Effect of 5-HT6 receptor antagonists on stress-induced defecation in rat: possible relevance for the treatment of irritable bowel syndrome

[Speaker] Melker Hagsater:1
[Co-author] Alexander Lisinski:1, Robert Pettersson:1, Elias Eriksson:1
1:Department of Pharmacology, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Sweden

Introduction: Whereas the role of serotonin for the regulation of gastrointestinal functioning has since long been discussed, studies on the possible role of 5-HT6 receptors in this context are sparse.

Objective: The aim of this study was to assess whether stress-induced defecation in rat, used as a model for irritable bowel syndrome (IBS), is influenced by antagonism of 5-HT6 receptors.

Methods: All rats were subjected to a fear-conditioning system where the unconditioned stimuli were electric foot-shocks (5 x 1s, 0.6 mA) and where context, i.e. the conditioning chamber, served as conditioned stimulus. The time between fear-conditioning and testing was 7 days in all experiments. One hour prior to testing, the rats received i.p. injections of the highly selective 5-HT6 antagonists SB399885 (Experiment I, II), SB271046 (Experiment II) or 0.9% saline. The effect of drug treatment on stress-induced defecation was measured as the number of fecal boli produced by each rat during testing. In addition to stress-induced defecation, context-conditioned freezing was evaluated as a measure of anxiety.
Results: Experiment I: There was a significant increase in the number of fecal boli and time spent freezing for conditioned control animals versus unconditioned control [p(defecation) < .05, p(freezing) < .001]. Animals treated with SB399885 displayed a dose-dependent reduction in the number of fecal boli [p(1 mg/kg) = .78, p(3 mg/kg) = .06, p(10 mg/kg) < .01], where animals receiving the highest dose (10 mg/kg) did not differ significantly from unconditioned control (p = .73). In contrast, there was no effect of treatment on time spent freezing. Experiment II: There were significant reductions in the number of fecal boli for both SB399885 (5 mg/kg) (p < .001) and SB271046 (5 mg/kg) (p < .001).
Conclusion: The marked and dose-dependent reduction in stress-induced defecation obtained by 5-HT6 receptor antagonism suggests that this might be a potential new treatment strategy for IBS. Since there was no general effect on fear (or anxiety) manifested as freezing, the effect does not seem secondary to stress reduction. As 5-HT6 receptors appear to be expressed almost exclusively in the brain, we however assume the effect to be centrally mediated.

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