Neuroprotective action of MPEP, a selective mGluR5 antagonist, in methamphetamine-induced dopaminergic neurotoxicity is associated with a decrease in dopamine outflow and inhibition of hyperthermia in rats.
The aim of this study was to examine the role of metabotropic glutamate receptor 5 (mGluR5) in the toxic action of methamphetamine on dopaminergic neurones in rats. Methamphetamine (10 mg/kg sc), administered five times, reduced the levels of dopamine and its metabolites in striatal tissue when measured 72 h after the last injection. A selective antagonist of mGluR5, 2-methyl-6-(phenylethynyl)pyridine (MPEP; 5 mg/kg ip), when administered five times immediately before each methamphetamine injection reversed the above-mentioned methamphetamine effects. A single MPEP (5 mg/kg ip) injection reduced the basal extracellular dopamine level in the striatum, as well as dopamine release stimulated either by methamphetamine (10 mg/kg sc) or by intrastriatally administered veratridine (100 microM). Moreover, it transiently diminished the methamphetamine (10 mg/kg sc)-induced hyperthermia and reduced basal body temperature. MPEP administered into the striatum at high concentrations (500 microM) increased extracellular dopamine levels, while lower concentrations (50-100 microM) were devoid of any effect. The results of this study suggest that the blockade of mGluR5 by MPEP may protect dopaminergic neurones against methamphetamine-induced toxicity. Neuroprotection rendered by MPEP may be associated with the reduction of the methamphetamine-induced dopamine efflux in the striatum due to the blockade of extrastriatal mGluR5, and with a decrease in hyperthermia.
Gołembiowska
K
K
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Cracow, Poland.
Konieczny
J
J
Wolfarth
S
S
Ossowska
K
K
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism* / Q000633:toxicity; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism
C578937:Grm5 protein, rat; D018696:Neuroprotective Agents; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D008694:Methamphetamine; C121465:6-methyl-2-(phenylethynyl)pyridine; D004298:Dopamine