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

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.

Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

“…The divalent metal ion Zn 21 has been reported to allosterically modulate GPCR function, not only GPR39 but also 5HT1A-serotonin (Barrondo and Sallés, 2009;Satała et al, 2015), a(1A)-adrenoreceptor (Ciolek et al, 2011), and b2-adrenergic receptor (Swaminath et al, 2002). Furthermore, the divalent metal ion Zn 21 can stimulate GPR68 (Abe-Ohya et al, 2015) and GPRC6A in the micromolar to millimolar range.…”

Allosteric Inhibition of Serotonin 5-HT7 Receptors by Zinc Ions

“…In the group of metabotropic serotonin (5-HT) receptors, the allosteric modulation of zinc ions has been demonstrated only for the 5-HT 1A subtype [ 6 , 7 ]. Initially, by investigating native rat brain cortical membranes, Zn 2+ was shown to function as a negative allosteric modulator of orthosteric ligand binding to 5-HT 1A receptors [ 6 ].…”

Antidepressant, Anxiolytic and Neuroprotective Activities of Two Zinc Compounds in Diabetic Rats

“…The antidepressant effect shown by Zn may be related to attenuation of the glutamatergic system by inhibition of N-methyl-D-aspartate (NMDA) receptor activity, as demonstrated in previous studies (Szewczyk et al, 2008(Szewczyk et al, , 2011. Zn antidepressant and anxiolytic activities can also occur via modulating the serotonergic system through a complex mechanism not yet fully elucidated involving the participation of pre-and postsynaptic 5-HT 1A Rs (Satała et al, 2016). However, the mechanisms of how zinc-associated anions work in DM are not yet well understood.…”

“…Different Zn compounds such as oxides, hydroaspartate, chloride were intraperitoneally administered at varying doses (Joshi et al, 2012;Torabi et al, 2013;Satała et al, 2016) to test antidepressant properties in several behavioral tests, suggesting that Zn may potentiate the action of antidepressants, in addition to reducing their side effects so that their supplementation has a therapeutic effect (Siwek et al, 2010;Ranjbar et al, 2013). Zn sulfate and gluconate are the most common compounds administered orally (Capdor et al, 2013;Roohani et al, 2013), with the choice of this route being important in T1DM since patients already use injectable insulin.…”