Methamphetamine produces neuronal inclusions in the nigrostriatal system and in PC12 cells

Abstract

Mice treated with the psychostimulant methamphetamine (MA) showed the appearance of intracellular inclusions in the nucleus of medium sized striatal neurones and cytoplasm of neurones of the substantia nigra pars compacta but not in the frontal cortex. All inclusions contained ubiquitin, the ubiquitin activating enzyme (E1), the ubiquitin protein ligase (E3-like, parkin), low and high molecular weight heat shock proteins (HSP 40 and HSP 70). Inclusions found in nigral neurones stained for a-synuclein, a proteic hallmark of Lewy bodies that are frequently observed in Parkinson's disease and other degenerative disorders. However, differing from classic Lewy bodies, MA-induced neuronal inclusions appeared as multilamellar bodies resembling autophagic granules. Methamphetamine reproduced this effect in cultured PC12 cells, which offered the advantage of a simple cellular model for the study of the molecular determinants of neuronal inclusions. PC12 inclusions, similar to those observed in nigral neurones, were exclusively localized in the cytoplasm and stained for a-synuclein. Time-dependent experiments showed that inclusions underwent a progressive fusion of the external membranes and developed an electrodense core. Inhibition of dopamine synthesis by a-methyl-p-tyrosine (aMpT), or administering the antioxidant S-apomorphine largely attenuated the formation of inclusions in PC12 cells exposed to MA. Inclusions were again observed when aMpTtreated cells were loaded with L-DOPA, which restored intracellular dopamine levels.

Single or multiple injections of methamphetamine increased dopamine turnover but did not decrease tyrosine hydroxylase levels or cleave caspase‐3 in caudate‐putamen

“…METH-induced neurotoxicity in monoaminergic systems has been observed in rats given single large doses (in the range of 20-100 mg/kg) (Cappon et al, 2000;Fukumura et al, 1998;Imam and Ali, 2001;Seiden and Vosmer, 1984) or 5-10 mg/kg, given four times at intervals of 2 h (Chapman et al, 2001). Toxicity in dopaminergic systems was also reported in mice given either a single dose of METH (25 mg/kg) (Hayashi et al, 2001) or multiple doses, with the animals receiving four injections of METH varying from 5 to 10 mg/kg at 2-h intervals (Ali et al, 1994;Fornai et al, 2004;Thomas et al, 2004). Recently, in vivo studies have suggested that METH can also cause neuronal apoptosis in rodents by the concurrent activation of mitochondrial and endoplasmic reticulum death pathways in mice striatal cells (Jayanthi et al, 2004), and by the upregulation of Fas ligand/Fas death pathway in rat striatal cells (Jayanthi et al, 2005).…”

Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and α-synuclein

“…1) even after repeated injections (11,12). Besides MPTP, at least three other toxins, rotenone (13)(14)(15), ubiquitin-proteasome inhibitors (16,17), and methamphetamine (18), produce a PD-like syndrome in mice, but unlike MPTP, these toxins also cause formation of ␣-synuclein-containing inclusions (13)(14)(15)(16)(17)(18).…”

The JNK inhibitor, SP600125, potentiates the glial response and cell death induced by methamphetamine in the mouse striatum

“…GFAP staining is considered to be a hallmark of neurotoxicity and has been closely associated with METH or MDMA-induced striatal dopaminergic neurotoxicity (Fornai et al, 2004;Busceti et al, 2008;Granado et al, 2011b;Ares-Santos et al, 2012). Genetic inactivation of dopamine D1 or D2 receptors prevents astrogliosis and provides protection against the neurotoxic effects of METH (Granado et al, 2011a;Ares-Santos et al, 2012).…”