Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity.
Methamphetamine (MA), a widely used drug of abuse, produces oxidative damage of nigrostriatal dopaminergic terminals. We examined the effect of subtype-selective ligands of metabotropic glutamate (mGlu) receptors on MA neurotoxicity in mice. MA (5 mg/kg, i.p.; injected three times, every 2 hr) induced, 5 d later, a substantial degeneration of striatal dopaminergic terminals associated with reactive gliosis. MA toxicity was primarily attenuated by the coinjection of the noncompetitive mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine and (E)-2-methyl-6-styrylpyridine both at 10 mg/kg, i.p.). In contrast, the mGlu1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (10 mg/kg, i.p.), and the mGlu2/3 receptor agonist (-)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (1 mg/kg, i.p.), failed to affect MA toxicity. mGlu5 receptor antagonists reduced the production of reactive oxygen species but did not reduce the acute stimulation of dopamine release induced by MA both in striatal synaptosomes and in the striatum of freely moving mice. We conclude that endogenous activation of mGlu5 receptors enables the development of MA neurotoxicity and that mGlu5 receptor antagonists are neuroprotective without interfering with the primary mechanism of action of MA.
Battaglia
Giuseppe
G
Instituto Neuromed Mediterraneo, Pozzilli (Isernia) 86077, Italy.
Fornai
Francesco
F
Busceti
Carla L
CL
Aloisi
Gabriella
G
Cerrito
Franca
F
De Blasi
Antonio
A
Melchiorri
Daniela
D
Nicoletti
Ferdinando
F
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006719:Homovanillic Acid / Q000032:analysis / Q000378:metabolism; D062385:Hydroxybenzoates / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D009419:Nerve Tissue Proteins; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D062385:Hydroxybenzoates; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011725:Pyridines; D017382:Reactive Oxygen Species; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C120148:SIB 1893; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C104077:metabotropic glutamate receptor type 1; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; C009135:2,3-dihydroxybenzoic acid; C121465:6-methyl-2-(phenylethynyl)pyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid