Effects of Antidepressants on G Protein-coupled Receptor Signaling and Viability in Xenopus laevis Oocytes

Background: Tricyclic antidepressants are structurally related to local anesthetics, suggesting that part of their analgesic action may result from properties shared with local anesthetics. Because local anesthetics block G protein-coupled receptor signaling (which explains, in part, their inflammatory modulating properties), the authors studied whether antidepressants have similar effects.

Methods: Peak Ca-activated Cl currents induced in Xenopus laevis oocytes by lysophosphatidic acid (10-4 m) were measured using a voltage clamp. The effects of a 30-, 120-, or 240-min incubation in amitriptyline, nortriptyline, imipramine, or fluoxetine were determined.

Results: After a 30-min incubation, low concentrations (10-7-10-5 m) of antidepressants had no effect on lysophosphatidic acid-induced currents. After prolonged incubation, only amitriptyline or nortriptyline inhibited lysophosphatidic acid signaling (each to 58% of the control response at 10-7 m after 240 min). At low concentrations, none of the compounds induced membrane damage (defined as a holding current of > 1 mu]A, 2% in control cells). Imipramine at 10-3 m induced damage in 100% of oocytes, and fluoxetine at 10-4 m induced damage in 71% of oocytes (P < 0.05 vs. control). Amitriptyline and nortriptyline had no effect.