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. 2021 Mar:202:173104.
doi: 10.1016/j.pbb.2021.173104. Epub 2021 Jan 12.

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

Hui Shen  1 , Kai Chen  2 , Rosa Anna M Marino  3 , Ross A McDevitt  4 , Zheng-Xiong Xi  5
Affiliations

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

Hui Shen et al. Pharmacol Biochem Behav. 2021 Mar.

Abstract

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.

Keywords: Accumbent; Dopamine; Glutamate; Methamphetamine; VGLUT2; VMAT2.

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Conflict of interest statement

Declaration of competing interest

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Identification of VGLUT2 expression in midbrain DA neurons. A-B: Representative confocal images, illustrating VGLUT2 mRNA (red)- and TH mRNA (green)-staining in the VTA of both VGLUT2-Het (Het) control mice and DA-VGLUT2-KO (cKO) mice. No VGLUT2 mRNA was detected in TH+ neurons in the VTA of the cKO mice. C: Averaged cell counts of TH+ only, VGLUT2+ only, and dual TH+-VGLUT2+ neurons in each section under 20× magnification in Het (n = 5) and cKO (n = 5) mice. D: cKO mice display a significant (~75%) reduction in dual TH+-VGLUT2+ neurons compared to Het control mice. **p < 0.01, compared to Het control mice. Data indicate means ± SEM.
Fig. 2.
Fig. 2.
Selective deletion of VGLUT2 from DA neurons blunted DA response to METH. A: Basal level of extracellular DA in the NAc in HET and cKO mice. B: NAc DA response to 0.5 mg/kg METH. There is no significant difference observed between two genotypes of mice. C: NAc DA response to a higher dose (1 mg/kg, i.p.) of METH. The cKO mice displayed a blunted DA response to METH compared to the HET control mice. *p < 0.05, **p < 0.01, ***p < 0.001, compared to baseline before METH injection. #p < 0.05, compared to HET.
Fig. 3.
Fig. 3.
Selective deletion of VGLUT2 from DA neurons blunted NAc glutamate response to METH. A: Basal level of extracellular glutamate in the NAc in HET and cKO mice. B: NAc glutamate response to 0.5 mg/kg METH. C: NAc glutamate response to 1 mg/kg METH. cKO mice displayed an attenuated glutamate response to METH compared to HET control mice. *p < 0.05, **p < 0.01, compared to baseline before METH injection. #p < 0.05, compared to HET.
Fig. 4.
Fig. 4.
Selective deletion of VGLUT2 from DA neurons blunted locomotor response to METH. A, B: Dose-dependent effects of METH in HET and cKO mice. C: Locomotor response (% baseline) to 0.5 mg/kg METH. D: Locomotor response (% baseline) to 1 mg/kg METH. METH, at 1 mg/kg, increased open-field locomotion in HET, but not in cKO mice. *p < 0.05, **p < 0.01, ***p < 0.001, compared to baseline before METH injection. #p < 0.05, ##p < 0.01, ###p < 0.001, compared to HET group.
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