Calcium Antagonist-like Action of Antidepressants Including Sertraline in PCl2 Cells / 신경정신의학

ABSTRACT

It has been known that antidepressants have calcium antagonist-like action in neuronal tissues. However, their mechanisms are still obscure. For the study of neurochemical machanism of antidepressants, the authors examined the effects of antidepressants(1-100 microM ) on the intracellular Ca2+ concentration ([Ca2+]i) and the membrane potential in PCl2 cells using fluorescent dyes, fura-2/AM and bisoxonol, respectively. The results were as follows 1) Sertraline, a selective serotonin reuptake inhibitor (SSRI), inhibited the increment of [Ca2+]i induced by high 60 mM KCI and 100 microM ATP with an IC50 value of 2.5 microM and 5.4 microM, respectively. 2) SSRIs(sertraline, paroxetine and fluoxetine) and tricyclic antidepressants(imipramine and amitriptyline) had strong effects on the inhibition of both voltage-dependent Ca2+ channel and receptor-dependent Ca2+ channel, whereas atypical antidepressant(trazodone) and MAO inhibitor(moclobemide) had lisle effects. 3) Sertraline itself depolarized the membrane potential in a sustained manner depending on its own concentration and it also increased the basal level of [Ca2+]i. 4) The increment of [Ca2+]i might be induced partly by the release from the intracellular calcium store, but mostly induced by the calcium transport through membrane. 5) Among those antidepressants tested, sertraline was the most potent one. Other SSRIs(paroxetine and fluoxetine) and tricyclic antidepressants(imipramine and amitriptyline) were moderately potent. Atypical antidepressant(trazodone) had little effects, and MAO inhibitor (moclobemide) had no effect on the depolarization. 6) External application of ATP induced temporary depolarization. This effect was blocked by prior treatment with sertraline with an IC50 value of 30 microM. 7) The increment of [Ca2+]i through voltage-dependent Ca2+ channel was almost inhibited by a selective calcium channel blocker(nimodipine). However, the ATP-induced increment of [Ca2+]i was partially inhibited by nimodipine. These inhibitory effects were potentiated by the addition of sertraline. In the light of these results, it is likely that SSRIs and tricyclic antidepressants could show the blocking effects on both voltage-dependent and receptor-dependent calcium channel by depolarizing neuronal cell membrane potential in a sustained manner and by increasing intracellular free calcium level.