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

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.

• Authors: Xia Li, Eliot L Gardner, Zheng-Xiong Xi
• Journal: Neuropharmacology (Neuropharmacology) Vol. 54 Issue 3 Pg. 542-51 (Mar 2008) ISSN: 0028-3908 [Print] England
• PMID: 18155073 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• 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

Topics

• Analysis of Variance
• Anesthetics, Local (pharmacology)
• Animals
• Baclofen (analogs & derivatives, 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)