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

Abstract.

Rationale: The defensive responses induced by electrical stimulation of dorsal periaqueductal grey (DPAG) of the rat have been proposed as a model of panic attacks in humans. Objective: The present experiments were carried out 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), fluoxetine (FLX; 1 and 5 mg/kg) or saline. Long-term effects were assessed prior to the treatment to avoid acute drug effects. Threshold logistic functions of defensive responses were compared by likelihood ratio coincidence tests. Results: CLM attenuated DPAG-evoked defensive behaviours at a time-course 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 responses disclosed selective threshold increases of galloping (75%) and trotting (138%) with 5 and 10 mg/kg, respectively. Thresholds of micturition were markedly increased (87%) by 5 mg/kg CLM. In turn, FLX (1 mg/kg) virtually abolished the galloping response. No threshold changes were observed following the long-term administration of the higher dose of either CLM or FLX. Saline-treated rats had a significant increase (35%) in galloping thresholds only. Conclusions: The present data partially validate the DPAG-evoked defence reaction of the rat as a model of panic attacks in humans. Attenuation of galloping by lower doses of FLX and CLM also suggests the prominent modulation of this response by serotonin.