Deletion of VGLUT2 in midbrain dopamine neurons attenuates dopamine and glutamate responses to methamphetamine in mice

• Published in: Pharmacology, biochemistry and behavior Vol. 202; p. 173104
• Main Authors: Shen, Hui, Chen, Kai, Marino, Rosa Anna M., McDevitt, Ross A., Xi, Zheng-Xiong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2021
• Subjects: Accumbent; Amphetamine-Related Disorders - metabolism; Animals; Behavior, Animal - drug effects; Dopamine; Dopamine - metabolism; Dopamine Uptake Inhibitors - pharmacology; Dopaminergic Neurons - metabolism; Gene Deletion; Gene Knockout Techniques; Glutamate; Glutamic Acid - metabolism; Locomotion - drug effects; Male; Mesencephalon - metabolism; Methamphetamine; Methamphetamine - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microdialysis - methods; Nucleus Accumbens - metabolism; Signal Transduction - drug effects; Vesicular Glutamate Transport Protein 2 - genetics; Vesicular Glutamate Transport Protein 2 - metabolism; VGLUT2; VMAT2; Accumbent; Dopamine; Glutamate; VGLUT2; Methamphetamine; VMAT2
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2021.173104

Methamphetamine (METH) is a highly addictive psychostimulant. The continuous use of METH may lead to its abuse and neurotoxicity that have been associated with METH-induced increases in release of dopamine (DA) and glutamate in the brain. METH action in DA has been shown to be mediated by redistribution of DA from vesicles into cytoplasm via vesicular monoamine transporter 2 (VMAT2) and the subsequent reversal of membrane DA transporter (DAT), while little is known about the mechanisms underlying METH-induced glutamate release. Recent studies indicate that a subpopulation of midbrain DA neurons co-expresses VMAT2 and vesicular glutamate transporter 2 (VGLUT2). Therefore, we hypothesized that METH-induced glutamate release may in part originate from such a dual phenotype of DA neurons. To test this hypothesis, we used Cre-LoxP techniques to selectively delete VGLUT2 from midbrain DA neurons, and then examined nucleus accumbens (NAc) DA and glutamate responses to METH using in vivo brain microdialysis between DA-VGLUT2-KO mice and their VGLUT2-HET littermates. We found that selective deletion of VGLUT2 from DA neurons did not significantly alter basal levels of extracellular DA and glutamate, but attenuated METH-induced increases in extracellular levels of DA and glutamate. In addition, DA-VGLUT2-KO mice also displayed lower locomotor response to METH than VGLUT2-HET control mice. These findings, for the first time, suggest that cell-type specific VGLUT2 expression in DA neurons plays an important role in the behavioral and neurochemical effects of METH. Glutamate corelease from DA neurons may in part contributes to METH-induced increase in NAc glutamate release. •Methamphetamine co-releases DA and glutamate, while the underlying mechanisms are unclear.•VGLUT2 and VMAT2 are colocalized in a subpopulation of DA neurons and promote DA and glutamate update into vesicles.•Deletion of VGLUT2 from DA neurons attenuates behavioral and neurochemical responses to methamphetamine.•These findings suggest that methamphetamine-enhanced DA/glutamate release may be in part derived from DA neurons.