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Updated: Sep 8, 2026
A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity
Giuseppe Battaglia1, Francesco Fornai, Carla L Busceti
1Instituto Neuromed Mediterraneo, Pozzilli (Isernia) 86077, Italy.
Abstract:
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.
Insights
Metabotropic glutamate 5 (mGlu5) receptor antagonists protect against methamphetamine (MA) neurotoxicity by reducing oxidative damage. These compounds offer neuroprotection without altering MA's acute dopamine release effects.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Methamphetamine (MA) abuse causes oxidative damage to dopaminergic neurons.
- Metabotropic glutamate (mGlu) receptors are implicated in neuronal function and drug toxicity.
Purpose of the Study:
- To investigate the neuroprotective effects of mGlu receptor subtype-selective ligands against MA-induced neurotoxicity in mice.
- To determine if mGlu5 receptor antagonists can prevent MA-induced damage to nigrostriatal dopaminergic terminals.
Main Methods:
- Mice were administered MA and various mGlu receptor ligands.
- Neurotoxicity was assessed by measuring dopaminergic terminal degeneration and reactive gliosis.
- Reactive oxygen species production and dopamine release were analyzed in striatal synaptosomes and in vivo.
Main Results:
- MA induced significant degeneration of striatal dopaminergic terminals and reactive gliosis.
- Co-administration of mGlu5 receptor antagonists (2-methyl-6-(phenylethynyl)pyridine and (E)-2-methyl-6-styrylpyridine) attenuated MA neurotoxicity.
- mGlu1 and mGlu2/3 receptor ligands did not affect MA toxicity.
- mGlu5 antagonists reduced reactive oxygen species production but not MA-induced dopamine release.
Conclusions:
- Endogenous activation of mGlu5 receptors is crucial for the development of MA neurotoxicity.
- mGlu5 receptor antagonists demonstrate neuroprotective properties against MA.
- mGlu5 antagonists offer a potential therapeutic strategy by providing neuroprotection without interfering with MA's primary mechanism of action.
