Agonist-stimulation of cerebral phosphoinositide turnover following long-term treatment with antidepressants.

Abstract

Receptor-mediated stimulation of the formation of inositol phosphates (IP) in cerebral tissue may serve as a useful tool for studying long-term changes in the function of serotonin-2 (5-HT2), alpha-1-adrenergic (al), and muscarinic-cholinergic (musc) receptors. In this study we have evaluated the effects of chronic treatment with various antidepressants on receptor-mediated formation of IP in rat brain. Imipramine (IMI: 10 mg/kg/day; 14 days), Bupropion (BUPR: 40 mg/kg/day; 14 days), Lithium (Li: 0.5% in diet; 7 days) and electroshock treatment (EST: 20-30 mA/day; 7 days) were investigated. Cross-chopped slices of cerebral cortex from control and treated rats were prelabelled with myo-3H-inositol in HEPES buffer containing 11.1 mM LiCl. Accumulation of IP was measured in the presence and absence of serotonin (5-HT, 10 uM), norepinepherine (NE, 5 uM), and carbamylcholine (CCH, 100 uM). Values for agonist-stimulated IP formation in control rats were: 5-HT = 123 +/- 5%; NE = 268 +/- 16%; CCh = 205 +/- 21% of the basal level. The IP response to 5-HT was significantly lower following BUPR and higher following EST. Responses to NE and CCH were significantly lower following BUPR treatment but were not affected by the other antidepressant treatments. These observations are consistent with results of receptor-binding studies indicating up-regulation of 5-HT2 receptors by EST but are not consistent with studies showing down-regulation of 5-HT2 receptors by IMI and a lack of effect on 5-HT2 receptors by BUPR. Our results are not supportive of the notion, based mainly on [3H]prazosin binding studies, that al receptors are up-regulated by EST as well as by different antidepressant drugs.