Memantine protects against amphetamine derivatives-induced neurotoxic damage in rodents.
We hypothesize that 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) interact with alpha-7 nicotinic receptors (nAChR). Here we examine whether memantine (MEM), an antagonist of NMDAR and alpha-7 nAChR, prevents MDMA and METH neurotoxicity. MEM prevented both serotonergic injury induced by MDMA in rat and dopaminergic lesion by METH in mice. MEM has a better protective effect in front of MDMA- and METH-induced neurotoxicity than methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist. The double antagonism that MEM exerts on NMDA receptor and on alpha-7 nAChR, probably contributes to its effectiveness. MEM inhibited reactive oxygen species production induced by MDMA or METH in synaptosomes. This effect was not modified by NMDA receptor antagonists, but reversed by alpha-7 nAChR agonist (PNU 282987), demonstrating a preventive effect of MEM as a result of it blocking alpha-7 nAChR. In synaptosomes, MDMA decreased 5-HT uptake by about 40%. This decrease was prevented by MEM and by MLA but enhanced by PNU 282987. A similar pattern was observed when we measured the dopamine transport inhibited by METH. The inhibition of both transporters by amphetamine derivatives seems to be regulated by the calcium incorporation after activation of alpha-7 nAChR. MDMA competitively displaces [(3)H]MLA from rat brain membranes. MEM and METH also displace [(3)H]MLA with non-competitive displacement profiles that fit a two-site model. We conclude that MEM prevents MDMA and METH effects in rodents. MEM may offer neuroprotection against neurotoxicity induced by MDMA and METH by preventing the deleterious effects of these amphetamine derivatives on their respective transporters.
Chipana
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C
Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Avda Joan XXIII s/n, Zona Universitaria Pedralbes, 08028 Barcelona, Spain.
Torres
I
I
Camarasa
J
J
Pubill
D
D
Escubedo
E
E
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000627:therapeutic use*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006213:Hallucinogens; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008559:Memantine / Q000627:therapeutic use*; D008694:Methamphetamine; D051379:Mice; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009457:Neuroglia / Q000187:drug effects; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism
D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D018696:Neuroprotective Agents; C498513:PNU-282987; D017382:Reactive Oxygen Species; D011978:Receptors, Nicotinic; D050486:Serotonin Plasma Membrane Transport Proteins; D008694:Methamphetamine; D016291:Dizocilpine Maleate; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D008559:Memantine