Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies

Grzegorz Satała, Beata Duszyńska, Katarzyna Stachowicz, Anna Rafalo, Bartlomiej Pochwat, Christine Luckhart, Paul R. Albert, Mireille Daigle, Kenji Tanaka, René Hen, Tomasz Lenda, Gabriel Nowak, Andrzej J. Bojarski, Bernadeta Szewczyk

研究成果: Article

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Recent data has indicated that Zn can modulate serotonergic function through the 5-HT1A receptor (5-HT1AR); however, the exact mechanisms are unknown. In the present studies, radioligand binding assays and behavioural approaches were used to characterize the pharmacological profile of Zn at 5-HT1ARs in more detail. The influence of Zn on agonist binding to 5-HT1ARs stably expressed in HEK293 cells was investigated by in vitro radioligand binding methods using the agonist [3H]-8-OH-DPAT. The in vivo effects of Zn were compared with those of 8-OH-DPAT in hypothermia, lower lip retraction (LLR), 5-HT behavioural syndrome and the forced swim (FST) tests. In the in vitro studies, biphasic effects, which involved allosteric potentiation of agonist binding at sub-micromolar Zn concentrations and inhibition at sub-millimolar Zn concentrations, were found. The in vivo studies showed that Zn did not induce LLR or elements of 5-HT behavioural syndrome but blocked such effects induced by 8-OH-DPAT. Zn decreased body temperature in rats and mice; however, Zn failed to induce hypothermia in the 5-HT1A autoreceptor knockout mice. In the FST, Zn potentiated the effect of 8-OH-DPAT. However, in the FST performed with the 5-HT1A autoreceptor knockout mice, the anti-immobility effect of Zn was partially blocked. Both the binding and behavioural studies suggest a concentration-dependent dual mechanism of Zn action at 5-HT1ARs, with potentiation at low dose and inhibition at high dose. Moreover, the in vivo studies indicate that Zn can modulate both presynaptic and postsynaptic 5-HT1ARs; however, Zn’s effects at presynaptic receptors seem to be more potent.

元の言語English
ページ(範囲)1-13
ページ数13
ジャーナルMolecular Neurobiology
DOI
出版物ステータスAccepted/In press - 2015 12 12

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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    Satała, G., Duszyńska, B., Stachowicz, K., Rafalo, A., Pochwat, B., Luckhart, C., Albert, P. R., Daigle, M., Tanaka, K., Hen, R., Lenda, T., Nowak, G., Bojarski, A. J., & Szewczyk, B. (受理済み/印刷中). Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors: In Vitro and In Vivo Studies. Molecular Neurobiology, 1-13. https://doi.org/10.1007/s12035-015-9586-3