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: Cristiane Lopes, Edna F R Pereira, Hui-Qiu Wu, Puranik Purushottamachar, Vincent Njar, Robert Schwarcz, Edson X Albuquerque
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 322 Issue 1 Pg. 48-58 (Jul 2007) ISSN: 0022-3565 [Print] United States
• PMID: 17446300 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Chrna7 protein, rat
• Receptors, Nicotinic
• alpha7 Nicotinic Acetylcholine Receptor
• Galantamine
• Atropine
• Kynurenic Acid
• Choline
• Dopamine

Topics

• Allosteric Regulation
• Alzheimer Disease (drug therapy)
• Animals
• Atropine (pharmacology)
• Cells, Cultured
• Choline (pharmacology)
• Corpus Striatum (drug effects)
• Dopamine (metabolism)
• Galantamine (pharmacology)
• Kynurenic Acid (antagonists & inhibitors)
• Male
• Rats
• Rats, Sprague-Dawley
• Receptors, Nicotinic (drug effects)
• alpha7 Nicotinic Acetylcholine Receptor