Inhibitory effect of antidepressants on the NMDA-evoked [(3)H]noradrenaline release from rat hippocampal slices

We have previously shown that monoamine uptake blocker-type antidepressants with different chemical structure and selectivity are able to inhibit neuronal nicotinic acetylcholine receptors (nAChRs) in concentrations observed during antidepressant treatment. The mechanism of action of these drugs is similar to that of mecamylamine, a channel blocker-type antagonist of nAChRs. Since mecamylamine has been shown to block also NMDA receptors, our aim was to investigate whether the monoamine uptake blockers may affect the function of these ionotropic glutamate receptors. We studied, therefore the effect of the two most potent nicotinic antagonist antidepressants, the tricyclic desipramine and the selective serotonin reuptake inhibitor fluoxetine on the NMDA-induced [(3)H]noradrenaline ([(3)H]NA) release from rat hippocampal slices. The NMDA-induced hippocampal [(3)H]NA release was effectively blocked by the selective, non-competitive NMDA antagonist MK-801 (IC(50)=0.54 microM), indicating that the [(3)H]NA release was mediated through NMDA receptors. This response was also dose-dependently inhibited by desipramine (IC(50)=14.57 microM) and fluoxetine (IC(50)=41.06 microM). The Na(+)-channel blocker TTX equally inhibited both the electrical stimulation- and the NMDA-evoked [(3)H]NA release (the IC(50) was 55 nM and 66 nM, respectively), whereas the antidepressants inhibited only the NMDA-evoked response. These data suggest that the inhibitory effect of fluoxetine and desipramine on the NMDA-evoked [(3)H]NA release is exerted directly on NMDA receptors rather than indirectly on Na(+)-channels. Due to accumulation processes the concentration of desipramine and fluoxetine in the brain might be in the same range as the observed IC(50) values, thus our data indicate that monoamine uptake blocker-type antidepressants are able to influence the function of NMDA receptors during antidepressant treatment, and the inhibitory effect on NMDA receptors might contribute to the therapeutic effects of these drugs.