Effect of antidepressants and neuroleptics on phosphoinositide metabolism in human platelets.
The effect of tricyclic antidepressants (imipramine, desipramine, amitriptyline) and several other antidepressants like iprindole, a monoamine oxidase inhibitor phenelzine, trazodone and mianserin as well as cocaine (a potent inhibitor of norepinephrine uptake), and neuroleptics (haloperidol, thioridazine, chlorpromazine) on [3H]inositol phosphate formation was investigated in human platelets. Basal and thrombin-induced [3H]inositol monophosphate ([3H]IP1), [3H]inositol bisphosphate ([3H]IP2) and [3H]inositol trisphosphate ([3H]IP3) production were measured in [3H]myoinositol-labeled platelets in the presence of lithium chloride and in the presence or absence of test drugs. Desipramine, imipramine, amitriptyline and iprindole inhibited thrombin-stimulated formation of [3H]IP2 and [3H]IP3 in human platelets but had no significant effect on [3H]IP1 formation. In contrast, trazodone, mianserin, cocaine and phenelzine had no effect on inositol phosphate formation in thrombin-stimulated human platelets. The neuroleptics thioridazine and chlorpromazine also decreased thrombin-stimulated [3H]IP2 and [3H]IP3 production but not [3H]IP1 in human platelets, whereas haloperidol had no significant effect. The effect of antidepressants and neuroleptics on the level of [3H]phosphatidylinositol ([3H]PI), [3H]phosphatidylinositol 4-phosphate ([3H]PIP) and [3H]phosphatidylinositol 4,5-bisphosphate ([3H]PIP2) was also determined. All of the drugs tested except phenelzine and thioridazine increased the accumulation of [3H]PI, [3H]PIP and [3H]PIP2. Thioridazine increased levels of [3H]PI but decreased the level of [3H]PIP and [3H]PIP2, whereas phenelzine had no effect on [3H]PI, [3H]PIP and [3H]PIP2 interconversion in human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
Pandey
S C
SC
University of Illinois, College of Medicine, Chicago.
Davis
J M
JM
Schwertz
D W
DW
Pandey
G N
GN
D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis* / Q000097:blood; D010716:Phosphatidylinositols / Q000378:metabolism*
D000929:Antidepressive Agents, Tricyclic; D014150:Antipsychotic Agents; D007295:Inositol Phosphates; D010716:Phosphatidylinositols