Competitive Antagonism between the Nicotinic Allosteric Potentiating Ligand Galantamine and Kynurenic Acid at α7* Nicotinic Receptors (original) (raw)
Research ArticleNEUROPHARMACOLOGY
, Edna F. R. Pereira, Hui-Qiu Wu, Puranik Purushottamachar, Vincent Njar, Robert Schwarcz and Edson X. Albuquerque
Journal of Pharmacology and Experimental Therapeutics July 2007, 322 (1) 48-58; DOI: https://doi.org/10.1124/jpet.107.123109
Abstract
Galantamine, a drug used to treat Alzheimer's disease, is a nicotinic allosteric potentiating ligand, and kynurenic acid (KYNA), a neuroactive metabolite of the kynurenine pathway, is an endogenous noncompetitive inhibitor of α7* nicotinic receptors (nAChRs) [the asterisk next to the nAChR subunit is intended to indicate that the exact subunit composition of the receptor is not known (Pharmacol Rev**51:**397–401, 1999)]. Here, possible interactions between KYNA and galantamine at α7* nAChRs were examined in vitro and in vivo. In the presence of tetrodotoxin (TTX), approximately 85% of cultured hippocampal neurons responded to choline (0.3–30 mM) with α7* nAChR-subserved whole-cell (type IA) currents. In the absence of TTX and in the presence of glutamate receptor antagonists, choline triggered inhibitory postsynaptic currents (IPSCs) by activating α7* nAChRs on GABAergic neurons synapsing onto the neurons under study. Galantamine (1–10 μM) potentiated, whereas KYNA (10 nM-1 mM) inhibited, choline-triggered responses. Galantamine (1 μM), applied before KYNA, shifted to the right the concentration-response relationship for KYNA to inhibit type IA currents, increasing the IC50 of KYNA from 13.9 ± 8.3 to 271 ± 131 μM. Galantamine, applied before or after KYNA, antagonized inhibition of choline-triggered IPSCs by KYNA. Local infusion of KYNA (100 nM) in the rat striatum reduced extracellular dopamine levels in vivo. This effect resulted from α7* nAChR inhibition and was blocked by coapplied galantamine (1–5 μM). It is concluded that galantamine competitively antagonizes the actions of KYNA on α7* nAChRs. Reducing α7* nAChR inhibition by endogenous KYNA may be an important determinant of the effectiveness of galantamine in neurological and psychiatric disorders associated with decreased α7* nAChR activity in the brain.
Footnotes
↵1 The asterisk next to the nAChR subunit is intended to indicate that the exact subunit composition of the receptor is not known (Lukas et al., 1999).
This work was supported by the United States Public Health Service Grant NS25296. Part of this work was presented: Lopes C, Pereira EFR, Schwarcz R, Burt DR, and Albuquerque EX (2006) Interactions between galantamine and kynurenic acid on α7 nicotinic receptors in hippocampal and striatal neurons. 2006 Annual Meeting of the Society for Neuroscience; 2006 Oct 14–18; Atlanta, GA. Program number 524.4/C67. Society for Neuroscience, Washington, DC.
doi:10,1124/jpet.107.123109
ABBREVIATIONS: AD, Alzheimer's disease; α-BGT, α-bungarotoxin; APL, allosteric potentiating ligand; APV, dl-2-amino-5-phosphonovaleric acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; IPSCs, inhibitory postsynaptic currents; KYNA, kynurenic acid; MLA, methyllycaconitine; nAChRs, nicotinic receptors; τd, decay-time constant; TTX, tetrodotoxin; ANOVA, analysis of variance.
- Received March 19, 2007.
- Accepted April 18, 2007.
The American Society for Pharmacology and Experimental Therapeutics
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