The effects of subchronic administration of various psychotropic agents on the density of 5HT 2 receptor binding sites in rat cerebral cortex were investigated. In addition to antidepressant agents, some neuroleptic drugs including chlorpromazine (CPZ), spiperon, and cisflupentixol reduced the numbers of 5HT-2 receptor binding sites after 21 days treatment. The more selective D-2 antagonist haloperidol and sulpiride were totally ineffective in this regard. Anxiolytic agents, benzodiazepine derivatives were also ineffective. Central 5, 7-DHT-induced lesion of 5HT neurons demonstrated that intact 5HT neurons were not required for the reduction of 5HT-2 receptors by desipramine (DMI). Co-administration of DMI and alpha-2 antagonist yohimbine (YOH) produced down-regulation of 5HT-2 receptors within 3 days, whereas each agent alone did not produce such effect. The effect of 3-day treatment with mianserin (MIA, alpha-2 and 5HT-2 antagonist) alone and DMI plus YOH producing 5HT-2 down-regulation, were not prevented by the pretreatment with DSP-4 which selectively destroyed NE neurons. These results suggest that the synaptic availability of 5HT may not be required for DMI-induced down regulation of 5HT-2 receptor binding sites, and the mechanisms mediated through postsynaptic alpha-2 and 5HT-2 receptors are important factors in the regulation of 5HT-2 receptor density. Evidence suggests that the 5HT-1 receptor site is functionally linked to adenylate cyclase in the brain, but a biochemical effector system which is linked to the 5HT-2 receptor site has not been found. The metabolism of inositol phospholipids in response to 5HT was, therefore, investigated in human platelets using sensitive radioisotopic method of Berridge (1983). In platelets prelabeled with 3H-myo-inositol, in Ca++ free HEPES buffer containing 10 mM LiCl, 5HT caused a dose-dependent accumulation of inositol-1-phosphate (IP1) during 15 min incubation. A maximal increase in IP1 formation was observed at 30 microM of 5HT and the EC50 value was 4 microM. Ketanserin, a selective 5HT-2 receptor antagonist was a potent inhibitor of 5HT-stimulated IP1 accumulation, with a Ki value of 12 nM, but a selective 5HT-1 antagonist, (-)-propranolol (1 microM) failed to block the 5HT response. These results indicate that 5HT is activating 5HT-2 receptors, but not 5HT-1 in human platelets. CPZ and imipramine inhibited 5HT-stimulated IP1 accumulation, with Ki values of 124 nM and 2.56 microM, respectively.