The mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) supports intravenous self-administration and induces conditioned place preference in the rat

Eur J Pharmacol. 2009 Apr 1;607(1-3):114-20. doi: 10.1016/j.ejphar.2009.01.049.

Abstract

We recently reported that the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) reduces intravenous self-administration of ketamine and, to a lesser extent, heroin in rats. We also found that MPEP potentiates conditioned place preference induced by these drugs, suggesting that the reduction of self-administration results from an MPEP-induced potentiation of the rewarding effect of the self-administered drug. The aim of the present study was to examine whether MPEP has intrinsic positive reinforcing and rewarding effects. In experiment 1, rats were trained to self-administer either ketamine [0.5 mg/kg/infusion, 2 h sessions, fixed-ratio (FR) 3] or heroin (0.05 mg/kg/infusion, 1 h sessions, FR 10), followed by a number of substitution sessions with MPEP (1 mg/kg/infusion) or saline. In experiment 2, drug-naïve rats were allowed to acquire intravenous self-administration of MPEP (1 mg/kg/infusion, 2 h sessions, FR 3) or saline. In experiment 3, rats were subjected to a single-trial unbiased conditioned place preference protocol with MPEP (0.3-10 mg/kg i.v., 20 min conditioning). It was found that (1) substitution with MPEP in rats which had learned to self-administer ketamine or heroin resulted in stable self-administration behavior, whereas substitution with saline resulted in a typical extinction profile, (2) drug-naïve rats learned to self-administer MPEP, but not saline, and self-administration remained stable for at least 7 sessions, and (3) MPEP induced dose-dependent place preference with a minimal effective dose of 3 mg/kg. These data clearly demonstrate that MPEP has (weak) positive reinforcing and rewarding effects when administered i.v.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / administration & dosage
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Heroin / administration & dosage*
  • Infusions, Intravenous
  • Ketamine / administration & dosage*
  • Male
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • Rats
  • Rats, Long-Evans
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Reinforcement Schedule
  • Reward
  • Self Administration
  • Time Factors

Substances

  • Excitatory Amino Acid Antagonists
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Ketamine
  • Heroin
  • 6-methyl-2-(phenylethynyl)pyridine