Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats

NEUROPHARMACOLOGY

卷:85

Article

D'Amore, V.¹  Santolini, I.¹  Celli, R.¹  Lionetto, L.²  De Fusco, A.¹  Simmaco, M.²  van Rijn, C. M.³  Vieira, E.⁴  Stauffer, S. R.^5,6  Conn, P. J.^5,6  Bosco, P.⁷  Nicoletti, F.^1,8  van Luijtelaar, G.³  Ngomba, R. T.¹ 

[1] IRCCS NEUROMED, Neuropharmacol Unit, I-86077 Pozzilli, Isernia, Italy

[2] St Andrea Hosp, Dept Neurosci & Mental Hlth, Rome, Italy

[3] Radboud Univ Nijmegen, Donders Ctr Cognit, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands

[4] pRED Discovery Chem F Hoffmann La Roche Ltd, Div Pharmaceut, Basel, Switzerland

[5] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA

[6] Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[7] IRCCS Oasi Maria SS Inst Res Mental Retardat & Br, Catania, Italy

[8] Univ Roma La Sapienza, Dept Physiol & Pharmacol, Rome, Italy

关键词: Absence epilepsy;    Spike-wave discharges;    WAG/Rij rats;    VU0360172;    RO0711401;    Tolerance;    Chronic treatment;    Group I mGlu receptors;   

DOI  :  10.1016/j.neuropharm.2014.05.005

来源: Elsevier

【 摘 要 】

Acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) reduces the incidence of spike-and wave discharges in the WAG/Rij rat model of absence epilepsy. However, from the therapeutic standpoint, it was important to establish whether tolerance developed to the action of these drugs. We administered either VU0360172 (3 mg/kg, s.c.) or RO0711401 (10 mg/kg, s.c.) to WAG/Rij rats twice daily for ten days. VU0360172 maintained its activity during the treatment, whereas rats developed tolerance to RO0711401 since the 3rd day of treatment and were still refractory to the drug two days after treatment withdrawal. In response to VU0360172, expression of mGlu5 receptors increased in the thalamus of WAG/Rij rats after 1 day of treatment, and remained elevated afterwards. VU0360172 also enhanced mGlu5 receptor expression in the cortex after 8 days of treatment without changing the expression of mGlu1a receptors. Treatment with RO0711401 enhanced the expression of both mGlu1a and mGlu5 receptors in the thalamus and cortex of WAG/Rij rats after 3-8 days of treatment. These data were different from those obtained in non-epileptic rats, in which repeated injections of RO0711401 and VU0360172 down-regulated the expression of mGlu1a and mGlu5 receptors. Levels of VU0360172 in the thalamus and cortex remained unaltered during the treatment, whereas levels of RO0711401 were reduced in the cortex at day 8 of treatment. These findings suggest that mGlu5 receptor PAMs are potential candidates for the treatment of absence epilepsy in humans (C) 2014 Elsevier Ltd. All rights reserved.

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