Showing papers on "Meth- published in 2019"

Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms

Abstract: Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- and stress-induced reinstatement of cocaine and priming-induced reinstatement of METH seeking behaviours. CBD also potentiated the extinction of cocaine- and amphetamine-induced conditioned place preference (CPP), impaired the reconsolidation of cocaine CPP and prevented priming-induced reinstatement of METH CPP. Observational studies suggest that CBD may reduce problems related with crack-cocaine addiction, such as withdrawal symptoms, craving, impulsivity and paranoia (Fischer et al., 2015). The potential mechanisms involved in the protective effects of CBD on addiction to psychostimulant drugs include the prevention of drug-induced neuroadaptations (neurotransmitter and intracellular signalling pathways changes), the erasure of aberrant drug-memories, the reversion of cognitive deficits induced by psychostimulant drugs and the alleviation of mental disorders comorbid with psychostimulant abuse. Further, preclinical studies and future clinical trials are necessary to fully evaluate the potential of CBD as an intervention for cocaine and methamphetamine addictive disorders.

Cross-talk between microglia and neurons regulates HIV latency.

Abstract: Despite effective antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are found in nearly one-third of patients. Using a cellular co-culture system including neurons and human microglia infected with HIV (hμglia/HIV), we investigated the hypothesis that HIV-dependent neurological degeneration results from the periodic emergence of HIV from latency within microglial cells in response to neuronal damage or inflammatory signals. When a clonal hμglia/HIV population (HC69) expressing HIV, or HIV infected human primary and iPSC-derived microglial cells, were cultured for a short-term (24 h) with healthy neurons, HIV was silenced. The neuron-dependent induction of latency in HC69 cells was recapitulated using induced pluripotent stem cell (iPSC)-derived GABAergic cortical (iCort) and dopaminergic (iDopaNer), but not motor (iMotorNer), neurons. By contrast, damaged neurons induce HIV expression in latently infected microglial cells. After 48-72 h co-culture, low levels of HIV expression appear to damage neurons, which further enhances HIV expression. There was a marked reduction in intact dendrites staining for microtubule associated protein 2 (MAP2) in the neurons exposed to HIV-expressing microglial cells, indicating extensive dendritic pruning. To model neurotoxicity induced by methamphetamine (METH), we treated cells with nM levels of METH and suboptimal levels of poly (I:C), a TLR3 agonist that mimics the effects of the circulating bacterial rRNA found in HIV infected patients. This combination of agents potently induced HIV expression, with the METH effect mediated by the σ1 receptor (σ1R). In co-cultures of HC69 cells with iCort neurons, the combination of METH and poly(I:C) induced HIV expression and dendritic damage beyond levels seen using either agent alone, Thus, our results demonstrate that the cross-talk between healthy neurons and microglia modulates HIV expression, while HIV expression impairs this intrinsic molecular mechanism resulting in the excessive and uncontrolled stimulation of microglia-mediated neurotoxicity.

Methamphetamine Activates Toll-Like Receptor 4 to Induce Central Immune Signaling within the Ventral Tegmental Area and Contributes to Extracellular Dopamine Increase in the Nucleus Accumbens Shell.

Abstract: Methamphetamine (METH) is a globally abused, highly addictive stimulant. While investigations of the rewarding and motivational effects of METH have focused on neuronal actions, increasing evidence suggests that METH can also target microglia, the innate immune cells of the central nervous system, causing release of proinflammatory mediators and therefore amplifying the reward changes in the neuronal activity induced by METH. However, how METH induces neuroinflammatory responses within the central nervous system (CNS) is unknown. Herein, we provide direct evidence that METH creates neuroinflammation, at least in part, via the activation of the innate immune Toll-like receptor 4 (TLR4). Biophysical studies revealed that METH bound to MD-2, the key coreceptor of TLR4. Molecular dynamics simulations showed METH binding stabilized the active heterotetramer (TLR4/MD-2)2 conformation. Classic TLR4 antagonists LPS-RS and TAK-242 attenuated METH induced NF-κB activation of microglia, whereas added MD-2 protein boosted METH-induced NF-κB activation. Systemically administered METH (1 mg/kg) was found to specifically up-regulate expression of both CD11b (microglial activation marker) and the proinflammatory cytokine interleukin 6 (IL-6) mRNAs in the ventral tegmental area (VTA), but not in either the nucleus accumbens shell (NAc) or prefrontal cortex (PFC). Systemic administration of a nonopioid, blood-brain barrier permeable TLR4 antagonist (+)-naloxone inhibited METH-induced activation of microglia and IL-6 mRNA overexpression in VTA. METH was found to increase conditioned place preference (CPP) as well as extracellular dopamine concentrations in the NAc, with both effects suppressed by the nonopioid TLR4 antagonist (+)-naloxone. Furthermore, intra-VTA injection of LPS-RS or IL-6 neutralizing antibody suppressed METH-induced elevation of extracellular NAc dopamine. Taken together, this series of studies demonstrate that METH-induced neuroinflammation is, at least in part, mediated by TLR4-IL6 signaling within the VTA, which has the downstream effect of elevating dopamine in the NAc shell. These results provide a novel understanding of the neurobiological mechanisms underlying acute METH reward that includes a critical role for central immune signaling and offers a new target for medication development for treating drug abuse.

Methamphetamine Self-Administration Elicits Sex-Related Changes in Postsynaptic Glutamate Transmission in the Prefrontal Cortex

Abstract: Preclinical and clinical research has shown that females are more vulnerable to the rewarding effects of stimulants, and it has been proposed that estrogens may play a role in this enhanced sensitivity; however sex differences in methamphetamine (METH)-induced neuroplasticity have not been explored. To address this gap in knowledge, we recorded from the prelimbic area of the prefrontal cortex (PL-PFC) of male and female rats following long access METH self-administration (SA) and investigated the resulting long-term synaptic neuroadaptations. Males and females took similar amounts of METH during SA; however, female rats exhibit significant synaptic baseline differences when compared to males. Furthermore, females exhibited a significant increase in evoked excitatory currents. This increase in evoked glutamate was correlated with increases in NMDA currents and was not affected by application of a GluN2B selective blocker. We propose that METH SA selectively upregulates GluN2B-lacking NMDA receptors (NMDAR) in the PFC of female rats. Our results may provide a mechanistic explanation for the sex differences reported for METH addiction in females.

Sex Differences in Escalated Methamphetamine Self-Administration and Altered Gene Expression Associated With Incubation of Methamphetamine Seeking.

Abstract: Background Methamphetamine (METH) use disorder is prevalent worldwide. There are reports of sex differences in quantities of drug used and relapses to drug use among individuals with METH use disorder. However, the molecular neurobiology of these potential sex differences remains unknown. Methods We trained rats to self-administer METH (0. 1 mg/kg/infusion, i.v.) on an fixed-ratio-1 schedule for 20 days using two 3-hour daily METH sessions separated by 30-minute breaks. At the end of self-administration training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 and 30. Twenty-four hours later, nucleus accumbens was dissected and then used to measure neuropeptide mRNA levels. Results Behavioral results show that male rats increased the number of METH infusions earlier during self-administration training and took more METH than females. Both male and female rats could be further divided into 2 phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH self-administration experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin and hypocretin/orexin receptors than males, whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of nucleus accumbens dynorphin after METH self-administration. Moreover, there were significant correlations between nucleus accumbens Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. Conclusion Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.

Withdrawal from chronic treatment with methamphetamine induces anxiety and depression-like behavior in mice.

Abstract: Methamphetamine (METH) is an illicit psychostimulant that is widely abused. After producing extreme pleasure, METH abuse leads to negative emotional states during withdrawal in clinical survey. However, the mood behavioral consequences of withdrawal from chronic METH exposure in animal experiments and related mechanisms have not been clarified yet. The aim of this study was to investigate the anxiety and depression-like phenotype in mice induced by withdrawal from chronic METH treatment and the potential molecular mechanism. We found that withdrawal from chronic METH treatment increased the immobility time during the forced swimming test and decreased central activities in open field test, indicating increased anxiety and depression-like behavior. Additional experiments showed that expression of brain-derived neurotrophic factor (BDNF), phosphorylated tropomyosin receptor kinase B (p-TrkB), phosphorylated extracellular signal-related kinase 1/2 (p-ERK1/2) and phosphorylated cAMP-response element binding protein (p-CREB) were decreased in the hippocampus and prefrontal cortex of mice in METH group and the level of mitogen activated protein kinase phosphatase-1 (MKP-1) was increased. Combined, our data show that withdrawal from chronic METH exposure induces anxiety and depression-like behavior associated with aberrant changes of proteins in BDNF-ERK-CREB pathway, providing new evidence for the involvement of BDNF pathway in the negative emotional states induced by withdrawal from METH.

Hydrogen Sulfide Protects Hippocampal Neurons Against Methamphetamine Neurotoxicity Via Inhibition of Apoptosis and Neuroinflammation

Abstract: Methamphetamine (METH) known as a highly neurotoxic compound associated with irreversible brain cell damage that results in neurological and psychiatric abnormalities. The mechanisms of METH intoxication mainly involve intraneuronal events including oxidative stress, excitotoxicity, and dopamine oxidation. Based on recent studies, H2S can protect neurons through anti-inflammatory, antioxidant, and antiapoptotic mechanisms. Therefore, we aimed to study the effects of protection of H2S against METH neurotoxicity. The 72 male Wistar rats were randomly allocated into six groups: control (n, 12), H2S (n, 12), METH (n, 12), METH + H2S 1 mg/kg (n, 12), METH + H2S 5 mg/kg (n, 12), and METH + H2S 10 mg/kg (n, 12) groups, (NaHS as a H2S donor; 1, 5, 10 mg/kg). METH neurotoxicity was induced by 40 mg/kg of METH in four intraperitoneal (IP) injections (e.g., 4 × 10 mg/kg q. 2 h, IP). NaHS was administered at 30 min, 24 h, and 48 h after the final injection of METH. Seven days after METH injection, the brains were removed for biochemical assessments, glial fibrillary acidic protein (GFAP), and caspase-3 immunohistochemistry staining. H2S treatment could significantly increase both superoxide dismutase and glutathione (P < 0.01), and a reduction was observed in malondialdehyde (P < 0.05) and TNF-α (P < 0.01) versus the METH group. Moreover, H2S could significantly decrease caspase-3 and GFAP-positive cells in the CA1 region of the hippocampus (P < 0.01) compared to the METH group. According to the findings, H2S makes significant neuroprotective impacts on METH neurotoxicity due to its antioxidant and anti-inflammatory activities.

Simultaneous determination of metabolic and elemental markers in methamphetamine-induced hepatic injury to rats using LC-MS/MS and ICP-MS.

Abstract: Methamphetamine (METH) is one of the most highly addictive illicit drugs abused all over the world. Much evidence indicates that METH abuse leads to major toxicity, medical consequences, and even severe public health consequences. Existing studies usually focus on the pathomechanism of METH-induced toxicity; therefore, data on metabolites and elements correlating with particular toxicity remain scarce. The objective of the present study is to develop appropriate analytical procedures to identify the differential metabolic and elemental biomarkers on METH-induced hepatic injury to rats. The rats were administrated with METH (15 mg/mL/kg, two times per day) via intraperitoneal (i.p.) injections for four consecutive days. The alanine aminotransferase and aspartate aminotransferase activity levels of in the rat serum of the METH group increase significantly compared with those of the control group, suggesting obvious hepatic injury. The results are further confirmed by the histopathological microscopic observation. A total of 18 small molecular metabolites and 19 elements are selected to perform the simultaneous quantification based on the combination of liquid chromatography coupled with tandem mass spectrometry and inductively coupled plasma mass spectrometry. Sample preparation was optimized to cover all the analytes. Both methods are optimized and validated according to developed guidelines such as limits of detection, limits of quantification, linearity, precision, and recovery. All the obtained data are within the satisfactory range. The normalized data were processed according to the partial least squares discrimination analysis (PLS-DA) model. Five differential metabolic and six elemental markers are identified in rat plasma based on the variable importance in projection (VIP) (> 1) and t test results. Overall, the results obtained in this study demonstrate the developed methods are suitable for simultaneous determination of metabolic and elemental markers in the hepatic injury to rats induced by METH.

Cognition and Related Neural Findings on Methamphetamine Use Disorder: Insights and Treatment Implications From Schizophrenia Research.

Abstract: Despite the prevalence of methamphetamine (meth) use disorder, research on meth is disproportionately scarce compared to research on other illicit drugs. Existing evidence highlights cognitive deficits as an impediment against daily function and treatment of chronic meth use. Similar deficits are also observed in schizophrenia, and this review therefore draws on schizophrenia research by examining similarities and differences between the two disorders on cognition and related neural findings. While meth use disorder and schizophrenia are two distinct disorders, they are highly co-morbid and share impairments in similar cognitive domains and altered brain structure/function. This narrative review specifically identifies overlapping features such as deficits in learning and memory, social cognition, working memory and inhibitory/impulse control. We report that while working memory deficits are a core feature of schizophrenia, such deficits are inconsistently observed following chronic meth use. Similar structural and functional abnormalities are also observed in cortical and limbic regions between the two disorders, except for cingulate activity where differences are observed. There is growing evidence that targeting cognitive symptoms may improve functional outcome in schizophrenia, with evidence of normalized abnormal brain activity in regions associated with cognition. Considering the overlap between meth use disorder and schizophrenia, targeting cognitive symptoms in people with meth use disorder may also improve treatment outcome and daily function.

Crocin Acting as a Neuroprotective Agent against Methamphetamine-induced Neurodegeneration via CREB-BDNF Signaling Pathway.

Abstract: Methamphetamine (METH) abuse causes neurodegeneration. Medicinal herb such as crocin has neuroprotective properties. The current study evaluates the role of CREB-BDNF signaling pathway in mediating the neuroprotective effects of crocin against METH-induced neurodegeneration in rats. Sixty adult male rats were divided randomly into group 1 and group 2 which received 0.7 mL/rat of normal saline and 10 mg/kg of METH intraperitoneally (i.p) respectively, and groups 3, 4, 5 and 6 which treated concurrently with METH (10 mg/kg) and crocin (10, 20, 40 and 80 mg/kg I.P respectively) for 21 days. Morris water maze (MWM) was used to evaluate cognitive activity. According to the critical role of hippocampus in cognitive behavior, the molecular and biochemical parts of our study were done in hippocampus and according to this, hippocampal neurodegenerative parameters and also CREB and BDNF levels were evaluated in isolated hippocampus. METH disturbed the learning, memory, and simultaneous treatment with various doses of crocin reduced the METH-induced cognition disturbances. In addition, METH treatment increased lipid peroxidation and the levels of oxidized form of glutathione (GSSG), interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and Bax, while reducing reduced form of glutathione (GSH), Bcl-2, P-CREB, and BDNF levels in the hippocampus. METH also reduced the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) in the hippocampus. In contrast, crocin (40 and 80 mg/kg) attenuated METH-induced apoptosis, oxidative stress, and inflammation, while elevating P-CREB and BDNF levels. Thus, crocin confers neuroprotection against METH-induced neurodegeneration in hippocampus and this is probably through activation of P-CREB/BDNF signaling pathway.

Apelin-13 Protects PC12 Cells Against Methamphetamine-Induced Oxidative Stress, Autophagy and Apoptosis

Abstract: Methamphetamine (METH) is a potent psychomotor stimulant that has a high potential for abuse in humans. In addition, it is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to METH causes psychosis and increases the risk of Parkinson’s disease. Apelin-13 is a novel endogenous ligand which studies have shown that may have a neuroprotective effect. Therefore, we hypothesized that Apelin-13 might adequately prevent METH-induced neurotoxicity via the inhibition of apoptotic, autophagy, and ROS responses. In this study, PC12 cells were exposed to both METH (0.5, 1, 2, 3, 4, 6 mmol/L) and Apelin-13 (0.5, 1.0, 2.0, 4.0, 8.0 μmol/L) in vitro for 24 h to measure determined dose, and then downstream pathways were measured to investigate apoptosis, autophagy, and ROS responses. The results have indicated that Apelin-13 decreased the apoptotic response post-METH exposure in PC12 cells by increasing cell viability, reducing apoptotic rates. In addition, the study has revealed Apelin-13 decreased gene expression of Beclin-1 by Real-Time PCR and LC3-II by western blotting in METH-induced PC12 cells, which demonstrated autophagy is reduced. In addition, this study has shown that Apelin-13 reduces intracellular ROS of METH-induced PC12 cells. These results support Apelin-13 to be investigated as a potential drug for treatment of neurodegenerative diseases. It is suggested that Apelin-13 is beneficial in reducing oxidative stress, which may also play an important role in the regulation of METH-triggered apoptotic response. Hence, these data indicate that Apelin-13 could potentially alleviate METH-induced neurotoxicity via the reduction of oxidative damages, apoptotic, and autophagy cell death.

The role of chaperone-mediated autophagy in neurotoxicity induced by alpha-synuclein after methamphetamine exposure.

Abstract: Introduction Chaperone-mediated autophagy (CMA) is an autophagy-lysosome pathway (ALP) that is different from the other two lysosomal pathways, namely, macroautophagy and microautophagy, and can selectively degrade cytosolic proteins in lysosomes without vesicle formation CMA activity declines in neurodegenerative diseases such as Parkinson's disease, and similar neurotoxicity can occur after methamphetamine (METH) treatment The relationship between CMA and METH-induced neurotoxicity is not clear Methods We detected changes in the chaperone protein Hsc70 and the lysosomal surface receptor Lamp-2a after METH treatment and then regulated these two proteins by small interfering RNA and DNA plasmid transfection to investigate how CMA influences METH-induced neurotoxicity Results We found that CMA activity is decreased after METH exposure in neurons and downregulated Lamp-2a can aggravate the neurotoxicity induced by α-Syn after METH exposure and that Hsc70 overexpression can relieve the abnormal levels of alpha-synuclein and its aggregate forms and the increase in cell apoptosis induced by METH Conclusions The results provide in vivo evidence for CMA plays a pivotal role in METH-induced neurotoxicity, and upregulation of Hsc70 expression significantly protects neuronal cells against METH-induced toxicity This research may pave the way for potential therapeutic approaches targeting CMA for METH abuse and neurodegenerative disorders

Recommendation to include hydroxyethyl (meth)acrylate in the British baseline patch test series.

Abstract: Background (Meth)acrylates are potent sensitizers and a common cause of allergic contact dermatitis (ACD). The frequency of (meth)acrylate ACD has increased with soaring demand for acrylic nails. A preliminary audit has suggested a significant rate of positive patch tests to (meth)acrylates using aimed testing in patients providing a clear history of exposure. To date, (meth)acrylates have not been routinely tested in the baseline patch test series in the U.K. and Europe. Objectives To determine whether inclusion of 2-hydroxyethyl methacrylate (2-HEMA) 2% in petrolatum (pet.) in the baseline series detects cases of treatable (meth)acrylate ACD. Methods During 2016-2017, 15 U.K. dermatology centres included 2-HEMA in the extended baseline patch test series. Patients with a history of (meth)acrylate exposure, or who tested positive to 2-HEMA, were selectively tested with a short series of eight (meth)acrylate allergens. Results In total 5920 patients were consecutively patch tested with the baseline series, of whom 669 were also tested with the (meth)acrylate series. Overall, 102 of 5920 (1·7%) tested positive to 2-HEMA and 140 (2·4%) to at least one (meth)acrylate. Had 2-HEMA been excluded from the baseline series, (meth)acrylate allergy would have been missed in 36 of 5920 (0·6% of all patients). The top (meth)acrylates eliciting a positive reaction were 2-HEMA (n = 102, 1·7%), 2-hydroxypropyl methacrylate (n = 61, 1·0%) and 2-hydroxyethyl acrylate (n = 57, 1·0%). Conclusions We recommend that 2-HEMA 2% pet. be added to the British baseline patch test series. We also suggest a standardized short (meth)acrylate series, which is likely to detect most cases of (meth)acrylate allergy.

Removal of methamphetamine by UV-activated persulfate: Kinetics and mechanisms

Abstract: In this study, removal of methamphetamine (METH) was investigated by UV activated persulfate (PS), and the influence of key factors was evaluated. Results suggested that METH degradation followed pseudo-first order reaction kinetics. The combination of UV and persulfate (UV/PS) could completely degrade 100 μg/L of METH in 30 min with a PS dosage of 200 μM at pH 7. Both hydroxyl radical ( OH) and sulfate radical (SO4− ) were confirmed to contribute to the degradation of METH. The bimolecular reaction rate constants of METH with OH and SO4− were 7.91 × 109 and 3.29 × 109 M−1 s−1, respectively. The degradation rate constant of METH was proportional to the PS dosage (0–800 μM) and was high at neutral pH condition. The presence of inorganic anions significantly reduced METH degradation to different degrees, with the inhibitory effect order of Cl− > NO3− > HCO3−. The degradation efficiency of METH was suppressed by the presence of humic acid due to the effect of UV absorption and free radical quenching. The degradation intermediates and products were identified by UPLC-MS/MS and possible transformation pathways were proposed. Results suggested that the combination of UV/PS is a promising treatment technique for the removal of METH in the water environment.

The effects of single-dose injections of modafinil and methamphetamine on epigenetic and functional markers in the mouse medial prefrontal cortex: potential role of dopamine receptors.

Abstract: METH use causes neuroadaptations that negatively impact the prefrontal cortex (PFC) leading to addiction and associated cognitive decline in animals and humans In contrast, modafinil enhances cognition by increasing PFC function Accumulated evidence indicates that psychostimulant drugs, including modafinil and METH, regulate gene expression via epigenetic modifications In this study, we measured the effects of single-dose injections of modafinil and METH on the protein levels of acetylated histone H3 (H3ac) and H4ac, deacetylases HDAC1 and HDAC2, and of the NMDA subunit GluN1 in the medial PFC (mPFC) of mice euthanized 1 h after drug administration To test if dopamine (DA) receptors (DRs) participate in the biochemical effects of the two drugs, we injected the D1Rs antagonist, SCH23390, or the D2Rs antagonist, raclopride, 30 min before administration of METH and modafinil We evaluated each drug effect on glutamate synaptic transmission in D1R-expressing layer V pyramidal neurons We also measured the enrichment of H3ac and H4ac at the promoters of several genes including DA, NE, orexin, histamine, and glutamate receptors, and their mRNA expression, since they are responsive to chronic modafinil and METH treatment Acute modafinil and METH injections caused similar effects on total histone acetylation, increasing H3ac and decreasing H4ac, and they also increased HDAC1, HDAC2 and GluN1 protein levels in the mouse mPFC In addition, the effects of the drugs were prevented by pre-treatment with D1Rs and D2Rs antagonists Specifically, the changes in H4ac, HDAC2, and GluN1 were responsive to SCH23390, whereas those of H3ac and GluN1 were responsive to raclopride Whole-cell patch clamp in transgenic BAC-Drd1a-tdTomato mice showed that METH, but not modafinil, induced paired-pulse facilitation of EPSCs, suggesting reduced presynaptic probability of glutamate release onto layer V pyramidal neurons Analysis of histone 3/4 enrichment at specific promoters revealed: i) distinct effects of the drugs on histone 3 acetylation, with modafinil increasing H3ac at Drd1 and Adra1b promoters, but METH increasing H3ac at Adra1a; ii) distinct effects on histone 4 acetylation enrichment, with modafinil increasing H4ac at the Drd2 promoter and decreasing it at Hrh1, but METH increasing H4ac at Drd1; iii) comparable effects of both psychostimulants, increasing H3ac at Drd2, Hcrtr1, and Hrh1 promoters, decreasing H3ac at Hrh3, increasing H4ac at Hcrtr1, and decreasing H4ac at Hcrtr2, Hrh3, and Grin1 promoters Interestingly, only METH altered mRNA levels of genes with altered histone acetylation status, inducing increased expression of Drd1a, Adra1a, Hcrtr1, and Hrh1, and decreasing Grin1 Our study suggests that although acute METH and modafinil can both increase DA neurotransmission in the mPFC, there are similar and contrasting epigenetic and transcriptional consequences that may account for their divergent clinical effects © 2018

Different doses of methamphetamine alter long-term potentiation, level of BDNF and neuronal apoptosis in the hippocampus of reinstated rats.

Abstract: Methamphetamine (METH) is a psychostimulant. The precise mechanisms of its effects remain unknown and current relapse treatments have low efficacy. However, brain-derived neurotrophic factor (BDNF) and neuronal plasticity are essential contributors, despite paradoxical reports and a lack of comprehensive studies. Therefore, we investigated the effects of different doses of METH on long-term potentiation (LTP), BDNF expression and neuronal apoptosis in the hippocampus of reinstated rats. Rats were injected intraperitoneally with METH (1, 5, or 10 mg/kg) or saline, and trained in a conditioned place preference paradigm. Following implementation of the reinstatement model, electrophysiology, western blotting and TUNEL assay were performed to assess behavior, LTP components, BDNF expression, and neuronal apoptosis, respectively. The results demonstrated that the preference scores, population spike amplitude and BDNF expression markedly decreased in the METH (10 mg/kg) group compared with the other groups. In contrast, METH (5 mg/kg) significantly increased these factors more than the control group. There was no change in variables between METH (1 mg/kg) and the control group. Also, apoptosis of the hippocampus was increased in the METH (10 mg/kg) group compared with the METH (5 mg/kg) group. These results suggest that alterations in synaptic plasticity, expression of BDNF and neuronal apoptosis in the hippocampus has a vital role in the context-induced reinstatement of METH seeking.

Methamphetamine-associated cognitive decline is attenuated by neutralizing IL-1 signaling

Abstract: Methamphetamine (METH) abusers are prone to develop a variety of comorbidities, including cognitive disabilities, and the immunological responses have been recognized as an important component involved in the toxicity of this drug. Cytokines are among the key mediators between systemic inflammatory status and tissue responses. One of these, interleukin 1 (IL-1), has been hypothesized to be involved in cognitive functions and also appears to play a pivotal role among inflammatory molecules. In the present study, we demonstrate that exposure of mice to METH markedly increased the protein level of IL-1β in hippocampal tissue. Additionally, METH administration induced a decline in spatial learning as determined by the Morris water maze test. We next evaluated the hypothesis that blocking IL-1β signaling can protect against METH-induced loss of cognitive functioning. The results indicated that METH-induced impaired spatial learning abilities were attenuated by co-administration of mouse IL-1 Trap, a dimeric fusion protein that incorporates the extracellular domains of both of the IL-1 receptor components required for IL-1 signaling (IL-1 receptor type 1 and IL-1 receptor accessory protein), linked to the Fc portion of murine IgG2a. This effect was associated with a decrease in hippocampal IL-1β level. The current study indicates for the first time that the loss of METH-related cognitive decline can be attenuated by neutralizing IL-1 signaling. Our findings suggest a potential new therapeutic pathway for treatment of altered cognitive abilities that occur in METH abusing individuals.

Pharmacotherapeutic strategies for methamphetamine use disorder: mind the subgroups.

Abstract: Introduction: Drug use related deaths are increasing and the lack of effective treatment for psychostimulants can be largely held responsible. Particularly, no pharmacotherapy is approved for methamphetamine (METH) use disorder despite decades of research. Only psychosocial interventions are clinically used, with limited long-term recovery and relapse.Areas covered: This review aims to select and describe the most relevant findings to date. Selected clinical trials were found in PubMed using the following keywords ('methamphetamine') and ('addiction' OR 'withdrawal' OR 'treatment' OR 'pharmacotherapy'). Randomized placebo-controlled trials enrolling treatment-seeking METH-dependent subjects and inherent secondary analysis were included.Expert opinion: Overall, end-of-treatment abstinence, reduced METH use or lower relapse rates were seen on METH dependent subgroups or attained significance only following post hoc analysis, irrespective of the medication tested. For example, light and heavy METH users seem to respond differently to pharmacotherapy. This together with the heterogeneous nature of the METH dependent population strongly suggests that some drugs herein described (e.g. mirtazapine, methylphenidate) should be further tested in clinical trials focused on subgroups. Lastly, objective measures, such as urinalysis, are mandatory to include in clinical trials and early treatment response and/or medication compliance should be carefully monitored and considered as predictors of success/failure.

The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice.

Abstract: Drug addiction is a chronic and relapsing brain disorder, influenced by complex interactions between endogenous and exogenous factors. Per2, a circadian gene, plays a role in drug addiction. Previous studies using Per2-knockout mice have shown a role for Per2 in cocaine, morphine and alcohol addiction. In the present study, we investigated the role of Per2 in methamphetamine (METH) addiction using Per2-overexpression and knockout mice. We observed locomotor sensitization responses to METH administration, and rewarding effects using a conditioned place preference test. In addition, we measured expression levels of dopamine and dopamine-related genes (monoamine oxidase A, DA receptor 1, DA receptor 2, DA active transporter, tyrosine hydroxylase and cAMP response element-binding protein 1) in the striatum of the mice after repeated METH treatments, using qRT-PCR. Per2-overexpressed mice showed decreased locomotor sensitization and rewarding effects of METH compared to the wildtype mice, whereas the opposite was observed in Per2 knockout mice. Both types of transgenic mice showed altered expression levels of dopamine-related genes after repeated METH administration. Specifically, we observed lower dopamine levels in Per2-overexpressed mice and higher levels in Per2-knockout mice. Taken together, Per2 expression levels may influence the addictive effects of METH through the dopaminergic system in the striatum of mice.

Methamphetamine functions as a novel CD4+ T-cell activator via the sigma-1 receptor to enhance HIV-1 infection.

Abstract: Methamphetamine (Meth) exacerbates HIV-1 pathobiology by increasing virus transmission and replication and accelerating clinical progression to AIDS. Meth has been shown to alter the expression of HIV-1 co-receptors and impair intrinsic resistance mechanisms of immune cells. However, the exact molecular mechanisms involved in augmenting HIV-1 replication in T-cells are still not yet clear. Here, we demonstrate that pretreatment with Meth of CD4+ T-cells enhanced HIV-1 replication. We observed upregulation of CD4+ T-cell activation markers and enhanced expression of miR-34c-5p and miR-155 in these cells. Further, we noted activation of the sigma-1 receptor and enhanced intracellular Ca2+ concentration and cAMP release in CD4+ T-cells upon Meth treatment, which resulted in increased phosphorylation and nuclear translocation of transcription factors NFκB, CREB, and NFAT1. Increased gene expression of IL-4 and IL-10 was also observed in Meth treated CD4+ T-cells. Moreover, proteasomal degradation of Ago1 occurred upon Meth treatment, further substantiating the drug as an activator of T-cells. Taken together, these findings show a previously unreported mechanism whereby Meth functions as a novel T-cell activator via the sigma-1 signaling pathway, enhancing replication of HIV-1 with expression of miR-34c-5p, and transcriptional activation of NFκB, CREB and NFAT1.