Effects of psychotropic drugs on the thrombin-induced liberation of arachidonate in human platelets

Objective: To compare the effects of chlorpromazine (CPZ), prochlorperazine (PCP), trifluoperazine (TFP), clozapine (CLO), haloperidol (HPD), quetiapine (QTP), pimozide (PMZ), and olanzapine (OLP) as well as the tricyclic antidepressants amitriptyline (AMI), imipramine (IMI), and nortriptyline (NTP) on thrombin-induced liberation of arachidonic acid (AA) in platelets. Methods. This work was carried out at the Department of Biomedicine, University of Bergen, Norway in 2006-2007. Human platelets pre labelled with [3H] arachidonate were incubated with thrombin in the absence and presence of the drugs, and the amount of free [3H] arachidonate liberated was determined. Myosin light chain (MLC) phosphorylation was determined in [32P] phosphate-labelled platelets after sodium dodecyl sulfate polyacrylamide gel electrophoresis. The effects of the drugs on the molecular area and surface pressure of phospholipid monolayers were determined in the Langmuir apparatus. Results. All drugs reduced arachidonate liberation with the ranking order of increasing potency: OLP QTP HPD AMI IMI PMZ NTP CPZ TFP P CP. Since phenothiazines are calmodulin antagonists, this property of the drugs was tested as reduction of thrombin-induced phosphorylation of MLC in [32P] Pi-labelled platelets. Only PCP, CPZ, TFP, and NTP reduced MLC phosphorylation. All 11 drugs studied markedly increased the mean molecular area of .dipalmitoyl phosphatidylserine monolayers at 370C Conclusions. The mechanism(s) for reduction of arachidonate liberation is thought to interfere with activation of cytosolic phospholipase A2 (cPLA2) by alteration of the PLA2 phospholipid substrate structure in platelet membranes.