Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1-13 |
| Number of pages | 13 |
| Journal | Molecular Neurobiology |
| DOIs | |
| Publication status | Accepted/In press - 2015 Dec 12 |
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Keywords
- 5-HT
- Autoreceptor
- Behavioural studies
- Binding
- Depression
- Serotonin
- Zn
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
Cite this
Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors : In Vitro and In Vivo Studies. / Satała, Grzegorz; Duszyńska, Beata; Stachowicz, Katarzyna; Rafalo, Anna; Pochwat, Bartlomiej; Luckhart, Christine; Albert, Paul R.; Daigle, Mireille; Tanaka, Kenji; Hen, René; Lenda, Tomasz; Nowak, Gabriel; Bojarski, Andrzej J.; Szewczyk, Bernadeta.
In: Molecular Neurobiology, 12.12.2015, p. 1-13.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Concentration-Dependent Dual Mode of Zn Action at Serotonin 5-HT1A Receptors
T2 - In Vitro and In Vivo Studies
AU - Satała, Grzegorz
AU - Duszyńska, Beata
AU - Stachowicz, Katarzyna
AU - Rafalo, Anna
AU - Pochwat, Bartlomiej
AU - Luckhart, Christine
AU - Albert, Paul R.
AU - Daigle, Mireille
AU - Tanaka, Kenji
AU - Hen, René
AU - Lenda, Tomasz
AU - Nowak, Gabriel
AU - Bojarski, Andrzej J.
AU - Szewczyk, Bernadeta
PY - 2015/12/12
Y1 - 2015/12/12
N2 - 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.
AB - 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.
KW - 5-HT
KW - Autoreceptor
KW - Behavioural studies
KW - Binding
KW - Depression
KW - Serotonin
KW - Zn
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UR - http://www.scopus.com/inward/citedby.url?scp=84949659260&partnerID=8YFLogxK
U2 - 10.1007/s12035-015-9586-3
DO - 10.1007/s12035-015-9586-3
M3 - Article
C2 - 26660328
AN - SCOPUS:84949659260
SP - 1
EP - 13
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
ER -