours at a timecourse similar to that observed in panic therapy. Administration of 10 mg/kg CLM for 21 days produced significant increases in the thresholds of immobility (24%), running (49%) and jumping (45%). Splitting of running into single re sponses disclosed selective threshold increases of galloping (75%) and trot ting (138%) with 5 and 10 mg/kg, respectively. Thresholds of micturition we re markedly increased (87%) by 5 mg/kg CLM. In turn, FLX (1 mg/kg) virtuall y abolished the galloping response. No threshold changes were observed foll owing the long-term administration of the higher dose of either CLM or FLX. Saline-treated rats had a significant increase (35%) in galloping threshol ds only. Conclusions: The present data partially validate the DPAG-evoked d efence reaction of the rat as a model of panic attacks in humans. Attenuati on of galloping by lower doses of FLX and CLM also suggests the prominent m odulation of this response by serotonin.