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




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Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, 08028 Barcelona, Spain





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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. View Full-Text

Keywords: MDMA; methamphetamine; nicotinic; neuroprotection; calcium influx MDMA; methamphetamine; nicotinic; neuroprotection; calcium influx





Author: David Pubill, Sara Garcia-Ratés, Jordi Camarasa and Elena Escubedo

Source: http://mdpi.com/



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