Methamphetamine (METH) is the primary drug within amphetamine-type stimulants which are the second most abused group of drugs worldwide. There is no pharmacological treatment addressed specifically to METH addiction, and behavioral therapy is shadowed by poor long-term recovery and relapse. Therefore, novel approaches to manage METH addiction are an urgent need. This review aims to describe the current state of physical exercise use on methamphetamine addiction management. The following searching terms in PubMed were used: ("physical exercise" OR "exercise") AND "methamphetamine." Relevant references from key publications and gray literature were also reviewed to identify additional citations for inclusion. Original investigation regarding physical exercise and methamphetamine addiction (clinical data) or neurobiological mechanisms of physical exercise in animal models of methamphetamine administration (preclinical data) was included. Overall, METH users demonstrated improvements, including better fitness and emotional measures, lower relapse rates, and sustained abstinence when compared to nonexercised individuals. The neurobiological mechanisms of physical exercise in METH users seem to reflect an interplay of several agents, including neurochemicals, oxidative stress, neurogenesis, gliogenesis, and blood-brain barrier as disclosed by preclinical data. Exercise-based interventions alone or as a conjoint therapy may be a useful tool for managing METH addiction.

Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis.

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Brain cognitive reserve refers to the ability of the brain to manage different challenges that arise throughout life, making it resilient to neuropathology. Hippocampal adult neurogenesis has been considered to be a relevant contributor for brain cognitive reserve and brain plasticity. Coriolus versicolor (CV), a common healthful mushroom, has been receiving increasing attention by its antitumoral, anti-inflammatory, antioxidant, antibacterial, and immunomodulatory properties, including in the hippocampus. Herein, we evaluated whether CV biomass oral administration for 2.5 months enhances hippocampal neurogenic reserve under normal/physiological conditions, by quantifying hippocampal dentate gyrus (DG) granular cell layer (GCL) and subgranular zone (SGZ) volumes, proliferation, number and dendritic complexity features of hippocampal newly-generated neurons. We also analyzed β-catenin levels in DG newly-generated immature neurons, because it plays a major role in neurogenesis. Although no differences were observed in the volume of GCL and SGZ layers, in proliferation and in the number of newly-generated neurons of controls and CV-administered mice, we found that CV administration promotes a significant increase in dendritic length and branching and total dendritic volume of immature neurons, suggesting a positive effect of oral CV administration in the hippocampal neurogenic reserve. We also observed that β-catenin levels are increased both in the nucleus and cytoplasm of DG immature neurons, suggesting that Wnt/β-catenin signalling may play an important role in the CV positive effect on the differentiation of these cells. These data unveil a so far unexplored neurogenic potential of CV supplementation, which emerges as a possible preventive strategy for different neurological conditions.

We report, for the first time, that a single METH injection triggers early self-care and hedonic deficits and impairs frontal cortical energetics in mice.

3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") is a widespread drug of abuse with known neurotoxic properties. The present study aimed to evaluate the differential toxic effects of MDMA in adolescent and aged Wistar rats, using doses pharmacologically comparable to humans. Adolescent (post-natal day 40) (3 × 5 mg/kg, 2 h apart) and aged (mean 20 months old) (2 × 5 mg/kg, 2 h apart) rats received MDMA intraperitoneally. Animals were killed 7 days later, and the frontal cortex, hippocampus, striatum and cerebellum brain areas were dissected, and heart, liver and kidneys were collected. MDMA caused hyperthermia in both treated groups, but aged rats had a more dramatic temperature elevation. MDMA promoted serotonergic neurotoxicity only in the hippocampus of aged, but not in the adolescents' brain, and did not change the levels of dopamine or serotonin metabolite in the striatum of both groups. Differential responses according to age were also seen regarding brain p-Tau levels, a hallmark of a degenerative brain, since only aged animals had significant increases. MDMA evoked brain oxidative stress in the hippocampus and striatum of aged, and in the hippocampus, frontal cortex, and striatum brain areas of adolescents according to protein carbonylation, but only decreased GSH levels in the hippocampus of aged animals. The brain maturational stage seems crucial for MDMA-evoked serotonergic neurotoxicity. Aged animals were more susceptible to MDMA-induced tissue damage in the heart and kidneys, and both ages had an increase in liver fibrotic tissue content. In conclusion, age is a determinant factor for the toxic events promoted by "ecstasy". This work demonstrated special susceptibility of aged hippocampus to MDMA neurotoxicity, as well as impressive damage to the heart and kidney tissue following "ecstasy".

Parkinson's disease (PD) prodromal stages comprise neuropsychiatric perturbations that critically compromise a patient's quality of life. These nonmotor symptoms (NMS) are associated with exacerbated innate immunity, a hallmark of overt PD. Physical exercise (PE) has the potential to improve neuropsychiatric deficits and to modulate immune network including receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in distinct pathological settings. Accordingly, the present study aimed to test the hypothesis that PE ) alleviates PD NMS and) modulates neuroimmune RAGE network in experimental PD. Adult Wistar rats subjected to long-term mild treadmill were administered intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probed for PD NMS before the onset of motor abnormalities. Twelve days after MPTP, neuroimmune RAGE network transcriptomics (real-time quantitative PCR) was analyzed in frontal cortex, hippocampus, and striatum. Untrained MPTP animals displayed habit-learning and motivational deficits without gross motor impairments (cued version of water-maze, splash, and open-field tests, respectively). A suppression of RAGE and neuroimmune-related genes was observed in frontal cortex on chemical and physical stressors (untrained MPTP: RAGE, TLR5 and -7, and p22 NADPH oxidase; saline-trained animals: RAGE, TLR1 and -5 to -11, TNF-α, IL-1β, and p22 NADPH oxidase), suggesting the recruitment of compensatory mechanisms to restrain innate inflammation. Notably, trained MPTP animals displayed normal cognitive/motivational performances. Additionally, these animals showed normal RAGE expression and neuroprotective PD-related gene upregulation in frontal cortex when compared with untrained MPTP animals. These findings corroborate PE efficacy in improving PD NMS and newly identify RAGE network as a neural substrate for exercise intervention. Additional research is warranted to unveil functional consequences of PE-induced modulation of RAGE/DJ-1 transcriptomics in PD premotor stages. This study newly shows that physical exercise (PE) corrects nonmotor symptoms of the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of experimental parkinsonism. Additionally, we show that suppression of neuroimmune receptor for advanced glycation end products (RAGE) network occurs in frontal cortex on chemical (MPTP) and physical (PE) interventions. Finally, PE normalizes frontal cortical RAGE transcriptomics and upregulates the neuroprotective gene in the intranasal MPTP model of experimental parkinsonism.