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

Abstract

The group III metabotropic glutamate receptor 7 (mGluR 7) has been implicated in many neurological and psychiatric diseases, including drug addiction. However, it is unclear whether and how mGluR 7 modulates nucleus accumbens (NAc) dopamine (DA), l-glutamate or γ-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 mGluR 7 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)-α-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 GABA B 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 mGluR 7 activation-induced inhibition of non-vesicular glutamate release. In contrast to its modulatory effect on GABA and glutamate, the mGluR 7 receptor does not appear to modulate NAc DA release.