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 gu inea 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 no t critically involved in the response. The hypothermia induced by SKF 99101H (30 mg/kg i.p.) was dose-dependently blocked by the 5-HT1D rece ptor 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, sugg esting that 5-HT2A/2B/2C or 5-HT3 receptors play no significant role i n 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 99 101H. The antagonists, when given alone, had no effect on body tempera ture, with the exception of prazosin (0.1 and 1.0 mg/kg). Three days o f treatment with parachloroamphetamine (30 mg/kg i.p.) depleted forebr ain 5-HT by similar to 75% in frontal cortex, hypothalamus, hippocampu s and striatum, but failed to alter the hypothermic response to SKF 99 101H. 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 centra lly acting 5-HT1D receptor antagonists.