Methyllycaconitine Prevents Methamphetamine-Induced Effects in Mouse Striatum: Involvement of α7 Nicotinic Receptors

Abstract

In a previous study, we demonstrated that in rat striatal synaptosomes, methamphetamine (METH)-induced reactive oxygen species (ROS) production was prevented by methyllycaconitine (MLA), a specific antagonist of ␣7 neuronal nicotinic acetylcholine receptors (␣7 nAChR). The aim of this study was to test the influence of MLA on acute METH effects and neurotoxicity in mice, using both in vivo and in vitro models. MLA inhibited METH-induced climbing behavior by 50%. Acute effects after 30-min preincubation with 1 M METH also included a decrease in striatal synaptosome dopamine (DA) uptake, which was prevented by MLA. METH-induced neurotoxicity was assessed in vivo in terms of loss of striatal dopaminergic terminals (73%) and of tyrosine hydroxylase levels (by 90%) at 72 h post-treatment, which was significantly attenuated by MLA. Microglial activation [measured as 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide binding] was also present at 24 h post-treatment and was fully prevented by MLA, tending to confirm its neuroprotective activity. MLA had no effect on METH-induced hyperthermia. Additionally, flow cytometry assays showed that METH-induced ROS generation occurs inside synaptosomes from mouse striatum. This effect implied release of vesicular DA and was calcium-, neuronal nitric-oxide synthase-, and protein kinase C-dependent. MLA and ␣-bungarotoxin, but not dihydro-␤-erythroidine (an antagonist that blocks nAChR-containing ␤2 subunits), fully prevented METH-induced ROS production without affecting vesicular DA uptake. The importance of this study lies not only in the neuroprotective effect elicited by the blockade of the ␣7 nicotinic receptors by MLA but also in that it proposes a new mechanism with which to study METH-induced acute and longterm effects.

Methamphetamine Causes Microglial Activation in the Brains of Human Abusers

“…Thus, the reactive microgliosis observed presently appears to reflect the effect of METH alone on the human brain. This conclusion is consistent with the preclinical data on the use of METH in rodents (Ladenheim et al, 2000;Escubedo et al, 2005). This idea is also supported by the fact that injection of the drug in mice that mimic recreational dose regimen (4 times ϫ 2 mg/kg injections per day given for a total of 3 d) also caused significant increases in activated microglia in the mouse brain (Thomas and Kuhn, 2005a).…”

Neuroprotective Effects of Kolaviron, a Biflavonoid Complex of <i>Garcinia kola</i>, on Rats Hippocampus against Methamphetamine-Induced Neurotoxicity

“…Methamphetamine (METH) administration induces stereotypic movements in laboratory rats and mice [15,21]. In the present study, METH-induced stereotypy was observed in all animals administrated with METH.…”

“…In this study, Kolaviron (KV) was seen to delay the onset of stereotypy induced by METH. This may be due to its antioxidant properties as METH has been shown to induce neurotoxity and subsequent behavioural effects by the generation of reactive oxygen species (ROS) from the increased extracellular dopamine [15,21,23]. A study has shown that (-)-Epigallocatethin-3-O-gallate (EGCG), a powerful antioxidant and the most abundant polyphenol/flavonoid in green tea, inhibits stereotypy following low dose of METH, cocaine and caffeine [24].…”

“…In the study, there was no observed significant difference in relative brain weight. This may be due to the selective destructive nature of METH [15] [16]. No available study has indicated significant difference in brain weight following METH administration.…”

“…Methamphetamine (METH) is known to induce neurotoxicity in animal models, by the production of reactive species thus resulting in oxidative stress [14,15]. METH has been shown to cause neurodegeneration in various parts of the brain including the striatum, parietal cortex, thalamus and hippocampus [14,16].…”