Negative allosteric modulation of metabotropic glutamate receptor 5 attenuates alcohol self-administration in baboons

Pharmacol Biochem Behav. 2021 Sep:208:173227. doi: 10.1016/j.pbb.2021.173227. Epub 2021 Jul 2.

Abstract

Many of the behavioral symptoms that define alcohol use disorder (AUD) are thought to be mediated by amplified glutamatergic activity. As a result, previous preclinical studies have investigated glutamate receptor inhibition as a potential pharmacotherapy for AUD, particularly the metabotropic glutamate receptor 5 (mGlu5). In rodents, mGlu5 negative allosteric modulators (NAMs) have been shown to decrease alcohol self-administration. However, their effect on non-human primates has not previously been explored. To bridge this gap, the effects of mGlu5 NAM pretreatment on sweetened alcohol (8% w/v in diluted KoolAid) self-administration in female baboons were evaluated. Two different mGlu5 NAMs were tested: 1) 3-2((-Methyl-4-thiazolyl) ethynyl) pyridine (MTEP) which was administered at a dose of 2 mg/kg IM; and 2) auglurant (N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide), a newly developed NAM, which was tested under two different routes (0.001, 0.01, 0.03, 0.1 mg/kg IM and 0.1, 0.3, 1.0 mg/kg PO). MTEP decreased both fixed ratio and progressive ratio responding for sweetened alcohol. Auglurant, administered IM, decreased alcohol self-administration at doses that did not affect self-administration of an alcohol-free sweet liquid reward (0.01 to 0.1 mg/kg). Oral administration of auglurant was not effective in decreasing alcohol self-administration. Our results extend positive findings from rodent studies on mGlu5 regulation of alcohol drinking to female baboons and further strengthen the rationale for targeting mGlu5 in clinical trials for AUD.

Keywords: Alcohol self-administration; Non-human primate; mGlu5.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcoholism / drug therapy*
  • Alcoholism / metabolism
  • Allosteric Regulation / drug effects
  • Aminopyridines / administration & dosage
  • Aminopyridines / pharmacology*
  • Animals
  • Ethanol / administration & dosage
  • Female
  • Glutamic Acid / metabolism
  • Humans
  • Papio
  • Picolinic Acids / administration & dosage
  • Picolinic Acids / pharmacology*
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*
  • Self Administration
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacology*

Substances

  • 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine
  • Aminopyridines
  • Picolinic Acids
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Thiazoles
  • VU0424238
  • Ethanol
  • Glutamic Acid