Physical exercise is effective in enhancing cognitive function, reducing anxiety and depressive symptoms, reducing cravings, and improving quality of life in methamphetamine (METH) addiction. However, little is known about the effect of exercise on metabolic profiles. We performed LC/MS-based targeted metabolic profiling on serum samples to investigate the metabolic characteristics of METH dependence and find the differences between METH-dependent individuals and nonusers and evaluated the metabolomic profiles of individuals with METH dependence following aerobic exercise training. We identified a total of 201 metabolites, among which 115 were differentially expressed under METH use. Among the differentially regulated metabolites, 72 were selected as potential biomarkers. Further analysis identified 19 pathways, among which glyoxylate and dicarboxylate metabolism; alanine, aspartate, and glutamate metabolism; and citrate cycle were most significantly affected by METH. The aerobic exercise intervention differentially regulated 55 metabolites, of which 51 were selected as potential biomarkers and were mainly enriched in 10 pathways. Interestingly, alanine, aspartate, and glutamate metabolism and nitrogen metabolism were the remarkably affected pathways. Furthermore, METH increased the serum levels of glutamate and decreased GABA, whereas exercise decreased the serum levels of glutamate and increased GABA. Results suggested that METH dependency disturbed normal metabolic homeostasis, whereas exercise restored metabolism.

(1) Background: Aging is the main risk factor for most neurodegenerative diseases, and the inhibition of Phosphodiesterase 4(PDE4) is considered a potential target for the treatment of neurological diseases. The purpose of this study was to investigate the inhibitory effect of moderate-intensity intermittent training (MIIT) on PDE4 in the hippocampus of rats with D-galactose (D-gal)-induced cognitive impairment, and the possible mechanism of improving spatial learning and memory. (2) Methods: the aging rats were treated with D-Gal (150 mg/kg/day, for 6 weeks). The aging rats were treated with MIIT for exercise intervention (45 min/day, 5 days/week, for 8 weeks). The Morris water maze test was performed before and after MIIT to evaluate the spatial learning and memory ability, then to observe the synaptic ultrastructure of the hippocampus CA1 region, to detect the expression of synaptic-related protein synaptophysin (SYP) and postsynaptic density protein 95 (PSD95), and to detect the expression of PDE4 subtypes, cAMP, and its signal pathway protein kinase A (PKA)/cAMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF), and the PDE4 methylation level. (3) Results: we found that MIIT for 8 weeks alleviated the decline in spatial learning and memory ability, and improved the synaptic structure of the hippocampus and the expression of synaptic protein SYP and PSD95 in D-Gal aging rats. To elucidate the mechanism of MIIT, we analyzed the expression of PDE4 isoforms PDE4A/PDE4B/PDE4D, cAMP, and the signaling pathway PKA/CREB/BDNF, which play an important role in memory consolidation and maintenance. The results showed that 8 weeks of MIIT significantly up-regulated cAMP, PKA, p-CREB, and BDNF protein expression, and down-regulated PDE4D mRNA and protein expression. Methylation analysis of the PDE4D gene showed that several CG sites in the promoter and exon1 regions were significantly up-regulated. (4) Conclusions: MIIT can improve the synaptic structure of the hippocampus CA1 area and improve the spatial learning and memory ability of aging rats, which may be related to the specific regulation of the PDE4D gene methylation level and inhibition of PDE4D expression.

This study aimed to investigate the changes in intestinal homeostasis and metabolism in mice after methamphetamine (MA) administration and exercise intervention. In this study, male C57BL/B6J mice were selected to establish a model of methamphetamine-induced addiction, and the gut microbiota composition, short-chain fatty acids (SCFAs), and amino acid levels were assessed by 16S rRNA, liquid chromatography–tandem mass spectrometry, and gas chromatography–tandem mass spectrometry, respectively. The results showed that 23 dominant microbiota, 12 amino acids, and 1 SCFA were remarkably higher and 9 amino acids and 6 SCFAs were remarkably lower in the exercise model group than in the control group. Among the top 10 markers with opposite trends between the exercise intervention group and model group, the differential microbiomes included Oscillibacter, Alloprevotella, Colidextribacter, Faecalibaculum, Uncultured, Muribaculaceae, and Negativibacillus; amino acids included proline; and SCFAs included isovaleric acid and pentanoic acid. Proline was negatively correlated with Negativibacillus and positively correlated with pentanoic acid. The results suggested that moderate-intensity aerobic exercise may modulate changes in the composition of the gut microbiota and the levels of amino acids and SCFAs induced by MA administration.

Objective: Drug dependence has become a major global public health problem. This study aimed to investigate the effects of moderate-intensity aerobic exercise on the blood–brain barrier and neurological damage in methamphetamine (MA)-dependent individuals. Methods: MA-dependent individuals (all males) were recruited and randomly divided into MA exercise group (MAE) and MA control group (MAC) by using random number table method. The MAE group underwent 12 weeks of moderate-intensity aerobic exercise, and the MAC group underwent conventional detoxification. The Neurofilament light chain (NfL), S100 calcium binding protein b (S100b), and Neuron-Specific Enolase (NSE) levels in the blood of MA-dependent individuals were measured before and after the exercise intervention. Results: After the exercise intervention was implemented, the amount of change in NfL in the plasma of the MAE (1.75 ± 1.40) group was significantly different from that of the MAC (0.60 ± 1.21) group (p < 0.01); the amount of change in NSE in the serum of the MAE [−1.51 (−3.99~0.31)] group was significantly different from that of the MAC [0.03 (−1.18~1.16)] group (p < 0.05); and the amount of change in S100b in the serum of the MAE [0.66 (0.40~0.95)] group was not significantly different from that of the MAC (0.60 (0.21~1.04)) group (p > 0.05). Conclusion: This study showed that 12 weeks of moderate-intensity aerobic exercise treatment significantly promoted the recovery of blood–brain barrier and neurological damage in MA-dependent patients compared with conventional withdrawal.

In recent years, an increasing number of studies have used metabolomics techniques to uncover the underlying mechanisms of diseases, including substance abuse. Although physical exercise has been considered as a potential treatment for methamphetamine (MA) abuse, there is still a lack of studies regarding exercise modulating the metabolic profile of the brain following MA use. This untargeted metabolomics study, based on liquid chromatography-mass spectrometry (LC-MS), investigated the effects of aerobic exercise on MA-induced metabolism in mice brain. We found that 2 weeks of treadmill training modulates MA-induced metabolic disturbances in the brain. Among these metabolites, 129 metabolites with significant differences were identified under MA induction, and 32 metabolites were significantly affected by exercise. The relevant differential metabolites were mainly enriched in glycerophospholipid metabolism, steroid hormone biosynthesis and degradation, and renin-angiotensin system pathways. To our knowledge, this is the first study to use LC-MS approach to explore the effects of aerobic exercise on MA-induced metabolic profiles in the brain. The findings of this study provide new insights into exercise therapy for MA use.