Nicotinic acetylcholine receptor antagonistic activity of monoamine uptakeblockers in rat hippocampal slices

The aim of our study was to investigate the effect of different monoamine u ptake blockers on the nicotine-evoked release of [H-3]noradrenaline ([H-3]N A) from rat hippocampal slices. We found that desipramine (DMI), nisoxetine , cocaine, citalopram, and nomifensine inhibit the nicotine-evoked release of [H-3]NA with an IC50 of 0.36, 0.59, 0.81, 0.93, and 1.84 mu M respective ly. These IC50 values showed no correlation with the inhibitory effect (K-i ) of monoamine uptake blockers on the neuronal NA transporter (r = 0.17, sl ope = 0.02), indicating that the NA uptake system is not involved in the pr ocess. In whole-cell patch clamp experiments neither drug blocked Na+ curre nts at 1 mu M in sympathetic neurons from rat superior cervical ganglia, an d only DMI produced a pronounced inhibition (52% decrease) at 10 mu M. Comp arison of the effect of DMI and tetrodotoxin (TTX) on the electrical stimul ation- and nicotine-evoked release of [H-3]NA showed that DMI, in contrast to TTX, inhibits only the nicotine-induced response, indicating that the ta rget of DMI is not the Na+ channel. Our data suggest that monoamine uptake blockers with different chemical structure and selectivity are able to inhi bit the nicotinic acetylcholine receptors in the CNS, Because these compoun ds are widely used in the therapy of depressed patients, our findings may h ave great importance in the evaluation of their clinical effects.