Protection against MDMA-induced dopaminergic neurotoxicity in mice by methyllycaconitine: involvement of nicotinic receptors.
Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. Previous studies demonstrated the participation of alpha-7 nicotinic receptors (nAChR) in the neurotoxic effect of methamphetamine. The aim of this paper was to study the role of this receptor type in the acute effects and neurotoxicity of MDMA in mice. In vivo, methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist, significantly prevented MDMA-induced neurotoxicity at dopaminergic but not at serotonergic level, without affecting MDMA-induced hyperthermia. Glial activation was also fully prevented by MLA. In vitro, MDMA induced intrasynaptosomal reactive oxygen species (ROS) generation, which was calcium-, nitric-oxide synthase-, and protein kinase C-dependent. Also, the increase in ROS was prevented by MLA and alpha-bungarotoxin. Experiments with reserpine point to endogenous dopamine (DA) as the main source of MDMA-induced ROS. MLA also brought the MDMA-induced inhibition of [3H]DA uptake down, from 73% to 11%. We demonstrate that a coordinated activation of alpha-7 nAChR, blockade of DA transporter function and displacement of DA from intracellular stores induced by MDMA produces a neurotoxic effect that can be prevented by MLA, suggesting that alpha-7 nAChR have a key role in the MDMA neurotoxicity in mice; however, the involvement of nicotinic receptors containing the beta2 subunit cannot be conclusively ruled out.
Chipana
C
C
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n., Zona Universitaria Pedralbes, 08028 Barcelona, Spain.
Camarasa
J
J
Pubill
D
D
Escubedo
E
E
D000157:Aconitine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000209:etiology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D017382:Reactive Oxygen Species / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D017382:Reactive Oxygen Species; D011978:Receptors, Nicotinic; D014316:Tritium; C054634:methyllycaconitine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D000157:Aconitine