Systemic Modulation of Group II mGluRs Increases Extracellular Lactate in the Rat Prefrontal Cortex.

Abstract

Background: Lactate is increasingly recognized as a dynamic indicator of neuronal activity and brain energy metabolism and is closely linked to glutamatergic neurotransmission via the astrocyte-neuron lactate shuttle. Group II metabotropic glutamate receptors (mGluR2/3) regulate glutamate release and have been implicated in psychiatric disorders; however, their role in cortical lactate metabolism remains unclear.

Methods: In this study, we examined the effects of pharmacological modulation of mGluR2/3 on extracellular lactate concentration (eLAC) in the medial prefrontal cortex of naïve rats using in vivo microdialysis. Systemic administration of an mGluR2/3 agonist (LY354740), an mGluR2 positive allosteric modulator (LY487379) and selective antagonists were evaluated. To explore the potential involvement of mGluR3 in cortical metabolism, we evaluated the effects of 2-PMPA, a glutamate carboxypeptidase II (GCP-II) inhibitor that increases endogenous levels of N-acetylaspartylglutamate (NAAG), which preferentially activates mGluR3 over mGluR2.

Results: Systemic administration of LY354740 or LY487379 unexpectedly increased eLAC. These effects of LY354740 and LY487379 were prevented by the mGluR2 antagonist Ro 64-5229. In addition, systemic administration of 2-PMPA increased eLAC, and this effect was blocked by LY341495, an mGluR2/3 antagonist.

Conclusions: These findings indicate that systemic modulation of group II mGluRs may engage indirect network-level mechanisms that influence cortical energy metabolism. These results provide new insight into the relationship between glutamatergic signaling and brain metabolic dynamics.