Excitation of interneurons in piriform cortex by 5-hydroxytryptamine: Blockade by MDL 100,907, a highly selective 5-HT_2A receptor antagonist

Abstract

Electrophysiological studies have suggested that a subpopulation of interneurons near the border of layer II and III in rat piriform cortex are excited by serotonin (5-hydroxytryptamine; 5-HT) via 5-HT_2A (formerly 5-HT₂) rather than 5-HT_2C (formerly 5-HT_1C) receptors. However, the pharmacological agents used in those studies were limited in specificity. In the present study, we tested a new, highly selective 5-HT_2A receptor antagonist MDL 100,907 (R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl-ethyl)]-4- piperidine-methanol, which has a 300-fold greater affinity for 5-HT_2A than 5-HT_1C receptors or α₁-adrenoceptors) on excitatory responses of interneurons to 5-HT in rat piriform cortex slices. We observed a parallel, reversible rightward shift in the 5-HT concentration-response curve in the presence of 1–10 nM concentrations of MDL 100,907. Schild regression analysis resulted in a slope of 1.13 and a K_d value of 1.17 which is close to the published K_i value of 0.36 for MDL 100,907. These data confirm that 5-HT_2A rather than 5-HT_2C receptors mediate excitation by 5-HT of interneurons in the piriform cortex. Because of its rapid equilibration and reversibility, MDL 100,907 appears to be an excellent tool for studies of 5-HT_2A receptor function in the brain.