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Microgliosis and down-regulation of adenosine transporter induced by methamphetamine in rats
E Escubedo1, L Guitart, F X Sureda
1Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia, Nucli Universitari de Pedralbes, 08028, Barcelona, Spain. escubedo@far.ub.es
Abstract:
Chronic administration of methamphetamine to rats induces neurotoxicity characterized by a loss of striatal dopaminergic terminals and reactive gliosis. Subcutaneous administration of methamphetamine in a scheduled procedure of four doses (10 mg/kg) at 2 h interval also induces a significant increase in the peripheral-type benzodiazepine receptor (PBR) density. This increase is maximum (76%) at 72 h post-treatment in the striatum and disappears at 7 days, suggesting that microglia may have a predominant role in necrosis-phagocytosis of neuronal debris rather than acting in a restorative manner. Microgliosis is not restricted to the striatum since it is also evident in cerebellum (75.4% of PBR increase) and hippocampus (37.2% of PBR increase). In the areas with high density of adenosine transporter, the microgliosis phenomenon correlates well with a decrease of this nucleoside transporter (about 39%). Although the microgliosis and the decrease in adenosine transporter could be parallel and not related events, we can speculate that when microglia are activated, a down-regulation of adenosine transporter occurs, playing a role in tissue homeostasis. With the same dosing schedule, methamphetamine induces HSP72 expression in both cytoplasmic and nuclear fractions of the striatum, cerebellum and hippocampus. This expression is also evident in the cerebral cortex, where adenosine transporter population did not show any variation.
Insights
Chronic methamphetamine exposure in rats causes neurotoxicity and reactive gliosis. This study reveals increased peripheral-type benzodiazepine receptor density, indicating microglial activation and potential roles in neuronal damage and tissue homeostasis.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- Chronic methamphetamine administration leads to neurotoxicity, including dopaminergic terminal loss and reactive gliosis.
- Methamphetamine-induced neurotoxicity involves changes in glial cell activity and receptor expression.
Purpose of the Study:
- To investigate the effects of chronic methamphetamine administration on peripheral-type benzodiazepine receptor (PBR) density and adenosine transporter levels in rat brain regions.
- To explore the role of microglia in methamphetamine-induced neurotoxicity and its impact on tissue homeostasis.
Main Methods:
- Rats received subcutaneous methamphetamine (10 mg/kg) in four doses at 2-hour intervals.
- Peripheral-type benzodiazepine receptor (PBR) density was measured using radioligand binding.
- Adenosine transporter levels and HSP72 expression were assessed in various brain regions.
Main Results:
- Methamphetamine significantly increased PBR density in the striatum (76%), cerebellum (75.4%), and hippocampus (37.2%), peaking at 72 hours.
- Microgliosis correlated with a decrease in adenosine transporter levels (39%) in specific brain areas.
- Methamphetamine induced HSP72 expression in the striatum, cerebellum, hippocampus, and cerebral cortex.
Conclusions:
- Methamphetamine-induced microgliosis suggests a role for microglia in neuronal debris phagocytosis rather than repair.
- Activated microglia may down-regulate adenosine transporters, potentially influencing tissue homeostasis.
- HSP72 expression indicates a cellular stress response to methamphetamine exposure across multiple brain regions.