Effect of trimipramine on depolarization-induced and Na(+)-Ca2+ exchange-induced 45calcium uptake in synaptosomes from the cortex of the rat brain.

The present study examined the inhibition of synaptosomal uptake of 45calcium by racemic trimipramine and nortrimipramine and by enantiomers of trimipramine. Trimipramine, nortrimipramine, (+)-trimipramine and (-)-trimipramine inhibited the net K(+)-induced uptake of 45calcium with IC50 values of 31, 39, 17 and 95 microM, respectively. No significant difference could be detected between the parent compound trimipramine and the metabolite nortrimipramine; however, the levorotatory isomer had an IC50 value significantly larger than the dextrorotatory isomer. At normal therapeutic doses, a 25-40% inhibition of net K(+)-induced uptake of 45calcium, could be expected with trimipramine or 30-50% inhibition for trimipramine and nortrimipramine combined; these data, therefore, do not exclude the possibility that inhibition of voltage-dependent calcium channels could contribute to the therapeutic effect of trimipramine. The order of potency of stereoisomers of trimipramine, for inhibition of calcium channels, was the same as their reported order of potency in the clinic; this parallelism adds support to the possible involvement of blockade of calcium channels in the antidepressant effect. With respect to uptake of 45calcium induced by the Na(+)-Ca2+ exchange process, all drugs inhibited this mechanism with a similar potency (IC50 74-91 microM); the drugs are not expected to have a significant effect on this exchange process, at therapeutic antidepressant doses.