5-HT3 receptor signaling in serotonin transporter-knockout rats: a female sex-specific animal model of visceral hypersensitivity

The irritable bowel syndrome (IBS) is a functional gastrointestinal motor and visceral sensation disorder that is more common in women than men. Female serotonin transporter (SERT) gene knockout (KO) rats exhibit hypersensitivity to colorectal balloon distention (CRD) that mimics colonic hypersensitivity occurring in female IBS patients. Alosetron, (5-HT3 receptor antagonist), is used to treat diarrhea-predominant IBS in female patients. Other 5-HT3 receptor antagonists are ineffective in treating IBS symptoms. The visceromotor response (VMR) to CRD in SERT KO and wild type (WT) rats was measured following subcutaneous (s.c.), intracerobroventricular (i.c.v.) or intrathecal (i.t.) treatment with 5-HT3 receptor antagonists and an agonist. Alosetron (s.c.) and granisetron (antagonists) caused a paradoxical increase in the VMR to CRD in SERT KO female rats. Alosetron (s.c.) increased the VMR to CRD in WT male rats. Alosetron (i.t.) increased the VMR to CRD in SERT KO female rats only and the 5-HT3 receptor a...