Purushottamachar Puranik - Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha7* nicotinic receptors.

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      Publication Details (including relevant citation   information):

      J   Pharmacol Exp Ther. 2007 Jul;322(1):48-58. Epub 2007 Apr 19.


      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.

          PMID: 17446300    

      Address (URL): http://jpet.aspetjournals.org/content/322/1/48.long