5-Hydroxytryptamine-stimulated inositol phospholipid hydrolysis in the mouse cortex has pharmacological characteristics compatible with mediation via 5-HT2 receptors but this response does not reflect altered 5-HT2 function after 5,7-dihydroxytryptamine lesioning or repeated antidepressant treatments

5-Hydroxytryptamine (5-HT; 3 × 10-8-1 × 10-5M) produced a dose-dependent increase in phosphatidyl-inositol/polyphosphoinositide (PI) turnover in mouse cortical slices, as measured by following production of 3H-la-belled inositol phosphates (IPs) in the presence of 10 mM LiCl. Analysis of individual IPs, in slices stimulated for 45 min, indicated substantial increases in inositol monophos-phate (IP1; 140%) and inositol bisphosphate (IP2; 95%) contents with smaller increases in inositol trisphosphate (IP3; 51%) and inositol tetrakisphosphatc (IP4; 48%) contents. The increase in IP3 level was solely in the 1.3,4-isomer. This response was inhibited by the nonselective 5-HT antagonists methysergide, metergoline, and spiper-one. It was also inhibited by the selective 5-HT2 antagonists ketanserin and ritanserin but not by the 5-HT1 antagonists isapirone, (-)-propranolol, or pindolol. 5-HT-stimulated IP formation was also unaltered by atropine, prazosin, and mepyramine. Lesioning brain 5-HT neurones using 5,7-di-hydroxytryptamine (5.7-DHT; 50 μg i.c.v.) produced a 210% (p < 0.01) increase in the number of 5-HT2-mediated head-twitches induced by 5-methoxy-N,N-dimethyltrypt-amine (2 mg/kg). However, 5,7-DHT lesioning had no effect on 5-HT-stimulated PI turnover in these mice. Similarly, an electroconvulsive shock (90 V, 1 s) given five times over a 10-day period caused an 85% (p < 0.01) increase in head-twitch responses but no change in 5-HT-stimulated PI turnover. Decreasing 5-HT2 function by twice-a-day injection of 5 mg/kg of zimeldine or desipramine (DMI) produced 59% (p < 0.01) and 56% (p < 0.01), respectively, reductions in head-twitch behaviour. Although zimeldine had no effect on 5-HT-stimulated IP formation, DMI treatment inhibited this by 33% at 3 μM 5-HT (p < 0.02). Previous studies have shown an excellent correlation between head-twitch responses and cortical 5-HT2 receptor number in C57/B1/6 mice. Hence, it is concluded that although the 5-HT-stimulated PI turnover in cortical slices has the characteristics of a 5-HT2 receptor-mediated response, it does not, in general, reflect adaptive changes in 5-HT2 receptor number and function.