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Pharmaceuticals 2011, 4(6), 822-847; doi:10.3390/ph4060822
Review

Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity

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Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, 08028 Barcelona, Spain
* Author to whom correspondence should be addressed.
Received: 7 April 2011 / Revised: 3 June 2011 / Accepted: 7 June 2011 / Published: 15 June 2011
(This article belongs to the Special Issue Drug Abuse Targets)
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Abstract

Amphetamine derivatives such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) are widely abused drugs in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As far as neurotoxicity is concerned, increased reactive oxygen species (ROS) production seems to be one of the main causes. Recent research has demonstrated that blockade of a7 nicotinic acetylcholine receptors (nAChR) inhibits METH- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, a7 nAChR antagonists (methyllycaconitine and memantine) attenuated in vivo the neurotoxicity induced by METH and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to a7 and heteromeric nAChR, with MDMA showing lower Ki values, while fluorescence calcium experiments indicated that MDMA behaves as a partial agonist on a7 and as an antagonist on heteromeric nAChR. Sustained Ca increase led to calpain and caspase-3 activation. In addition, modulatory effects of MDMA on a7 and heteromeric nAChR populations have been found.
Keywords: MDMA; methamphetamine; nicotinic; neuroprotection; calcium influx MDMA; methamphetamine; nicotinic; neuroprotection; calcium influx
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Pubill, D.; Garcia-Ratés, S.; Camarasa, J.; Escubedo, E. Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity. Pharmaceuticals 2011, 4, 822-847.

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