Effects of antidepressant drugs on inositol phospholipid hydrolysis in rat cerebral cortical slices.

The effects of several different types of antidepressant drugs on phosphoinositide hydrolysis by slices of rat cerebral cortex was investigated by prelabeling inositol phospholipids with [3H]inositol and then measuring the formation of [3H]inositol phosphates (a total fraction consisting of the mono- and poly-phosphates was collected) in the presence of 10 mM LiCl. All of the drugs tested (amitriptyline, trimipramine, mianserin, desipramine, tranylcypromine, and citalopram) inhibited NE-stimulated [3H]inositol phosphate formation. This inhibition appeared to be due to antagonism of alpha 1-receptors. In addition to inhibiting the effects of NE, the tricyclic antidepressants themselves were able to stimulate [3H]inositol phosphate formation. This stimulation occurred at drug concentrations higher than that needed to inhibit stimulation by NE. Stimulatory effects of the antidepressants themselves were not blocked by the alpha 1-antagonist, prazosin. An examination of the types of inositol phosphates formed revealed that formation of inositol monophosphate was stimulated, but that inositol biphosphate production was decreased by tricyclic antidepressants compared to control.