title: The anti-absence effect of mGlu5 receptor amplification with VU0360172 is maintained during and after antiepileptogenesis.
abstract: OBJECTIVE
  Ethosuximide (ETX) is the drug of choice for the treatment of patients with absence seizures - taking into account both its efficacy, tolerability and antiepileptogenic properties. However, 47% of subjects failed in ETX-therapy, and most antiepileptic drugs have cognitive side effects. VU0360172, a positive allosteric modulator (PAM) of mGluR5, has been proposed as a new anti-absence drug. Here it is investigated whether anti-epileptogenesis induced by ETX alters the sensitivity of VU0360172, and whether cognition is affected during and after chronic ETX treatment.
  
  
  METHODS
  EEG's were recorded before and after a challenge with VU0360172 in chronic ETX and in control WAG/Rij rats during and after treatment. Rats were also exposed to a cue discrimination learning task in a Y-maze both during and after treatment. At the end of the experiment, mGlu5 receptors were quantified by Western Blot analysis.
  
  
  RESULTS
  Antiepileptogenesis was successfully induced by ETX and VU0360172 showed a time and dose dependent anti-absence action in the control group. VU0360172 kept its anti-absence action in chronic ETX treated rats both during and after treatment, without time and dose dependency. This anti-absence effect of VU0360172 in both groups matched the lack of differences in mGluR5 expression. Chronic ETX enhanced the number of completed trials, the number of correct choices in the Y-maze and the number of consumed sucrose pallets.
  
  
  CONCLUSIONS
  VU0360172 maintains its anti-absence effects after chronic treatment; as such, VU0360172 can also be used as a adjunctive therapy in patients with absence epilepsy. The enhanced motivation and cognitive performance by ETX might be mediated by the antidepressant action of ETX as expressed by an increase in the rewarding properties of sucrose pallets.
authors.affiliation: IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: D'Amore
authors.affiliation: Biological Psychology, Donders Centre for Cognition, Radboud University, Nijmegen, The Netherlands.
authors.forename: Renée H L
authors.initials: RH
authors.lastname: Raaijmakers
authors.affiliation: IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Santolini
authors.affiliation: Biological Psychology, Donders Centre for Cognition, Radboud University, Nijmegen, The Netherlands.
authors.forename: Clementina M
authors.initials: CM
authors.lastname: van Rijn
authors.affiliation: IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Richard Teke
authors.initials: RT
authors.lastname: Ngomba
authors.affiliation: IRCCS Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Biological Psychology, Donders Centre for Cognition, Radboud University, Nijmegen, The Netherlands.
authors.forename: Gilles
authors.initials: G
authors.lastname: van Luijtelaar
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004569:Electroencephalography / Q000187:drug effects; D004832:Epilepsy, Absence / Q000517:prevention & control*; D005013:Ethosuximide / Q000494:pharmacology*; D005518:Food Preferences / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000096:biosynthesis*; D013788:Thalamus / Q000378:metabolism; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; C581972:N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide; D064529:Receptor, Metabotropic Glutamate 5; D009536:Niacinamide; D005013:Ethosuximide
keywords: Antiepileptogenesis; Electroencephalography; Ethosuximide; Genetic absence epilepsy model; WAG/Rij rats; Western blots; Y-maze learning; mGluR5