Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug

Vilca, Samara J.; Margetts, Alexander V.; Höglund, Leon; Fleites, Isabella; Bystrom, Lauren L.; Pollock, Tate A.; Bourgain-Guglielmetti, Florence; Wahlestedt, Claes; Tuesta, Luis M.

doi:10.1016/j.bbi.2024.05.038

Brain, Behavior, and Immunity

2024

DOI: 10.1016/j.bbi.2024.05.038

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Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug

Samara J. Vilca,

Alexander V. Margetts,

Leon Höglund

et al.

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2024

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Cited by 2 publications

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α-Pyrrolidinooctanophenone facilitates activation of human microglial cells via ROS/STAT3-dependent pathway

Sakai,

Hattori,

Morikawa

et al. 2024

Forensic Toxicol

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Purpose Pyrrolidinophenone derivatives (PPs) are amphetamine-like designer drugs containing a pyrrolidine ring, and their adverse effects resemble those of methamphetamine (METH). Microglial activation has been recently suggested as a key event in eliciting the adverse effects against dysfunction of the central nervous system. The aim of this study is to clarify the mechanisms of microglial activation induced by PPs. Methods We employed the human microglial cell line HMC3 to assess microglial activation induced by PPs and evaluated the capacities for proliferation and interleukin-6 (IL-6) production that are characteristic features of the activation events. Results The WST-1 assay indicated that viability of HMC3 cells was increased by treatment with sublethal concentrations (5–20 µM) of α-pyrrolidinooctanophenone (α-POP), a highly lipophilic PP, whereas it was decreased by treatment with concentrations above 40 µM. Treatment with sublethal α-POP concentrations up-regulated the expression and secretion of IL-6. Additionally, α-POP-induced increase in cell viability was restored by pretreating with N-acetyl-l-cysteine, a reactive oxygen species (ROS) scavenger, and stattic, an inhibitor of signal transducer and activator of transcription 3 (STAT3), respectively, suggesting that activation of the ROS/STAT3 pathway is involved in the α-POP-induced activation of HMC3 cells. The increases in cell viability were also observed in HMC3 cells treated with other α-POP derivatives and METH. Conclusions These results suggest that enhanced productions of ROS and IL-6 are also involved in microglial activation by drug treatment and that HMC3 cell-based system is available to evaluate accurately the microglial activation induced by abused drugs.

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α-Pyrrolidinooctanophenone facilitates activation of human microglial cells via ROS/STAT3-dependent pathway

Sakai,

Hattori,

Morikawa

et al. 2024

Forensic Toxicol

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Peripheral molecular and brain structural profile implicated stress activation and hyperoxidation in methamphetamine use disorder

Su,

Song,

et al. 2024

Psychiatry Clin Neurosci

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AimMethamphetamine use disorders (MUDs) cause widespread disruptions in metabolomic and immunologic processes, highlighting the need for new therapeutic approaches. The purpose of this study was to find molecular and neuroimaging biomarkers for methamphetamine addiction.MethodsIn this study, we recruited 231 patients with MUD at varying stages of withdrawal and 40 healthy controls to quantify the blood levels of 52 molecules using enzyme‐linked immunosorbent assay.ResultsThe overall molecular disruption caused by methamphetamine was inversely related to withdrawal time (P = 0.0008), with partial recovery observed after 1 year of follow‐up (P = 2.20 × 10−5). Molecules related to stress, immune activation, oxidative products, and cardiac injury were significantly elevated in all MUD groups, while antioxidation enzymes were downregulated. Additionally, the blood level of brain‐derived neurotrophic factor was significantly correlated with gray matter volumes in nine brain regions (fusiform gyrus, orbitofrontal cortex, temporal pole, caudate, cerebellum crus, and vermis, adjusted P < 0.05) among patients with MUD.ConclusionThese findings suggest that patients with MUD exhibit elevated levels of immune response, stress, and oxidative stress, which are associated with brain structural abnormalities.

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Microglia contribute to methamphetamine reinforcement and reflect persistent transcriptional and morphological adaptations to the drug

Cited by 2 publications

References 95 publications

α-Pyrrolidinooctanophenone facilitates activation of human microglial cells via ROS/STAT3-dependent pathway

α-Pyrrolidinooctanophenone facilitates activation of human microglial cells via ROS/STAT3-dependent pathway

Peripheral molecular and brain structural profile implicated stress activation and hyperoxidation in methamphetamine use disorder

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