5-HYDROXYTRYPTAMINE-STIMULATED INOSITOL PHOSPHOLIPID HYDROLYSIS IN RAT CEREBRAL-CORTEX SLICES - PHARMACOLOGICAL CHARACTERIZATION AND EFFECTS OF ANTIDEPRESSANTS

Abstract

The ability of 5-hydroxytryptamine (5-HT) and related agonists to stimulate hydrolysis of inositol phospholipids was examined in rat cerebral cortex slices using a direct assay which involves prelabeling with [3H]inositol and assaying [3H]inositol phosphates in the presence of lithium. 5-HT agonists stimulated [3H]inositol phosphate accumulation in a dose-related but biphasic manner and only the high-affinity component of the dose-response curve was sensitive to antagonists. This response to 5-HT was blocked potently by ketanserin and other putative 5-HT2 antagonists but the overall pattern of apparent drug affinities was inconsistent with that seen at 5-HT2 sites labeled with [3H]ketanserin in cortical membranes. Pretreatment of slices with the alkylating antagonist phenoxybenzamine reduced the inositol phospholipid response to 5-HT to a greater extent than the suppression of [3H]ketanserin binding. Similarly, chronic but not acute treatment of rats with the antidepressants iprindole and imipramine resulted in a greater loss of 5-HT-induced inositol phospholipid hydrolysis than specific [3H]ketanserin binding. However, the effect of antidepressants was agonist-specific in that neither .alpha.-1 adrenoceptor nor muscarinic receptor stimulation were altered by acute or chronic treatment.