Nicotinic acetylcholine receptor antagonistic property of the selective dopamine uptake inhibitor, GBR-12909 in rat hippocampal slices.
Previously we found that inhibitors of noradrenaline (NA) and/or 5-HT reuptake are able to inhibit neuronal nicotinic acetylcholine receptors (nAChRs) in the CNS most probably by a channel blocker-type mechanism. The aim of our study was to clarify whether selective dopamine uptake inhibitors also possess this property, therefore we investigated the effect of GBR-12909 on the nicotine-evoked release of [3H]NA from rat hippocampal slices. GBR-12909, similar to selective NA and 5-HT uptake blockers, inhibited the nicotine-evoked release with an IC50 of 2.32 microM. The ability of monoamine uptake blockers to inhibit nicotine-evoked [3H]NA release (IC50) and NA reuptake (Ki) showed no correlation, indicating that the NA uptake system is not involved in the inhibition of the response to nicotine. Previously we have shown in whole cell patch clamp experiments, that GBR-12909, depending on the stimulation pattern, inhibits Na+-currents with an IC50 in the 6-35 microM concentration range [Mike A, Karoly R, Vizi ES, Kiss JP (2003) Inhibitory effect of the DA uptake blocker GBR-12909 on sodium channels of hippocampal neurons. Neuroreport 14:1945-1949]. To study whether the inhibition of Na+-channels is involved in the action of GBR-12909 on the nicotine-evoked [(3)H]NA release, we compared the effect of GBR-12909 and the Na(+)-channel blocker tetrodotoxin (TTX) on the electrical stimulation- and nicotine-evoked response. TTX prevented the release of [3H]NA induced by both types of stimulation, whereas GBR-12909 inhibited only the nicotine-induced response, indicating that under our experimental conditions the target of GBR-12909 is not the Na+-channel. These data indicate that the selective DA uptake inhibitor GBR-12909 is able to inhibit nAChRs, that is, the nAChR antagonistic property of monoamine uptake inhibitors is independent of their selectivity. The fact that monoamine uptake inhibitors with different chemical structure and selectivity are able to inhibit nAChRs may reveal some common properties of nicotinic receptors and monoamine uptake carriers.
Szasz
B K
BK
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, 43 Szigony u., H-1083 Budapest, Hungary.
Vizi
E S
ES
Kiss
J P
JP
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009538:Nicotine / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism
D000779:Anesthetics, Local; D018765:Dopamine Uptake Inhibitors; D018733:Nicotinic Antagonists; D010879:Piperazines; D014316:Tritium; D013779:Tetrodotoxin; D009538:Nicotine; C043425:vanoxerine