Anxiety-like symptoms are common symptoms of methamphetamine (METH) users, especially in the acute withdrawal period, which is an important factor for the high relapse rate during METH acute withdrawal. Exercise has been demonstrated to relieve anxiety-like symptoms during METH withdrawal, but the underlying mechanisms of this anti-anxiety effect are still unclear. Activated microglia and abnormal neuroinflammation play an important role in the pathogenesis of anxiety-like symptoms after METH withdrawal. Moreover, peripheral immune factors were also significantly associated with anxiety symptoms. However, the effects of treadmill exercise on microglial function and neuroinflammation in the striatum and hippocampus during acute METH withdrawal have not been reported. In the current study, we found severe peripheral immune dysfunction in METH users during acute withdrawal, which may in part contribute to anxiety symptoms during METH acute withdrawal. We also showed that 2 weeks of METH exposure induced anxiety-like symptoms in the acute withdrawal period. Additionally, METH exposure resulted in increased microglial activation and proinflammatory cytokines released in the mouse striatum and hippocampus during acute withdrawal. We next evaluated the effects of treadmill exercise in countering anxiety-like symptoms induced by METH acute withdrawal. The results showed that anxiety-like symptoms induced by acute METH withdrawal were attenuated by coadministration of treadmill exercise. In addition, treadmill exercise counteracted METH-induced microglial activation in the mouse striatum and various subregions of the hippocampus. Furthermore, treadmill exercise also reversed the increase in proinflammatory cytokines induced by acute METH withdrawal in the mouse striatum, hippocampus and serum. Our findings suggest that the anti-anxiety effect of treadmill exercise may be mediated by reducing microglial activation and regulating central and peripheral inflammatory responses.
Background: Methamphetamine (METH) is a highly addictive, psychoactive drug which can harm individual health and lead to great social problems. Various approaches have been adopted to address the problems arising from METH addiction, but relapse rates remain high. Recently, it has been found that comprehensive treatment combined with scientific and appropriate exercise interventions can improve the mental state and physical fitness of drug addicts and promote their physical and mental rehabilitation. Long-term, regular exercise improves the symptoms of METH withdrawal and reduces METH relapse. This study aimed to investigate the effects and regulated gene expression related to running exercise in METH-addicted mice.Methods: Male C57BL/6J mice were used to construct a METH addiction model. We performed a running exercise intervention and used conditioned place preference (CPP) to measure the effects of the running intervention on the METH-addicted mice. We also performed RNA sequencing (RNA-seq) and transcriptome analysis on the mice hippocampi, and the functions and differentially expressed genes (DEGs) that were significantly regulated by exercise intervention in the METH-addicted mice were analyzed and noted. Results:The results showed that days of CPP were shortened to 3 days in METH-addicted mice that underwent moderate exercise intervention, compared to 6 days in METH-addicted mice that went without exercise intervention. In addition, hippocampal transcriptome analysis revealed 12 DEGs significantly regulated by exercise intervention. By performing Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, it was revealed that the function of immune responses was significantly enriched in the METH-addicted mice undertaking exercise. The expression of 12 DEGs was verified by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), which showed that relative messenger RNA (mRNA) expression of DEGs was consistent with the RNA-seq results.Conclusions: A running intervention can promote the recovery of METH addiction in mice, and the 12 candidate DEGs from the mouse hippocampus can be used for further research on the regulatory mechanisms of exercise in METH-addicted mice.
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