期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 322, 期 1, 页码 48-58出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.107.123109
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资金
- NINDS NIH HHS [NS25296] Funding Source: Medline
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 alpha 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 alpha 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 alpha 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 alpha 7* nAChRs on GABAergic neurons synapsing onto the neurons under study. Galantamine ( 1 - 10 mM) potentiated, whereas KYNA ( 10 nM-1 mM) inhibited, choline- triggered 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 mu M. 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 alpha 7* nAChR inhibition and was blocked by coapplied galantamine ( 1 - 5 mu M). It is concluded that galantamine competitively antagonizes the actions of KYNA on alpha 7* nAChRs. Reducing alpha 7* nAChR inhibition by endogenous KYNA may be an important determinant of the effectiveness of galantamine in neurological and psychiatric disorders associated with decreased alpha 7* nAChR activity in the brain.
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