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

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Abstract
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.

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