The metabotropic glutamate receptor 7 (mGluR7) allosteric agonist AMN082 modulates nucleus accumbens GABA and glutamate, but not dopamine, in rats

Neuropharmacology. 2008 Mar;54(3):542-51. doi: 10.1016/j.neuropharm.2007.11.005. Epub 2007 Nov 19.

Abstract

The group III metabotropic glutamate receptor 7 (mGluR7) has been implicated in many neurological and psychiatric diseases, including drug addiction. However, it is unclear whether and how mGluR7 modulates nucleus accumbens (NAc) dopamine (DA), L-glutamate or gamma-aminobutyric acid (GABA), important neurotransmitters believed to be involved in such neuropsychiatric diseases. In the present study, we found that systemic or intra-NAc administration of the mGluR7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) dose-dependently lowered NAc extracellular GABA and increased extracellular glutamate, but had no effect on extracellular DA levels. Such effects were blocked by (R,S)-alpha-methylserine-O-phosphate (MSOP), a group III mGluR antagonist. Intra-NAc perfusion of tetrodotoxin (TTX) blocked the AMN082-induced increases in glutamate, but failed to block the AMN082-induced reduction in GABA, suggesting vesicular glutamate and non-vesicular GABA origins for these effects. In addition, blockade of NAc GABAB receptors by 2-hydroxy-saclofen itself elevated NAc extracellular glutamate. Intra-NAc perfusion of 2-hydroxy-saclofen not only abolished the enhanced extracellular glutamate normally produced by AMN082, but also decreased extracellular glutamate in a TTX-resistant manner. We interpret these findings to suggest that the increase in glutamate is secondary to the decrease in GABA, which overcomes mGluR7 activation-induced inhibition of non-vesicular glutamate release. In contrast to its modulatory effect on GABA and glutamate, the mGluR7 receptor does not appear to modulate NAc DA release.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Anesthetics, Local / pharmacology
  • Animals
  • Baclofen / analogs & derivatives
  • Baclofen / pharmacology
  • Benzhydryl Compounds / pharmacology*
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • GABA Antagonists / pharmacology
  • Glutamic Acid / metabolism*
  • Male
  • Microdialysis / methods
  • Nucleus Accumbens / drug effects*
  • Phosphoserine / pharmacology
  • Rats
  • Rats, Long-Evans
  • Tetrodotoxin / pharmacology
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Anesthetics, Local
  • Benzhydryl Compounds
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • GABA Antagonists
  • N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride
  • methylserine phosphate
  • Phosphoserine
  • Glutamic Acid
  • Tetrodotoxin
  • gamma-Aminobutyric Acid
  • Baclofen
  • Dopamine
  • 2-hydroxysaclofen