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

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.