Intracranial microdialysis of salicylic acid to detect hydroxyl radical generation by antidepressant drugs in the rat

Abstract

We examined the effect of the antidepressant drugs nomifensine, imipramine and nortriptyline on the generation of hydroxyl radicals (·OH) in the rat brain using striatal microdialysis. All these drugs are inhibitors of MAO-A or MAO-B, but were more potent inhibitors of MAO-B in vitro. When the tricyclic antidepressant drugs nortriptyline and imipramine (1 mM) were directly infused into the rat brain through a microdialysis probe for 60 min, the level of 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum gradually decreased in a time-dependent manner. When salicylic acid in Ringer's solution (0.5 mM or 0.5 nmol/μl/min) in addition to the tricyclic antidepressants was infused through the microdialysis probe to detect the generation of ·OH, as reflected by the formation of dihydroxybenzoic acid (DHBA) in the striatum, marked transient elevations in the dialysate levels of 2,3- and 2,5-DHBA were observed. However, when the noncyclic antidepressant drug nomifensine was used, there was no increase in DHBA. The present results suggest that the dopamine (DA) that accumulates in the extracelluar fluid after treatment with tricyclic antidepressant drugs undergoes autooxidation, which in turn leads (possibly by an indirect mechanism) to the formation of cytotoxic ·OH free radicals. © 1997 John Wiley & Sons, Ltd.