Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha7* nicotinic receptors.

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TitleCompetitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha7* nicotinic receptors.
Publication TypeJournal Article
Year of Publication2007
AuthorsLopes, C, Pereira, EFR, Wu, H-Q, Purushottamachar, P, Njar, VCO, Schwarcz, R, Albuquerque, EX
JournalJ Pharmacol Exp Ther
Date Published2007 Jul
KeywordsAllosteric Regulation, Alzheimer Disease, Animals, Atropine, Cells, Cultured, Choline, Corpus Striatum, Dopamine, Galantamine, Kynurenic Acid, Male, Rats, Rats, Sprague-Dawley, Receptors, Nicotinic

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 alpha7* 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 alpha7* 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 alpha7* 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 alpha7* nAChRs on GABAergic neurons synapsing onto the neurons under study. Galantamine (1-10 microM) potentiated, whereas KYNA (10 nM-1 mM) inhibited, choline-triggered responses. Galantamine (1 microM), applied before KYNA, shifted to the right the concentration-response relationship for KYNA to inhibit type IA currents, increasing the IC(50) of KYNA from 13.9 +/- 8.3 to 271 +/- 131 microM. 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 alpha7* nAChR inhibition and was blocked by coapplied galantamine (1-5 microM). It is concluded that galantamine competitively antagonizes the actions of KYNA on alpha7* nAChRs. Reducing alpha7* nAChR inhibition by endogenous KYNA may be an important determinant of the effectiveness of galantamine in neurological and psychiatric disorders associated with decreased alpha7* nAChR activity in the brain.

Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID17446300
Grant ListNS25296 / NS / NINDS NIH HHS / United States