ATYPICAL ANTIDEPRESSANTS INHIBIT DEPOLARIZATION-INDUCED CALCIUM-UPTAKE IN RAT HIPPOCAMPUS SYNAPTOSOMES

The effect of the atypical antidepressants mianserin, iprindole, and f luoxetine on synaptosomal calcium uptake was tested under conditions w here a selective action on voltage-dependent calcium channels can be d ocumented. Synaptosomes from rat hippocampus were incubated with (45)c alcium either in choline-rich medium or in depolarizing (60 mM K+) cho line-rich medium, and drug effects on calcium uptake in these two cond itions, as well as on the net depolarization-induced calcium uptake, w ere studied in the range of concentrations 0.6-200 mu M. A concentrati on-dependent marked inhibition of uptake in depolarizing choline mediu m was observed for the three antidepressants, whereas only a minor deg ree of inhibition of uptake in resting choline medium was present at t he highest drug concentration; as a result, the concentration-effect r elationships exhibited a strong concentration-dependent inhibition of net depolarization-induced calcium uptake. The IC50 values, calculated by interpolation of the last three or four points of the concentratio n-effect relationships, were 27, 39, and 68 mu M for fluoxetine, iprin dole, and mianserin, respectively. Significant degrees of calcium chan nel inhibition are not expected at brain concentrations of mianserin a nd iprindole that are likely to be encountered during clinical use; ho wever, the fluoxetine concentration-effect relationship established in the present study, coupled with the published ratio of 20:1 for brain :plasma concentrations of fluoxetine-norfluoxetine in humans, suggests that brain calcium channel function could be appreciably reduced in s ome patients treated with this atypical antidepressant.