Kynurenic acid, by targeting α7 nicotinic acetylcholine receptors, modulates extracellular GABA levels in the rat striatum in vivo

Authors

  • Sarah Beggiato,

    Corresponding author
    • Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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  • Tiziana Antonelli,

    1. Department of Medical Sciences, University of Ferrara, Ferrara, Italy
    2. Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Ferrara, Italy
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  • Maria Cristina Tomasini,

    1. Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Ferrara, Italy
    2. Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
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  • Sergio Tanganelli,

    1. Department of Medical Sciences, University of Ferrara, Ferrara, Italy
    2. Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Ferrara, Italy
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  • Kjell Fuxe,

    1. Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
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  • Robert Schwarcz,

    1. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
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  • Luca Ferraro

    1. Laboratory for the Technology of Advanced Therapies (LTTA Centre), University of Ferrara, Ferrara, Italy
    2. Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
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  • The work originated from: Department of Clinical and Experimental Medicine, Pharmacology Section and LTTA Centre, University of Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy.

Correspondence: Sarah Beggiato, as above.

E-mail: bggsrh@unife.it

Abstract

Kynurenic acid (KYNA) is an astrocyte-derived non-competitive antagonist of the α7 nicotinic acetylcholine receptor (α7nAChR) and inhibits the NMDA receptor (NMDAR) competitively. The main aim of the present study was to examine the possible effects of KYNA (30 – 1000 nm), applied locally by reverse dialysis for 2 h, on extracellular GABA levels in the rat striatum. KYNA concentration-dependently reduced GABA levels, with 300 nm KYNA causing a maximal reduction to ~60% of baseline concentrations. The effect of KYNA (100 nm) was prevented by co-application of galantamine (5 μm), an agonist at a site of the α7nAChR that is very similar to that targeted by KYNA. Infusion of 7-chlorokynurenic acid (100 nm), an NMDAR antagonist acting selectively at the glycineB site of the receptor, affected neither basal GABA levels nor the KYNA-induced reduction in GABA. Inhibition of endogenous KYNA formation by reverse dialysis of (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 1 mm) increased extracellular GABA levels, reaching a peak of 156% of baseline levels after 1 h. Co-infusion of 100 nm KYNA abolished the effect of ESBA. Qualitatively and quantitatively similar, bi-directional effects of KYNA on extracellular glutamate were observed in the same microdialysis samples. Taken together, the present findings suggest that fluctuations in endogenous KYNA levels, by modulating α7nAChR function, control extracellular GABA levels in the rat striatum. This effect may be relevant for a number of physiological and pathological processes involving the basal ganglia.

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