Adaptive changes in group-II metabotropic glutamate receptors underlie the deficit in recognition memory induced by methamphetamine in mice

Cognitive dysfunction is associated with methamphetamine use disorder. Here, we used genetic and pharmacological approaches to examine the involvement of either mGlu2 or mGlu3 receptors in memory deficit induced by methamphetamine in mice. Methamphetamine treatment (1 mg/kg, i.p., once a day for 5 days followed by 7 days of withdrawal) caused an impaired performance in the novel object recognition (NOR) test in wild-type mice, but not in mGlu2^-/- or mGlu3^-/- mice. Memory deficit in wild-type mice challenged with methamphetamine was corrected by systemic treatment with selectively negative allosteric modulators of mGlu2 or mGlu3 receptors (compounds VU6001966 and VU0650786, respectively). Methamphetamine treatment in wild-type mice caused large increases in levels of mGlu2/3 receptors, the type-3 activator of G protein signaling (AGS3), Rab3A and the vesicular glutamate transporter, vGlut1 in the prefrontal cortex (PFC). Methamphetamine did not alter mGlu2/3-mediated inhibition of cAMP formation, but abolished the ability of postsynaptic mGlu3 receptors to boost mGlu5 receptor-mediated inositol phospholipid hydrolysis in PFC slices. Remarkably, activation of presynaptic mGlu2/3 receptors did not inhibit, but rather amplified depolarization-induced [³H]-D-aspartate release in synaptosomes prepared from the PFC of methamphetamine-treated mice.These findings demonstrate that exposure to methamphetamine causes changes in the expression and function of mGlu2 and mGlu3 receptors, which might alter excitatory synaptic transmission in the PFC, and raise the attractive possibility that selective inhibitors of mGlu2 or mGlu3 receptors (or both) may be used to improve cognitive dysfunction in individuals affected by methamphetamine use disorder.Significance Statement Targeting cognitive dysfunction may reduce methamphetamine craving and relapse in individuals who use methamphetamine. Using the novel object recognition (NOR) test for the study of recognition memory we found that cognitive impairment caused by methamphetamine in mice was corrected by genetic deletion or selective pharmacological blockade of either mGlu2 or mGlu3 receptors, two metabotropic glutamate receptor subtypes that control synaptic activity by restraining glutamate release. Interestingly, mGlu2/3 receptors were up-regulated in the prefrontal cortex of methamphetamine-treated mice, and showed an inverse mode of operation by enhancing depolarization-induced glutamate release. These findings suggest that selective mGlu2 or mGlu3 receptor antagonists may improve cognitive function in individuals affected by methamphetamine use disorder.