Group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) shape mechanisms of methamphetamine addiction, but the individual role played by the two subtypes is unclear. We measured methamphetamine-induced conditioned place preference (CPP) and motor responses to single or repeated injections of methamphetamine in wild-type, mGlu2−/−, and mGlu3−/− mice. Only mGlu3−/− mice showed methamphetamine preference in the CPP test. Motor response to the first methamphetamine injection was dramatically reduced in mGlu2−/− mice, unless these mice were treated with the mGlu5 receptor antagonist, MTEP. In contrast, methamphetamine-induced sensitization was increased in mGlu3−/− mice compared to wild-type mice. Only mGlu3−/− mice sensitized to methamphetamine showed increases in phospho-ERK1/2 levels in the nucleus accumbens (NAc) and free radical formation in the NAc and medial prefrontal cortex. These changes were not detected in mGlu2−/− mice. We also measured a series of biochemical parameters related to the mechanism of action of methamphetamine in naïve mice to disclose the nature of the differential behavioural responses of the three genotypes. We found a reduced expression and activity of dopamine transporter (DAT) and vesicular monoamine transporter-2 in the NAc and striatum of mGlu2−/− and mGlu3−/− mice, whereas expression of the DAT adaptor, syntaxin 1A, was selectively increased in the striatum of mGlu3−/− mice. Methamphetamine-stimulated dopamine release in striatal slices was largely reduced in mGlu2−/−, but not in mGlu3−/−, mice. These findings suggest that drugs that selectively enhance mGlu3 receptor activity or negatively modulate mGlu2 receptors might be beneficial in the treatment of methamphetamine addiction and associated brain damage.
|Publication status||Published - Sept 15 2021|
- Metabotropic glutamate receptors
- Methamphetamine addiction
- Nucleus accumbens
- Syntaxin 1A
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience