1. Minocycline prevents neuronal hyperexcitability and neuroinflammation in medial prefrontal cortex, as well as memory impairment caused by repeated toluene inhalation in adolescent rats.
- Author
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Cruz SL, Armenta-Reséndiz M, Carranza-Aguilar CJ, and Galván EJ
- Subjects
- Administration, Inhalation, Animals, Gene Expression drug effects, Inhalant Abuse, Interleukin-1beta genetics, Male, Memory Disorders chemically induced, NLR Family, Pyrin Domain-Containing 3 Protein physiology, Neurons physiology, Prefrontal Cortex pathology, Prefrontal Cortex physiopathology, Rats, Rats, Wistar, Reactive Oxygen Species antagonists & inhibitors, Toluene administration & dosage, Transforming Growth Factor beta genetics, Anti-Inflammatory Agents administration & dosage, Memory Disorders prevention & control, Minocycline administration & dosage, Neurons drug effects, Prefrontal Cortex drug effects, Toluene toxicity
- Abstract
Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1β (IL-1β), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor β (TGF-β). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them., Competing Interests: Declaration of Competing Interest Funding was provided by grant 239192 (SLC); CB 2016-281617 (EJG) and scholarships 261795 (MAR) and 338376 (CJCA) from Conacyt (National Council of Science and Technology) Mexico., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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