Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices.
The aim of our study was to investigate the effect of different monoamine uptake blockers on the nicotine-evoked release of [3H]noradrenaline ([3H]NA) from rat hippocampal slices. We found that desipramine (DMI), nisoxetine, cocaine, citalopram, and nomifensine inhibit the nicotine-evoked release of [3H]NA with an IC50 of 0.36, 0.59, 0.81, 0.93, and 1.84 microM, respectively. These IC50 values showed no correlation with the inhibitory effect (Ki) of monoamine uptake blockers on the neuronal NA transporter (r = 0.17, slope = 0.02), indicating that the NA uptake system is not involved in the process. In whole-cell patch clamp experiments neither drug blocked Na+ currents at 1 microM in sympathetic neurons from rat superior cervical ganglia, and only DMI produced a pronounced inhibition (52% decrease) at 10 microM. Comparison of the effect of DMI and tetrodotoxin (TTX) on the electrical stimulation- and nicotine-evoked release of [3H]NA showed that DMI, in contrast to TTX, inhibits only the nicotine-induced response, indicating that the target of DMI is not the Na+ channel. Our data suggest that monoamine uptake blockers with different chemical structure and selectivity are able to inhibit the nicotinic acetylcholine receptors in the CNS. Because these compounds are widely used in the therapy of depressed patients, our findings may have great importance in the evaluation of their clinical effects.
Hennings
E C
EC
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest.
Kiss
J P
JP
De Oliveira
K
K
Toth
P T
PT
Vizi
E S
ES
D000818:Animals; D046508:Culture Techniques; D003891:Desipramine / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009627:Nomifensine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
D014179:Neurotransmitter Uptake Inhibitors; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D015222:Sodium Channels; D005473:Fluoxetine; C011386:nisoxetine; D009627:Nomifensine; D013779:Tetrodotoxin; D003891:Desipramine; D009638:Norepinephrine