Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity
Pharmaceuticals June 15, 2011 Elena Escubedo, Sara Garcia-Ratés, Jordi Camarasa et al. 4 citations
Amphetamine derivatives like methamphetamine (METH) and MDMA (ecstasy) are neurotoxic in animal models and linked to cognitive impairments in heavy users. Their main targets are monoamine transporters, causing increased monoamine release. A key cause of neurotoxicity is increased production of reactive oxygen species (ROS). Blockade of α7 nicotinic acetylcholine receptors (nAChR) inhibits METH- and MDMA-induced ROS production in striatal synaptosomes, a process dependent on calcium and NO-synthase activation. α7 nAChR antagonists attenuated neurotoxicity in vivo, and memantine prevented cognitive impairment. MDMA acts as a partial agonist on α7 and an antagonist on heteromeric nAChR, with sustained calcium increases leading to calpain and caspase-3 activation.