Molecular mechanisms underlying methamphetamine action and neurotoxicity

National Institute On Drug Abuse

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Abstract

Using conditional VgluT2-KO mice, in which vesicular glutamate transporter 2 (VgluT2) is deleted from DA neurons, we found that METH produced a dose-dependent increase in extracellular DA and glutamate in the nucleus accumbens (NAc). Selective deletion of VgluT2 from DA neurons did not significantly alter basal DA or glutamate release, but significantly attenuated METH-induced increases in release of DA and glutamate as well as locomotor response to METH. These findings, for the first time, indicate that METH may act on a specific phenotype of DA-glutamate in the midbrain, producing both behavioral and neurochemical effects. Importantly, small increases (within a physiology-relevant range) in extracellular DA and glutamate are DA neuroprotective as we reported previously in our 2018 PNAS paper. However, excessive co-release of DA and glutamate by high doses of METH may produce an addictive or synergistic neurotoxic effect on midbrain DA neurons, and therefore, increase DA neuron vulnerability to environmental neurotoxin and potentiate the development of PD.