5-HT1D RECEPTORS MEDIATE SKF 99101H-INDUCED HYPOTHERMIA IN THE GUINEA-PIG

The selective, brain penetrant, 5-HT1D receptor agonist SKF 99101H (10-30 mg/kg i.p.) caused a dose-related fall in rectal temperature in guinea pigs which lasted longer than 2 h. Sumatriptan (1.0-100 mg/kg i.p.), a selective 5-HT1D agonist which does not penetrate the brain, did not produce hypothermia, suggesting that peripheral mechanisms are not critically involved in the response. The hypothermia induced by SKF 99101H (30 mg/kg i.p.) was dose-dependently blocked by the 5-HT1D receptor antagonists GR 127935 (0.01-1mg/kg i.p.) and GR 125743 (0.01-3 mg/kg i.p.), confirming the role of 5-HT1D receptors. Mianserin (0.3-10.0 mg/kg i.p.) and granisetron (0.1-3.0 mg/kg i.p.) were inactive, suggesting that 5-HT2A/2B/2C or 5-HT3 receptors play no significant role in the generation of the hypothermic response. Nor was the hypothermia reversed by prazosin (0.03-1.0 mg/kg i.p.), idazoxan (0.03-1.0 mg/kg i.p.) or scopolamine (0.01-0.3 mg/kg i.p.), thereby excluding mediation by alpha(1)- and alpha(2)-adrenoceptors and muscarinic receptors. WAY 100635 (0.1-1.0 mg/kg) significantly potentiated the effect of SKF 99101H. The antagonists, when given alone, had no effect on body temperature, with the exception of prazosin (0.1 and 1.0 mg/kg). Three days of treatment with parachloroamphetamine (30 mg/kg i.p.) depleted forebrain 5-HT by similar to 75% in frontal cortex, hypothalamus, hippocampus and striatum, but failed to alter the hypothermic response to SKF 99101H. The hypothermia is, therefore, unlikely to be mediated by 5-HT1D receptors located on 5-HT neurons. SKF 991O1H-induced hypothermia in the guinea pig may serve as a useful model for investigation of centrally acting 5-HT1D receptor antagonists.