QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.089748v1 315/2/658    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Escubedo, E. Articles by Pubill, D. Search for Related Content PubMed PubMed Citation Articles by Escubedo, E. Articles by Pubill, D.

NEUROPHARMACOLOGY

Methyllycaconitine Prevents Methamphetamine-Induced Effects in Mouse Striatum: Involvement of 7 Nicotinic Receptors

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Nucli Universitari de Pedralbes, Universitat de Barcelona, Barcelona, Spain

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 µM 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 long-term effects.

Address correspondence to: David Pubill, Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Av. Joan XXIII s/n; 08028 Barcelona, Spain. E-mail: d.pubill{at}ub.edu

This article has been cited by other articles:

				Y. Sekine, Y. Ouchi, G. Sugihara, N. Takei, E. Yoshikawa, K. Nakamura, Y. Iwata, K. J. Tsuchiya, S. Suda, K. Suzuki, et al. Methamphetamine Causes Microglial Activation in the Brains of Human Abusers J. Neurosci., May 28, 2008; 28(22): 5756 - 5761. [Abstract] [Full Text] [PDF]