THE SEROTONIN 5-HT2C RECEPTOR IS A PROMINENT SEROTONIN RECEPTOR IN BASAL GANGLIA - EVIDENCE FROM FUNCTIONAL-STUDIES ON SEROTONIN-MEDIATED PHOSPHOINOSITIDE HYDROLYSIS

Serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A and 5-HT2C receptors belo ng to the class of phosphoinositide-specific phospholipase C (PLC)-lin ked receptors. Conditions were established for measuring 5-HT2A-linked and 5-HT2C-linked PLC activity in membranes prepared from previously frozen rat frontal cortex and caudate. In the presence of Ca2+ (300 nM ) and GTP gamma S (1 mu M), 5-HT increased PLG activity in caudate mem branes. Pharmacological analysis using the selective 5-HT2A antagonist , spiperone, and the nonselective 5-HT2A/2C antagonist, mianserin, dem onstrated that over half of the 5-HT-stimulated PLC activity was due t o stimulation of 5-HT2C receptors as opposed to 5-HT2A receptors. Radi oligand binding assays with [H-3]RP 62203 and [H-3]-mesulergine were u sed to quantify 5-HT2A and 5-HT2C sites, respectively, in caudate. Fro m these data, the B-max for caudate 5-HT2A sites and 5-HT2C 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- HT2A-selective antagonists, spiperone and ketanserin. Taken together, the results indicate that 5-HT2A- and 5-HT2C-linked PLC activity can b e discerned in brain regions possessing both receptor subtypes using m embranes prepared from previously frozen tissue. More importantly, sig nificant 5-HT2C-mediated phosphoinositide hydrolysis was observed in c audate, despite the relatively low density of 5-HT2C sites. The signif icance of these observations with respect to the physiological functio n of 5-HT2C receptors is discussed.