title: 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) potentiates ketamine and heroin reward as assessed by acquisition, extinction, and reinstatement of conditioned place preference in the rat.
abstract: The mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) has been shown to reduce intravenous self-administration of ketamine and, to a limited extent, heroin in rats. We investigated whether MPEP affects the rewarding effect of ketamine and heroin as assessed in a conditioned place preference (CPP) paradigm. Sprague Dawley rats were subjected to a standard unbiased CPP protocol. Rats were conditioned with either ketamine or heroin (0.316-31.6 and 0.0125-0.5 mg/kg i.p., respectively), in combination with MPEP (10 mg/kg, i.p.) or its vehicle. The effect of MPEP (10 mg/kg) on the duration of extinction and on reinstatement of ketamine- and heroin-induced CPP was also examined. Ketamine and heroin induced CPP with a minimal effective dose (MED) of 10 mg/kg and 0.25 mg/kg, respectively. MPEP (1-31.6 mg/kg) did not induce CPP by itself; however, co-treatment with MPEP resulted in a 10-fold and 5-fold leftward shift in the MED of ketamine and heroin for inducing CPP, respectively. MPEP slowed extinction of ketamine-induced CPP, but not of heroin-induced CPP, and once extinction was achieved, was able to reinstate CPP in both groups. These findings indicate that a moderate dose of MPEP (10 mg/kg i.p.) potentiates, rather than attenuates, the rewarding effect of ketamine and heroin. Moreover, these data suggest that the attenuating effect of MPEP on ketamine and heroin intravenous self-administration is due to an increase, rather than a decrease, of the rewarding/reinforcing effect of these compounds.
authors.affiliation: Solvay Pharmaceuticals, Clinical Candidate Selection, Weesp, The Netherlands. Elizabeth.vanderkam@solvay.com
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: van der Kam
authors.forename: Jean
authors.initials: J
authors.lastname: De Vry
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Tzschentke
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects*; D003932:Heroin / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward
chemical_list: D011725:Pyridines; D007649:Ketamine; D003932:Heroin; C121465:6-methyl-2-(phenylethynyl)pyridine