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NEUROPHARMACOLOGY

Competitive Antagonism between the Nicotinic Allosteric Potentiating Ligand Galantamine and Kynurenic Acid at 7* Nicotinic Receptors

Department of Pharmacology and Experimental Therapeutics (C.L., E.F.R.P., P.P., V.N., R.S., E.X.A.), Maryland Psychiatric Research Center (H.-Q.W., R.S.), University of Maryland School of Medicine, Baltimore, Maryland

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 7* 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 7* 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 7* 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 7* 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 7* nAChR inhibition and was blocked by coapplied galantamine (1–5 µM). It is concluded that galantamine competitively antagonizes the actions of KYNA on 7* nAChRs. Reducing 7* nAChR inhibition by endogenous KYNA may be an important determinant of the effectiveness of galantamine in neurological and psychiatric disorders associated with decreased 7* nAChR activity in the brain.

Address correspondence to: Dr. Edson X. Albuquerque; 655 W. Baltimore St.; Baltimore, MD, 21201. E-mail: ealbuque{at}umaryland.edu