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Receptor Subtype-Dependent Positive and Negative Modulation of GABA_A Receptor Function by Niflumic Acid, a Nonsteroidal Anti-Inflammatory Drug

Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland (S.T.S, S.M., M.U.-O.); Turku Graduate School of Biomedical Sciences, University of Turku, Turku, Finland (S.T.S.); Clinical Research Group, Department of Psychiatry, University of Mainz, Mainz, Germany (H.L.); and Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland (S.T.S., T.M., E.R.K.)

In addition to blocking cyclooxygenases, members of the fenamate group of nonsteroidal anti-inflammatory drugs have been proposed to affect brain GABA_A receptors. Using quantitative autoradiography with GABA_A receptor-associated ionophore ligand [³⁵S]t-butylbicyclophosphorothionate (TBPS) on rat brain sections, one of the fenamates, niflumate, at micromolar concentration was found to potentiate GABA actions in most brain areas, whereas being in the cerebellar granule cell layer an efficient antagonist similar to furosemide. With recombinant GABA_A receptors expressed in Xenopus laevis oocytes, we found that niflumate potentiated 3 µM GABA responses up to 160% and shifted the GABA concentration-response curve to the left in 122 receptors, the predominant GABA_A receptor subtype in the brain. This effect needed the 2 subunit, because on 12 receptors, niflumate exhibited solely an antagonistic effect at high concentrations. The potentiation was not abolished by the specific benzodiazepine site antagonist flumazenil. Niflumate acted as a potent antagonist of 62 receptors (with or without 2 subunit) and of X22 receptors containing a chimeric 1 to 6 subunit, which suggests that niflumate antagonism is dependent on the same transmembrane domain 1- and 2-including fragment of the 6 subunit as furosemide antagonism. This antagonism was noncompetitive because the maximal GABA response, but not the potency, was reduced by niflumate. These data show receptor subtype-dependent positive and negative modulatory actions of niflumate on GABA_A receptors at clinically relevant concentrations, and they suggest the existence of a novel positive modulatory site on 122 receptors that is dependent on the 2 subunit but not associated with the benzodiazepine binding site.

Received January 14, 2003; accepted June 11, 2003.

Address correspondence to: Dr. Esa R. Korpi, Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, P.O. Box 63, University of Helsinki, Helsinki FIN-00014, Finland. E-mail: esa.korpi{at}helsinki.fiy

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