Effect of imipramine treatments on the 5-HT 1A -receptor-mediated inhibition of panic-like behaviours in rats

Abstract

The escape behaviour induced in rats by injecting D,L-homocysteic acid (DHL) 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 Finally, 8-OH-DPAT failed to inhibit the DLH-induced flight and freezing behaviours in rats withdrawn from imipramine after long-term treatment (10 mg/kg per day x 21 days).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.

Alprazolam potentiates the antiaversive effect induced by the activation of 5-HT1A and 5-HT2A receptors in the rat dorsal periaqueductal gray

“…In the same animal model of panic used in this study, facilitation of 5-HT neurotransmission in the DPAG has been reported after long (24 days) but not short-term (6 days) treatment with the antipanic drugs imipramine and fluoxetine (de Bortoli et al 2006;Jacob et al 2002;Mongeau and Marsden 1997). As in the present study, this evidence was gathered after the intra-DPAG injection of 8-OH-DPAT and DOI, suggesting that, in this midbrain area, the reactivity of both 5-HT 1A and 5-HT 2A receptors was enhanced.…”

“…Clinical results show that these compounds exert their full antipanic effects when given chronically, although the time of onset may vary among the groups; alprazolam, for instance, has a more rapid action than imipramine or fluoxetine (Andersch et al 1991;Kasper and Resinger 2001). In the case of SNRIs and SSRIs, this delayed onset of effect has been taken as an indication that neuroplastic adaptive changes may ultimately underlie their clinically relevant actions (Hensler 2003;Hjorth et al 2000;Jacob et al 2002;Mongeau and Marsden 1997;Zanoveli et al 2005).…”

“…More recently, it has been reported that long-, but not short-term administration of imipramine (Jacob et al 2002;Mongeau and Marsden 1997) and fluoxetine (de Bortoli et al 2006) facilitate the inhibitory effect on escape caused by the intra-DPAG injection of 5-HT 1A and 5-HT 2A receptor agonists. This effect was not observed after long-term treatment with buspirone (de Bortoli et al 2006), a partial 5-HT 1A receptor agonist with clinically relevant anxiolytic properties but ineffective in panic disorder (Connor and Davidson 1998;den Boer and Slaap 1998).…”

“…Accordingly, recently obtained behavioral evidence suggests that sensitization of 5-HT receptors in the dorsal periaqueductal gray matter (DPAG) is involved in the panicolytic effect of imipramine and fluoxetine (Jacob et al 2002;Mongeau and Marsden 1997;Zanoveli et al 2005;de Bortoli et al 2006). The DPAG in the midbrain has long been associated with panic.…”

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

“…These lines of evidence may suggest the presence of diverse HTR2C populations, or, better, the expression of HTR2C receptors in the surface of interneurons embedded in inhibitory or facilitative pathways in the midbrain and limbic forebrain respectively. Antidepressant chronic treatment is effective against anxiety disorders, and it has been associated with modulation in the activity of HTR1A and HTR2A receptors in the midbrain [Mongeau and Marsden, 1997;Jacob et al, 2002;Zanoveli et al, 2005;de Bortoli et al, 2006;Zanoveli et al, 2007], whilst evidence for the HTR2C is sparse and divergent [Jacob et al, 2002;Moreira and Guimaraes, 2005] and further investigations are required. The other relevant structure within the midbrain is the SN, which receives afferences from the dorsolateral striatum, and directly projects to the thalamic motor nuclei.…”