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Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator
Gausiha Rathitharan1,2, Jennifer Truong1,2, Junchao Tong1,3,4
1Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Abstract:
Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)-seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high-dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C-11](R)-PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second-generation TSPO radioligand, [F-18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (VT ) of [F-18]FEPPA was estimated with a two-tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM-ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F-18]FEPPA VT (P = .81). No significant correlations between [F-18]FEPPA VT and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self-reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F-18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data.
Insights
Brain microglial activation, a marker of neuroinflammation, was not elevated in chronic methamphetamine users. This suggests microglia may not be a primary target for treating methamphetamine use disorder.
Area of Science:
- Neuroscience
- Radiochemistry
- Addiction Psychiatry
Background:
- Microglial activation (microgliosis) is implicated in methamphetamine (MA) seeking behavior.
- Previous studies show conflicting results regarding microgliosis in human MA users.
- Translocator protein 18 kDa (TSPO) is a biomarker for microgliosis.
Purpose of the Study:
- To investigate brain microgliosis in chronic MA users using a novel PET radioligand.
- To assess the relationship between MA use and TSPO binding.
- To evaluate microglia as a potential therapeutic target for MA use disorder.
Main Methods:
- Positron emission tomography (PET) imaging with [F-18]FEPPA, a second-generation TSPO radioligand.
- Quantification of regional total volume of distribution (VT) in 10 brain regions.
- Comparison of MA users (n=11) and controls (n=26), with correction for TSPO rs6971 polymorphism.
Main Results:
- No significant difference in [F-18]FEPPA VT was found between MA users and controls (P = .81).
- No correlations were observed between [F-18]FEPPA VT and MA use parameters (duration, dosage, blood concentration) or craving.
- Preliminary findings do not support substantial brain microgliosis in MA use disorder.
Conclusions:
- The study does not provide evidence for significant brain microgliosis in chronic MA users.
- Absence of increased TSPO binding may be due to insufficient MA dose or blunted microglial response.
- Microglia's role as a therapeutic target in MA addiction requires further investigation.
