Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity
Elena Escubedo, Sara Garcia-ratés, Jordi Camarasa, David Pubill
Pharmaceuticals June 15, 2011 Peer reviewed DOI: 10.3390/ph4060822 via DOAJ
Summary
Blockade of a7 nicotinic acetylcholine receptors (nAChR) reduces the neurotoxicity and cognitive impairment caused by methamphetamine (METH) and MDMA, as shown in studies with antagonists like methyllycaconitine and memantine. These substances inhibit the reactive oxygen species production linked to these drugs, which is dependent on calcium and NO-synthase activation. MDMA acts as a partial agonist on a7 nAChR while being an antagonist on heteromeric nAChR, affecting calcium influx and subsequent neurotoxic processes.
Study at a glance
| Key finding | Blockade of a7 nAChR inhibits METH- and MDMA-induced reactive oxygen species production and reduces their neurotoxic effects. |
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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.