Competitive Antagonism between the Nicotinic Allosteric Potentiating Ligand Galantamine and Kynurenic Acid at alpha7* Nicotinic Receptors

摘要

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 mu M) potentiated,whereas KYNA (10 nM-1 mM)inhibited,choline-trig-gered responses.Galantamine (1 mu M),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 /xM.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 mu M).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.