Pharmacological activation of mGlu4 and mGlu7 receptors, by LSP2-9166, reduces ethanol consumption and relapse in rat

Neuropharmacology. 2018 May 1;133:163-170. doi: 10.1016/j.neuropharm.2018.01.031. Epub 2018 Jan 31.

Abstract

Addiction is a chronic and highly relapsing disorder hypothesized to be produced by an imbalance between excitatory and inhibitory neurotransmission. For more than a decade, emerging evidence indicates that manipulation of glutamatergic neurotransmission, by group III mGlu receptors (mGlu4/7/8), could be a promising approach to develop therapeutic agents for the treatment of addiction. Thus, the aim of the present study is to determine whether LSP2-9166, a mixed mGlu4/mGlu7 orthosteric agonist, could reduce ethanol self-administration, ethanol motivation and reacquisition after protracted abstinence in a preclinical model of excessive ethanol intake. Male Long Evans rats were chronically trained to consume large amount of ethanol in operant cages for several weeks. Once they reached a stable level of consumption (about 1 g of pure ethanol/kg bodyweight/15min), the effect of LSP2-9166 was evaluated on different aspects of the operant self-administration behavior. In this study, we found that the intracerebroventricular infusion of LSP2-9166 dose dependently reduced ethanol consumption, motivation for ethanol and reacquisition of ethanol self-administration after abstinence. Together, these results support recent preclinical findings showing that pharmacological modulation of mGlu receptors may serve as an effective treatment for reducing ethanol consumption and relapse.

Keywords: LSP2-9166; Operant ethanol self-administration; Rat; Relapse; mGlu4; mGlu7.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / drug therapy*
  • Aminobutyrates / pharmacology*
  • Aminobutyrates / therapeutic use
  • Analysis of Variance
  • Animals
  • Conditioning, Operant / drug effects*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Ethanol / administration & dosage
  • Excitatory Amino Acid Agonists / therapeutic use*
  • Food Preferences / drug effects
  • Male
  • Rats
  • Rats, Long-Evans
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / metabolism*
  • Recurrence
  • Self Administration
  • Sucrose / administration & dosage

Substances

  • Aminobutyrates
  • Excitatory Amino Acid Agonists
  • LSP2-9166
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 7
  • Ethanol
  • Sucrose
  • metabotropic glutamate receptor 4