EFFECT OF SOME STEREOISOMERIC TRICYCLIC ANTIDEPRESSANTS ON CA-45 UPTAKE IN SYNAPTOSOMES FROM RAT HIPPOCAMPUS

The present study has examined the inhibition of synaptosomal calcium-45 uptake by trimipramine, oxaprotiline and doxepin, and their stereoisomers, in synaptosomes from the rat hippocampus. No significant difference in potency could be established for inhibition of net depolarization-induced calcium-45 uptake for any pair of antipodes, and the IC50 values for calcium channel blockade were in the vicinity of 30 muM for this group of compounds. Trimipramine, doxepin and oxaprotiline also inhibited the calcium-45 uptake mediated by Na+-Ca2+ exchange, with IC50 values of 71 muM, 110 muM, and 100 muM, respectively. The similar potency of doxepin isomers for inhibition of voltage-dependent calcium channels is in harmony with their reported similar potency in the clinic. A slight difference in potency is reported between the isomers of oxaprotiline in the behavioral despair test in rats, and the dextrorotatory isomer of trimipramine is reported to be a much more potent antidepressant than the levorotatory isomer: these order of potencies do not correspond perfectly with the similar potency of the antipodes against voltage-dependent calcium channels. The present study of stereoisomeric tricyclic antidepressants therefore fails to provide unequivocal support for the hypothesis that calcium channel blockade by tricyclic antidepressants is involved in their therapeutic effect.