Effect of imipramine treatments on the 5-HT1A-receptor-mediated inhibition of panic-like behaviours in rats

The escape behaviour induced in rats by injecting D,L-homocysteic acid (DLH) into the dorsal periaqueductal grey area (DPAG) was used as an animal model of panic attacks to investigate the effect of imipramine, a drug used for the treatment of panic disorder, on the sensitivity of 5-HT1A receptors in the DPAG. Rats given imipramine (10 mg/kg per day SC for 3 weeks or IP for 2-3 days) received 250 nl saline or the 5-HT1A agonist 8-OH-DPAT (8.6 nmol) into the DPAG 10 min before inducing the escape response with DLH. As expected, 8-OH-DPAT produced a marked decrease in the average speed of the DLH-induced flight response. The short-term treatment with imipramine changed neither the DLH-induced escape behaviour nor the effect of prior 8-OH-DPAT administration on this response. In contrast, long-term treatment with imipramine enhanced the 5-HT1A-mediated inhibition, as the decrement in the amplitude of the flight response produced by 8-OH-DPAT was 96% after this treatment compared to 41% in controls. The injection of 8-OH-DPAT also significantly decreased the amplitude of the freezing behaviour observed at the end of the flight response in rats given imipramine for 3 weeks, but not in controls. The long-term imipramine treatment, however, did not significantly decrease the amplitude of DLH-induced flight and freezing behaviours in absence of prior 8-OH-DPAT administration. Finally, 8-OH-DPAT failed to inhibit the DLH-induced flight and freezing behaviours in rats withdrawn from imipramine after long-term treatment (10 mg/kg per day x 21 days). It is suggested that an alteration at the level of the DPAG-5-HT1A receptor system is implicated in the therapeutic and withdrawal effect of imipramine in panic disorder.