An allosteric potentiator of metabotropic glutamate (mGlu) 2 receptors reduces the cocaine-stimulated ERK1/2 phosphorylation in the mouse striatum.

Metabotropic glutamate (mGlu) receptors are involved in the experience-dependent neuroplasticity in the mesolimbic reward circuit. A Gα-coupled mGlu2 subtype is distributed presynaptically in the striatum. These autoreceptors may have a significant influence over striatal neurons in their intracellular signaling pathways in response to a psychostimulant. Here we explored the effect of pharmacological potentiation of mGlu2 receptors on cocaine-stimulated phosphorylation (activation) of extracellular signal-regulated kinases (ERK) in the mouse striatum in vivo. We found that an mGlu2 selective positive allosteric modulator (PAM) LY487379 after a systemic injection did not alter basal phosphorylation of ERK1/2 or c-Jun N-terminal kinases in the striatum. However, pretreatment with LY487379 blocked the ERK1/2 phosphorylation induced by cocaine in the two subdivisions of the striatum, i.e., the caudate putamen and nucleus accumbens. LY487379 also blocked the cocaine-induced phosphorylation of Elk-1, a transcription factor downstream to the ERK pathway. Additionally, LY487379 reduced locomotor behavioral responses to cocaine. These results demonstrate that the mGlu2 PAM LY487379 possesses the ability to attenuate the activation of the ERK1/2 pathway in striatal neurons and reduce locomotor activity in response to cocaine in vivo.