title: Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats.
abstract: 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.
authors.affiliation: I.R.C.C.S., NEUROMED, Neuropharmacology Unit, Parco Tecnologico, Località Camerelle 86077 Pozzilli, Isernia, Italy.
authors.forename: V
authors.initials: V
authors.lastname: D'Amore
authors.affiliation: I.R.C.C.S., NEUROMED, Neuropharmacology Unit, Parco Tecnologico, Località Camerelle 86077 Pozzilli, Isernia, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Santolini
authors.affiliation: I.R.C.C.S., NEUROMED, Neuropharmacology Unit, Parco Tecnologico, Località Camerelle 86077 Pozzilli, Isernia, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Celli
authors.affiliation: Department of Neuroscience and Mental Health, St. Andrea Hospital, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Lionetto
authors.affiliation: I.R.C.C.S., NEUROMED, Neuropharmacology Unit, Parco Tecnologico, Località Camerelle 86077 Pozzilli, Isernia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Fusco
authors.affiliation: Department of Neuroscience and Mental Health, St. Andrea Hospital, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Simmaco
authors.affiliation: Donders Centre for Cognition, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: van Rijn
authors.affiliation: pRED Discovery Chemistry F. Hoffmann-La Roche Ltd, Pharmaceutical Division, Basel, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Vieira
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Stauffer
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: IRCCS Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bosco
authors.affiliation: I.R.C.C.S., NEUROMED, Neuropharmacology Unit, Parco Tecnologico, Località Camerelle 86077 Pozzilli, Isernia, Italy; Department of Physiology and Pharmacology, University "Sapienza", Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Donders Centre for Cognition, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: van Luijtelaar
authors.affiliation: I.R.C.C.S., NEUROMED, Neuropharmacology Unit, Parco Tecnologico, Località Camerelle 86077 Pozzilli, Isernia, Italy. Electronic address: richardngomba@neuromed.it.
authors.forename: R T
authors.initials: RT
authors.lastname: Ngomba
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004361:Drug Tolerance; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000188:drug therapy* / Q000503:physiopathology*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D008297:Male; D008822:Mice, Transgenic; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011912:Rats, Inbred ACI; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D013788:Thalamus / Q000187:drug effects / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D018683:Excitatory Amino Acid Agents; C578937:Grm5 protein, rat; C581972:N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D009536:Niacinamide
keywords: Absence epilepsy; Chronic treatment; Group I mGlu receptors; RO0711401; Spike–wave discharges; Tolerance; VU0360172; WAG/Rij rats