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.

No abstract

ABSTRACT3 H]spiperone to Chinese hamster ovary-transfected D 3 receptors when radioligands were used at 0.2 and 0.5 nM, respectively. However, even at high concentrations (5 M), SB269,652 only submaximally inhibited the specific binding of these radioligands when they were employed at 10-fold higher concentrations. By analogy, although SB269,652 potently blocked D 3 receptor-mediated activation of G␣ i3 and phosphorylation of extracellular-signal-regulated kinase (ERK)1/2, when concentrations of dopamine were increased by 10-fold, from 1 M to 10 M, SB269,652 only submaximally inhibited dopamine-induced stimulation of G␣ i3 . SB269,652 (up to 10 M) only weakly and partially (by approximately 20 -30%) inhibited radioligand binding to D 2 receptors. Likewise, SB269,652 only submaximally suppressed D 2 receptor-mediated stimulation of G␣ i3 and G␣ qi5 (detected with the aequorin assay) and phosphorylation of ERK1/2 and Akt. Furthermore, SB269,652 only partially (35%) inhibited the dopamine-induced recruitment of ␤-arrestin2 to D 2 receptors. Finally, Schild analysis using G␣ i3 assays, and studies of radioligand association and dissociation kinetics, supported allosteric actions of SB269,652 at D 3 and D 2 receptors.

No abstract

No abstract