Central 5-HT3 receptor-induced hypothermia in mice: Interstrain differences and comparison with hypothermia mediated via 5-HT1A receptor

The selective agonist of serotonin 5-HT3 receptor 1-(3-chlorophenyl)biguanide hydrochloride (m-CPBG) administered intracerebroventricularly (40, 80 or 160 nmol) produced long-lasting dose-dependent hypothermic response in AKR/2J mice. m-CPBG (160 nmol i.c.v.) induced profound hypothermia (delta t = −4 °C) that lasted up to 7 h. m-CPBG (40 nmol i.c.v.)-induced hypothermia was attenuated by 5-HT3 receptor antagonist ondansetron pretreatment. At the same time, intraperitoneal administration of m-CPBG in a wide range of doses (0.5, 1.0, 5.0 or 10.0 mg/kg) did not affect the body temperature. These findings indicate: (1) the implication of central, rather than peripheral 5-HT3 receptor in the thermoregulation; (2) the inability of m-CPBG to cross blood–brain barrier in mice. The comparison of brain 5-HT3-induced hypothermic reaction in six inbred mouse strains (DBA/2J, CBA/Lac, C57BL/6, BALB/c, ICR, AKR/J) was performed and two highly sensitive to m-CPBG strains (CBA/Lac and C57BL/6) were found. In the same six mouse strains the functional activity of 5-HT1A receptor was studied. The comparison of hypothermic reactions produced by 5-HT1A receptor agonist 8-OH-DPAT (1.0 mg/kg i.p.) and m-CPBG revealed significant correlation between 5-HT3 and 5-HT1A-induced hypothermia in five out of six investigated mouse strains. 5-HT1A receptor antagonist p-MPPI pretreatment (1 mg/kg i.p.) diminished hypothermia produced by centrally administered m-CPBG (40 nmol i.c.v.). The data suggest the cross-talk between 5-HT1A and 5-HT3 receptors in the mechanism of 5-HT-related hypothermia.