Increases in cytoplasmic dopamine compromise the normal resistance of the nucleus accumbens to methamphetamine neurotoxicity

Abstract

Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the caudate–putamen (CPu) where long-term DA depletion and microglial activation are most evident. Even damage within the CPu is remarkably heterogenous with lateral and ventral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared of the damage that accompanies binge METH intoxication. Increases in cytoplasmic DA produced by reserpine, L-DOPA or clorgyline prior to METH uncover damage in the NAc as evidenced by microglial activation and depletion of DA, tyrosine hydroxylase (TH), and the DA transporter. These effects do not occur in the NAc after treatment with METH alone. In contrast to the CPu where DA, TH, and DA transporter levels remain depleted chronically, DA nerve ending alterations in the NAc show a partial recovery over time. None of the treatments that enhance METH toxicity in the NAc and CPu lead to losses of TH protein or DA cell bodies in the substantia nigra or the ventral tegmentum. These data show that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of METH to include brain structures not normally targeted for damage by METH alone. The resistance of the NAc to METH-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of METH neurotoxicity by alterations in DA homeostasis is significant in light of the important roles played by this brain structure.

Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone

“…In support of this conclusion, although there are no studies on 4MM release, an in vitro study found the magnitude of DA release mediated by MeCa to be similar to METH, and greater than that of MEPH (Simmler et al, 2013). Consequently, a greater release in DA would promote the hypothesis that MeCa would induce greater neurotoxicity than MEPH and/or 4MM, since it has been shown in multiple studies that increasing the amount of DA available for release enhances METH toxicity (Kita et al, 1995, Thomas et al, 2008, 2009). Indeed, the depletion levels reported above support this hypothesis.…”

“…Whereas METH can release both cytosolic and vesicular stores, MEPH is only able to access the newly synthesized DA in the cytosol, limiting the amount of neurotransmitter it can release. Increasing the available pool of DA by either VMAT 2 inhibition or exogenous supplementation is known to potentiate the toxicity of METH (Thomas et al, 2008(Thomas et al, , 2009. Thus, it is feasible that the inability of MEPH to release DA via VMAT 2 would blunt its neurotoxic potential.…”

Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat

“…Vulnerability to MA has been linked to cytosolic content of DA. Thus, when blockade of DA storage occurs, MA toxicity is greater (Thomas et al 2009). Conversely, the blockade of de novo DA biosynthesis mitigates MA toxicity (Thomas et al 2008).…”

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence

“…Normalization of levels of a biologically important neurotransmitter could help normalize behavior. However, a practical safety issue is that, based on animal data, levodopa should probably not be administered at a time when residual MA is present in part because of possible damage to dopamine neurons (Thomas et al, 2009)-a consideration that could limit the use of levodopa in MA users who have a transient dopamine deficiency. We also suggest that, before any efficacy investigation, a safetytolerability clinical trial in MA users of levodopa in subjects who are in a controlled setting and are free of residual drug might be warranted.…”