title: Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha7* nicotinic receptors.
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 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.
authors: Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors: Cristiane
authors: C
authors: Lopes
authors: Edna F R
authors: EF
authors: Pereira
authors: Hui-Qiu
authors: HQ
authors: Wu
authors: Puranik
authors: P
authors: Purushottamachar
authors: Vincent
authors: V
authors: Njar
authors: Robert
authors: R
authors: Schwarcz
authors: Edson X
authors: EX
authors: Albuquerque
mesh_terms: D000494:Allosteric Regulation; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002478:Cells, Cultured; D002794:Choline / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D005702:Galantamine / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000037:antagonists & inhibitors*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005702:Galantamine; D001285:Atropine; D007736:Kynurenic Acid; D002794:Choline; D004298:Dopamine