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Published on: August 15, 2012
Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine
David M Thomas1, Donald M Kuhn
1Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Abstract:
Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine-induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low-dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug-induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug-induced hyperthermia.
Insights
Developing tolerance to methamphetamine neurotoxicity in mice blunts microglial activation and dopamine depletion. This tolerance mechanism is separate from methamphetamine-induced hyperthermia.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Methamphetamine causes persistent damage to dopamine nerve endings in the striatum.
- Tolerance to methamphetamine's neurotoxic effects develops with repeated, low-dose exposure.
- Mechanisms of tolerance are unclear, but not solely due to drug bioavailability or hyperthermia.
Purpose of the Study:
- To investigate if a methamphetamine tolerance regimen attenuates the microglial response to a neurotoxic challenge.
- To explore the role of microglia in methamphetamine neurotoxicity and tolerance.
Main Methods:
- Mice received a low-dose methamphetamine tolerance regimen.
- Subsequent neurotoxic challenge with methamphetamine was administered.
- Dopamine content and microglial activation in the striatum were assessed.
- Hyperthermia response was monitored.
Main Results:
- Tolerance regimen mice showed minor dopamine reduction and low microglial activation.
- Pre-treatment with tolerance regimen significantly attenuated dopamine depletion after neurotoxic challenge.
- Microglial activation following toxic challenge was also blunted in tolerant mice.
- Methamphetamine-induced hyperthermia persisted despite tolerance.
Conclusions:
- Tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation.
- These findings dissociate methamphetamine's neurotoxicity from its hyperthermic effects.
- Microglia play a key role in mediating methamphetamine-induced neurotoxicity and its tolerance.
