A rapid oxidation and persistent decrease in the vesicular monoamine transporter 2 after methamphetamine

Abstract

Methamphetamine (METH) produces long-term decreases in markers of dopamine (DA) terminals in animals and humans. A decrease in the function of the vesicular monoamine transporter 2 (VMAT2) has been associated with damage to striatal DA terminals caused by METH; however, a possible mechanism for this decrease in VMAT2 function has not been defined. The current study showed that METH caused a rapid decrease to 68% of controls in VMAT2 protein immunoreactivity of the vesicular fraction from striatal synaptosomes within 1 h after a repeated high-dose administration regimen of METH. This decrease was associated with a 75% increase in nitrosylation of VMAT2 protein in the synaptosomal fraction as measured by nitrosocysteine immunoreactivity of VMAT2 protein. The rapid decreases in VMAT2 persisted when evaluated 7 days later and were illustrated by decreases in VMAT2 immunoreactivity and DA content of the vesicular fraction to 34% and 51% of control values, respectively. The decreases were blocked or attenuated by prior injections of the neuronal nitric oxide synthase inhibitor, S-methyl-L-thiocitrulline. These studies demonstrate that METH causes a rapid neuronal nitric oxide synthase-dependent oxidation of VMAT2 and long-term decreases in VMAT2 protein and function. The results also suggest that surviving DA terminals after METH exposure may have a compromised capacity to buffer cytosolic DA concentrations and DA-derived oxidative stress.

Methamphetamine-Induced Dopamine Transporter Complex Formation and Dopaminergic Deficits: The Role of D2 Receptor Activation

“…For example, multiple high-dose administrations of METH rapidly (within 1 h) decrease VMAT2 activity (Brown et al, 2000), an effect that may be caused by a rapid redistribution of VMAT2 to a location that is not retained in the preparation of synaptosomes (Riddle et al, 2002) and oxidation of VMAT2 (Eyerman and Yamamoto, 2007). The decrease in VMAT2 function and a loss of VMAT2 immunoreactivity persist 24 h after treatment (Eyerman and Yamamoto, 2005;Chu et al, 2008).…”

“…Studies involving rodents indicate there are many effects caused by repeated high-dose administrations of METH including, but not limited to, oxidative stress (for review, see Brown and Yamamoto, 2003;Krasnova and Cadet, 2009), astrocytic/microglial activation (O'Callaghan and Miller, 1994;LaVoie et al, 2004;Thomas et al, 2004), DAT complex formation (Baucum et al, 2004;Hadlock et al, 2009), and alterations in vesicular monoamine transporter 2 (VMAT2) function (Brown et al, 2000;Eyerman and Yamamoto, 2007;Guillot et al, 2008). However, the relationship among these factors has not been elucidated fully.…”

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

“…Inhibiting neuronal nitric oxide synthase activity prior to METH exposure prevents VMAT2 nitrosylation and subsequent loss of activity (Eyerman and Yamamoto, 2007), suggesting that reactive species modification of VMAT2 may alter function under at least some pathophysiological conditions.…”

“…Of note, nitrosylation of the VMAT2 is reported to occur shortly after METH exposure and results in reduced vesicular DA uptake (Eyerman and Yamamoto, 2007). Inhibiting neuronal nitric oxide synthase activity prior to METH exposure prevents VMAT2 nitrosylation and subsequent loss of activity (Eyerman and Yamamoto, 2007), suggesting that reactive species modification of VMAT2 may alter function under at least some pathophysiological conditions.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Furthermore, blockade of nitric oxide synthase provides full protection against METH-induced loss of DA (Itzhak and Ali, 1996), whereas coadministration of a peroxynitrite decomposition catalyst partially prevents toxicity (Imam et al, 1999). Specific targets have also been identified as METH-induced nitrosylation, coupled with loss of function, and have been observed on the VMAT-2 protein (Eyerman and Yamamoto, 2007). In addition to nitric oxide synthase, other enzymes may also be involved.…”