title: 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-HT1Areceptor (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-HT1Aautoreceptor knockout mice. In the FST, Zn potentiated the effect of 8-OH-DPAT. However, in the FST performed with the 5-HT1Aautoreceptor 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.
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences , Smetna 12, PL 31-343, Krakow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences , Smetna 12, PL 31-343, Krakow, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Duszyńska
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences , Smetna 12, PL 31-343, Krakow, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stachowicz
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences , Smetna 12, PL 31-343, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rafalo
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences , Smetna 12, PL 31-343, Krakow, Poland.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Pochwat
authors.affiliation: Ottawa Hospital Research Institute, UOttawa Brain and Mind Research Institute , 451 Smyth Road #2464, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Luckhart
authors.affiliation: Ottawa Hospital Research Institute, UOttawa Brain and Mind Research Institute , 451 Smyth Road #2464, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Albert
authors.affiliation: Ottawa Hospital Research Institute, UOttawa Brain and Mind Research Institute , 451 Smyth Road #2464, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Mireille
authors.initials: M
authors.lastname: Daigle
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo, 160-8582, Japan.
authors.forename: Kenji F
authors.initials: KF
authors.lastname: Tanaka
authors.affiliation: Department of Psychiatry, Columbia University Medical Center and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY, 10032, USA.
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences , Smetna 12, PL 31-343, Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lenda
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences , Smetna 12, PL 31-343, Krakow, Poland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences , Smetna 12, PL 31-343, Krakow, Poland.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences , Smetna 12, PL 31-343, Krakow, Poland. szewczyk@if-pan.krakow.pl.
authors.forename: Bernadeta
authors.initials: B
authors.lastname: Szewczyk
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D001522:Behavior, Animal; D001831:Body Temperature / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007103:Immobilization; D007700:Kinetics; D018345:Mice, Knockout; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology*
chemical_list: D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D015032:Zinc
keywords: 5-HT1A; Autoreceptor; Behavioural studies; Binding; Depression; Serotonin; Zn