The Serotonin 5‐HT 2C Receptor Is a Prominent Serotonin Receptor in Basal Ganglia: Evidence from Functional Studies on Serotonin‐Mediated Phosphoinositide Hydrolysis

Serotonin (5‐hydroxytryptamine; 5‐HT) 5‐HT 2A and 5‐HT 2C receptors belong to the class of phosphoinositide‐specific phospholipase C (PLC)‐linked receptors. Conditions were established for measuring 5‐HT 2A ‐linked and 5‐HT 2C ‐linked PLC activity in membranes prepared from previously frozen rat frontal cortex and caudate. In the presence of Ca 2+ (300 n M ) and GTPγS (1 µ M ), 5‐HT increased PLC activity in caudate membranes. Pharmacological analysis using the selective 5‐HT 2A antagonist, spiperone, and the nonselective 5‐HT 2A/2C antagonist, mianserin, demonstrated that over half of the 5‐HT‐stimulated PLC activity was due to stimulation of 5‐HT 2C receptors as opposed to 5‐HT 2A receptors. Radioligand binding assays with [ 3 H]RP 62203 and [ 3 H]‐mesulergine were used to quantify 5‐HT 2A and 5‐HT 2C sites, respectively, in caudate. From these data, the B max for caudate 5‐HT 2A sites and 5‐HT 2C sites was 165.4 ± 9.7 fmol/mg of protein and 49.7 ± 3.3 fmol/mg of protein, respectively. In contrast to that in caudate, PLC activity in frontal cortex was stimulated by 5‐HT in a manner that was inhibited by the 5‐HT 2A ‐selective antagonists, spiperone and ketanserin. Taken together, the results indicate that 5‐HT 2A ‐ and 5‐HT 2C ‐linked PLC activity can be discerned in brain regions possessing both receptor subtypes using membranes prepared from previously frozen tissue. More importantly, significant 5‐HT 2C ‐mediated phosphoinositide hydrolysis was observed in caudate, despite the relatively low density of 5‐HT 2C sites. The significance of these observations with respect to the physiological function of 5‐HT 2C receptors is discussed.