Modulation of dlPFC function and decision-making capacity by repetitive transcranial magnetic stimulation in methamphetamine use disorder.

This study explores the impact of repetitive transcranial magnetic stimulation (rTMS) on decision-making capabilities in individuals with methamphetamine use disorder (MUD), alongside potential underlying psychological mechanisms. Employing the Iowa Gambling Task (IGT) and computational modeling techniques, we assessed the decision-making processes of 50 male MUD participants (24 underwent rTMS treatment, 26 received no treatment) and 39 healthy controls (HC). We compared pre- and post-rTMS treatment alterations in the left dorsolateral prefrontal cortex (dlPFC). Results revealed inferior performance in the IGT among the MUD group, characterized by aberrant model parameters in the Value-Plus-Perseverance (VPP) model, including heightened learning rate, outcome sensitivity, and reinforcement learning weight, alongside diminished response consistency and loss aversion. RTMS treatment demonstrated efficacy in reducing craving scores, enhancing decision-making abilities, and partially restoring normalcy to certain model parameters in the MUD cohort. Nonetheless, no linear relationship between changes in model parameters and craving was observed. These findings lend support to the somatic marker hypothesis, implicating the dlPFC in the decision-making deficits observed in MUD, with rTMS potentially ameliorating these deficits by modulating the function of these brain regions. This study not only offers novel insights and methodologies for MUD rehabilitation but also underscores the necessity for further research to corroborate and refine these findings. Trial Registration www.chictr.org.cn Identifier: No. ChiCTR17013610.

Transcranial magnetic stimulation for methamphetamine use disorder: A scoping review within the neurocircuitry model of addiction.

The use of methamphetamine in the United States is increasing, contributing now to the "fourth wave" in the national opioid epidemic crisis. People who suffer from methamphetamine use disorder (MUD) have a higher risk of death. No pharmacological interventions are approved by the FDA and psychosocial interventions are only moderately effective. Transcranial Magnetic Stimulation (TMS) is a relatively novel FDA-cleared intervention for the treatment of Major Depressive Disorder (MDD) and other neuropsychiatric conditions. Several lines of research suggest that TMS could be useful for the treatment of addictive disorders, including MUD. We will review those published clinical trials that show potential effects on craving reduction of TMS when applied over the dorsolateral prefrontal cortex (DLPFC) also highlighting some limitations that affect their generalizability and applicability. We propose the use of the Koob and Volkow's neurocircuitry model of addiction as a frame to explain the brain effects of TMS in patients with MUD. We will finally discuss new venues that could lead to a more individualized and effective treatment of this complex disorder including the use of neuroimaging, the exploration of different areas of the brain such as the frontopolar cortex or the salience network and the use of biomarkers.

The mediating role of trait impulsivity in the relation between cue-induced craving and functional connectivity within the salience network among abstinent patients with methamphetamine use disorder.

Given the widespread use and relapse of methamphetamine (METH), it has caused serious public health burdens globally. However, the neurobiological basis of METH addiction remains poorly understood. Therefore, this study aimed to use magnetic resonance imaging (MRI) to investigate changes in brain networks and their connection to impulsivity and drug craving in abstinent individuals with METH use disorder (MUDs). A total of 110 MUDs and 55 age- and gender-matched healthy controls (HCs) underwent resting-state functional MRI and T1-weighted imaging scans, and completed impulsivity and cue-induced craving measurements. We applied independent component analysis to construct functional brain networks and multivariate analysis of covariance to investigate group differences in network connectivity. Mediation analyses were conducted to explore the relationships among brain-network functional connectivity (FC), impulsivity, and drug craving in the patients. MUDs showed increased connectivity in the salience network (SN) and decreased connectivity in the default mode network compared to HCs. Impulsivity was positively correlated with FC within the SN and played a completely mediating role between METH craving and FC within the SN in MUDs. These findings suggest alterations in functional brain networks underlying METH dependence, with SN potentially acting as a core neural substrate for impulse control disorders.

Neurofunctional changes related to methamphetamine and sexual cues in methamphetamine dependence from short- to long-term abstinence.

AIMS: Abuse of methamphetamine has aroused concern worldwide. Stimulant use and sexual behaviours have been linked in behavioural and epidemiological studies. Although methamphetamine-related neurofunctional differences are reported in previous studies, only few studies have examined neurofunctional changes related to methamphetamine and sexual cues in methamphetamine dependence from short- to long-term abstinence. METHODS: Neurofunctional changes were measured using a cue-reactivity task involving methamphetamine, sexual, and neutral cues in 20 methamphetamine abusers who were evaluated after a short- (1 week to 3 months) and long-term (10-15 months) abstinence. RESULTS: Five brain regions mainly involved in the occipital lobe and the parietal lobe were found with the group-by-condition interaction. Region-of-interest analyses found higher sexual-cue-related activation than other two activations in all five brain regions in the long-term methamphetamine abstinence group while no group differences were found. Negative relationships between motor impulsivity and methamphetamine- or sexual-cue-related activations in the left middle occipital gyrus, the superior parietal gyrus and the right angular gyrus were found. CONCLUSIONS: The findings suggested that methamphetamine abstinence may change the neural response of methamphetamine abusers to methamphetamine and sexual cues, and the neurofunction of the five brain regions reported in this study may partly recover with long-term methamphetamine abstinence. Given the use and relapse of methamphetamine for sexual purposes, the findings of this study may have particular clinical relevance.

Can Methamphetamine-Induced Cardiotoxicity be Ameliorated by Aerobic Training and Nutrition Bio-shield Superfood Supplementation in Rats After Withdrawal?

The abuse of methamphetamine is a significant threat to cardiovascular health and has detrimental effects on the myocardium. The present study aims to explore potential interventions that can mitigate myocardial pyroptosis in rats following methamphetamine withdrawal. A total of 104 male Wistar rats were randomly assigned to eight groups. The rats underwent a methamphetamine administration protocol, receiving intraperitoneal injections of 10 mg/kg during the 1st week, followed by a weekly dose escalation of 1 mg/kg from the second to the 6th week and two times per day. Concurrently, the rats engaged in 6 weeks of moderate-intensity treadmill aerobic training, lasting 60 min per day, 5 days a week. Simultaneously, the Nutrition bio-shield Superfood (NBS) supplement was administered at a dosage of 25 g/kg daily for 6 weeks. The study assessed the expression levels of Caspase-1, Interleukin-1beta (IL-1ß), and Interleukin-18 (IL-18) genes in myocardial tissue. Data analysis utilized a one-way analysis of variance (p ≤ 0.05). The findings revealed that methamphetamine usage significantly elevated the expression of Caspase-1, IL-1ß, and IL-18 genes (p ≤ 0.05). Conversely, methamphetamine withdrawal led to a notable reduction in the expression of these genes (p ≤ 0.05). Noteworthy reductions in Caspase-1, IL-1ß, and IL-18 expression were observed following aerobic training, supplementation, and the combined approach (p ≤ 0.05). The chronic use of methamphetamine was associated with cardiac tissue damage. This study highlights the potential of aerobic training and NBS Superfood supplementation in mitigating the harmful effects of methamphetamine-induced myocardial pyroptosis. The observed reductions in gene expression levels indicate promising interventions to address the cardiovascular consequences of methamphetamine abuse. The findings of this study suggest that a combination of aerobic exercise and NBS Superfood supplementation can provide a promising approach to mitigate the deleterious effects of methamphetamine on the heart. These findings can be useful for healthcare professionals and policymakers to design effective interventions to prevent and manage the adverse effects of methamphetamine abuse.

Overview of Methamphetamine-Associated Pulmonary Arterial Hypertension.

TOPIC IMPORTANCE: The global surge in methamphetamine use is a critical public health concern, particularly due to its robust correlation with methamphetamine-associated pulmonary arterial hypertension (MA-PAH). This association raises urgent alarms about the potential escalation of MA-PAH incidence, posing a significant and imminent challenge to global public health. REVIEW FINDINGS: This comprehensive review meticulously explores MA-PAH, offering insights into its epidemiology, pathophysiology, clinical presentation, diagnostic intricacies, and management strategies. The pathogenesis, yet to be fully described, involves complex molecular interactions, including alterations in serotonin signaling, reduced activity of carboxylesterase 1, oxidative stress, and dysregulation of pulmonary vasoconstrictors and vasodilators. These processes culminate in the structural remodeling of the pulmonary vasculature, resulting in pulmonary arterial hypertension. MA-PAH exhibits a more severe clinical profile in functional class and hemodynamics compared with idiopathic pulmonary arterial hypertension. Management involves a multifaceted approach, integrating pulmonary vasodilators, cessation of methamphetamine use, and implementing social and rehabilitation programs. These measures aim to enhance patient outcomes and detect potential relapses for timely intervention. SUMMARY: This review consolidates our understanding of MA-PAH, pinpointing knowledge gaps for future studies. Addressing these gaps is crucial for advancing diagnostic accuracy, unraveling mechanisms, and optimizing treatment for MA-PAH, thereby addressing the evolving landscape of this complex health concern.

Modeling methamphetamine use disorder and relapse in animals: short- and long-term epigenetic, transcriptional., and biochemical consequences in the rat brain.

Methamphetamine use disorder (MUD) is a neuropsychiatric disorder characterized by binge drug taking episodes, intervals of abstinence, and relapses to drug use even during treatment. MUD has been modeled in rodents and investigators are attempting to identify its molecular bases. Preclinical experiments have shown that different schedules of methamphetamine self-administration can cause diverse transcriptional changes in the dorsal striatum of Sprague-Dawley rats. In the present review, we present data on differentially expressed genes (DEGs) identified in the rat striatum following methamphetamine intake. These include genes involved in transcription regulation, potassium channel function, and neuroinflammation. We then use the striatal data to discuss the potential significance of the molecular changes induced by methamphetamine by reviewing concordant or discordant data from the literature. This review identified potential molecular targets for pharmacological interventions. Nevertheless, there is a need for more research on methamphetamine-induced transcriptional consequences in various brain regions. These data should provide a more detailed neuroanatomical map of methamphetamine-induced changes and should better inform therapeutic interventions against MUD.

Difference in topological organization of white matter structural connectome between methamphetamine and heroin use disorder.

The psychological symptoms caused by heroin and methamphetamine are significantly different in people with substance use disorders. The topological organization of structural connections that may underlie these differences remains unknown. The study sample consisted of 23 males with methamphetamine use disorder (MAUD), 20 males with heroin use disorder (HUD), and 21 male healthy controls (HCs) who were demographically matched. Diffusion tensor imaging and probabilistic tractography were used for white matter network construction. Psychological symptoms were evaluated by the Symptom Checklist-90. Using graph theoretical analysis, we examined the difference in graph-level and nodal-level properties among the groups. The network Hubs distribution and the relationship between the network alterations and psychological symptoms were identified. The MAUD group demonstrated significantly higher scores on anxiety, hostility, and symptoms of schizophrenia than the HUD and HCs groups. The HUD group showed significantly higher global efficiency and network strength than the HCs group, and higher network strength than the MAUD group. Compared with the HUD group, the MAUD group showed significantly lower Nodal Strength and efficiency, distributed mainly in the temporal, parietal, and occipital regions. We also found the network Hubs were decreased in the MAUD group, but increased in the HUD group. The Nodal Strength in the right superior temporal gyrus was significantly correlated with psychological symptoms in the MAUD group. These findings reflect the significant differences in topological structural connection between HUD and MAUD. This evidence helps shed some light on the neurobiological mechanisms of the psychological differences between HUD and MAUD, and extend our understanding of the structural disruption underlying MAUD-related psychological symptoms.

Differential methamphetamine-induced behavioral effects in male and female mice lacking regulator of G Protein signaling 4.

Methamphetamine-induced behavioral effects are mediated by several neurotransmitters that act via the G-protein coupled receptors (GPCRs). The functioning of GPCRs are negatively regulated by regulators of G-protein signaling (RGS) proteins. The goal of this study was to assess the role of two specific RGS proteins namely the RGS2 and the RGS4 proteins in methamphetamine-induced behaviors. The effects of methamphetamine (1 mg/kg; i.p.) on conditioned place preference (CPP) and locomotor activity were assessed in genetically modified male and female mice lacking either RGS2 or RGS4 and their wildtype littermates to achieve the above goal. Locomotor activity after methamphetamine administration was assessed in both methamphetamine-naïve and -experienced mice. Methamphetamine-induced CPP at the tested dose was blocked in male, but not female, mice lacking RGS4 compared to respective controls. Interestingly, methamphetamine-induced increase in locomotor activity at the tested dose was observed in methamphetamine-experienced, but not in the methamphetamine-naïve, male mice lacking RGS4. However, methamphetamine-induced increase in locomotor activity at the tested dose was blocked in both methamphetamine-naïve and -experienced female mice lacking RGS4. Interestingly, methamphetamine-induced rewarding effects and methamphetamine-induced increase in locomotor activity at the tested dose were observed in mice lacking RGS2, irrespective of sex and/or history of methamphetamine exposure. Together, the data suggest that RGS4 plays a role in methamphetamine-induced behaviors and could serve as a potential target for medications intended to treat the acute effects of methamphetamine.

The effects of alcohol drinking on subsequent methamphetamine self-administration and relapse in adolescent female rats.

Alcohol and Methamphetamine (Meth) are widely abused drugs that are frequently co-abused, though this pattern of polysubstance abuse is rarely studied. Alcohol use during adolescence is associated with subsequent Meth dependence in humans and female adolescents may be more vulnerable than males to serial alcohol and Meth use. However, it is unknown if prior alcohol drinking impacts subsequent Meth-taking in female rats. This study uses a novel method of serial voluntary alcohol drinking and Meth self-administration in female adolescent Sprague Dawley rats (n = 35) to model human patterns of co-abuse. Rats demonstrated a steady time-based increase in alcohol preference versus water, starting at 33.3 ± 3.4% on day 1-48.0 ± 3.6% by the final day of EtOH, with a peak EtOH preference of 49.7 ± 3.7% on day 17 of the drinking paradigm (P < 0.001, one-way repeated measures ANOVA). All rats rapidly acquired Meth self-administration, demonstrating a 4.6 ± 1.4 fold increase in active presses for Meth and a 5.2 ± 1.8 fold increase in Meth intake (mg/kg) within 7 days, and maintained high levels of Meth intake throughout 21 days of self-administration. Prior alcohol drinking did not alter the increase in Meth self-administration compared to alcohol naïve control rats. However, after 7 days of Meth abstinence, a history of alcohol drinking reduced cue-primed reinstatement of Meth seeking. These findings demonstrate that prior alcohol consumption does not alter overall Meth self-administration but does persistently reduce cue-primed Meth seeking after prolonged alcohol abstinence.

Electroacupuncture alleviates spatial memory deficits in METH withdrawal mice by enhancing astrocyte-mediated glutamate clearance in the dCA1.

Methamphetamine (METH) elicits endogenous glutamate (Glu) in the brain, which could partially explain METH-induced memory deficits. Here, we investigated the therapeutic effects of electroacupuncture (EA) on spatial memory deficits in METH withdrawal mice and its potential synaptic mechanisms. We found that EA at acupoints 'Baihui' and 'Yintang' ameliorated the impaired spatial memory in METH withdrawal mice. In parallel, EA attenuated the Glu levels in vivo and suppressed the neuronal activities within dCA1 of METH withdrawal mice, as indicated by the decreasing c-Fos levels and the amplitude of mEPSP. In the dCA1, EA decreased A1-like astrocytes but increased astrocytic glutamatergic transporting molecules including glutamate transporter 1 and glutamine synthase. However, EA seemed to have no effects on presynaptic Glu transmission from the dCA3, as evidenced by the similiar levels of c-Fos in the dCA3 neurons, synaptic vesicular markers of dCA3 neural terminals and values of paired-pulse ratio in the dCA1 neurons between EA-treated and sham EA-treated METH withdrawal mice. These findings suggest that EA might normalize the dCA1 Glu levels at least in part through enhancing astrocyte-mediated Glu clearance. Taken together, astrocytes might be a novel target for developing therapeutic interventions against the impaired memory behaviours in METH users, and EA represents a promising non-invasive therapeutic strategy for the management of drug-caused memory deficits.

Prior Methamphetamine Use Disorder History Does Not Impair Interoceptive Processing of Soft Touch in HIV Infection.

INTRODUCTION: Interoception, defined as the sense of the internal state of one's body, helps motivate goal-directed behavior. Prior work has shown that methamphetamine (METH) use disorder is associated with altered interoception, and that this may contribute to risky behavior. As people with HIV (PWH) may also experience disrupted bodily sensations (e.g., neuropathy), an important question is whether PWH with a history of METH use disorder might exhibit greater impairment of interoceptive processing. METHODS: Eighty-three participants stratified by HIV infection and a past history of methamphetamine use disorder experienced a soft touch paradigm that included slow brush strokes on the left forearm and palm during blood-oxygen level-dependent functional MRI acquisition. To assess differences in interoception and reward, voxelwise analyses were constrained to the insula, a hub for the evaluation of interoceptive cues, and the striatum, which is engaged in reward processing. RESULTS: Overall, individuals with a history of METH use disorder had an attenuated neural response to pleasant touch in both the insula and striatum. Longer abstinence was associated with greater neural response to touch in the insula, suggesting some improvement in responsivity. However, only PWH with no METH use disorder history had lower brain activation in the insula relative to non-using seronegative controls. CONCLUSIONS: Our findings suggest that while METH use disorder history and HIV infection independently disrupt the neural processes associated with interoception, PWH with METH use disorder histories do not show significant differences relative to non-using seronegative controls. These findings suggest that the effects of HIV infection and past methamphetamine use might not be additive with respect to interoceptive processing impairment.

Utility of a controlled amphetamine withdrawal paradigm among adults who use methamphetamine: A pilot clinical trial.

BACKGROUND: The continued increase in prevalence of methamphetamine use in the United States has resulted in a significant increase in the number of patients entering treatment for methamphetamine use. However, no robustly efficacious pharmacologic treatment for methamphetamine use or withdrawal has been identified to date after stopping methamphetamine use. AIMS: Given the association between methamphetamine withdrawal and relapse during early treatment, this study tested a controlled d-amphetamine withdrawal paradigm among methamphetamine-using individuals. METHODS: Treatment-seeking adults who used methamphetamine (N = 34; 47% female; 100% white) were enrolled in a 4-week, randomized, double-blind, placebo-controlled trial in a residential setting, in which all participants were maintained on d-amphetamine (30 mg BID) during week 1, then half were switched to placebo during weeks 2-3. All participants received placebo during week 4. Outcomes included vital signs, withdrawal, cravings for methamphetamine, mood, and cognition. Bivariate analyses tested treatment group differences on baseline demographic and outcome variables. Repeated measures models examined main and interaction effects of treatment over time. RESULTS/OUTCOMES: Participants were successfully randomized and safely stabilized on d-amphetamine. Craving for methamphetamine increased during weeks 2-3 in the placebo group relative to those on d-amphetamine. Interactions with age and heart rate were noted. CONCLUSIONS/INTERPRETATION: To our knowledge, this is the first double-blind, placebo-controlled trial measuring pharmacologic effects of abruptly stopping controlled d-amphetamine administration in adults who use methamphetamine. Results support the potential of this withdrawal paradigm to further examine the efficacy of pharmacologic agents in ameliorating methamphetamine withdrawal symptoms.

Voluntary oral methamphetamine increases memory deficits and contextual sensitization during abstinence associated with decreased PKMζ and increased κOR in the hippocampus of female mice.

BACKGROUND: Female populations exhibit vulnerabilities to psychostimulant addiction, as well as cognitive dysfunction following bouts of abuse. AIMS: The goal for this study was to advance our understanding of the mechanisms that produce sex disparities in drug addiction. METHODS: We used an animal model for voluntary oral methamphetamine administration (VOMA) and focused on male and female mice that consumed 7.6-8.2 mg/kg of methamphetamine (MA) per day during the last 18 days of the paradigm. RESULTS: The VOMA-exposed female mice displayed increased locomotor activity in the drug-administration context compared to male mice, demonstrating sex-specific changes in contextual sensitization. During 2 weeks of forced abstinence, mice underwent further behavioral testing. We show that abstinence increased open-arm entries on the elevated plus maze in both sexes. There were no differences in immobility on the tail suspension test. In a hippocampal-dependent radial arm maze task, VOMA-treated female mice, but not male mice, showed working memory deficits. Hippocampal tissue was collected and analyzed using Western blotting. VOMA-exposed female mice exhibited increased kappa opioid receptor (κOR) expression in the hippocampus compared to male mice, suggesting a vulnerability toward abstinence-induced dysphoria. Female VOMA mice also exhibited a decrease in the memory protein marker, protein kinase M zeta (PKMζ), in the hippocampus. CONCLUSIONS: Our study reveals sex-specific effects following abstinence from chronic MA consumption on hippocampal κOR and PKMζ expression, suggesting that these neural changes in female mice may underlie spatial memory deficits and identify an increased susceptibility to dysregulated neural mechanisms. These data validate VOMA as a model sensitive to sex differences in behavior and hippocampal neurochemistry following chronic MA exposure.

Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders.

The neurovascular units (NVU) are the minimal functional units of the blood-brain barrier (BBB), composed of endothelial cells, pericytes, astrocytes, microglia, neurons, and the basement membrane. The BBB serves as an important interface for immune communication between the brain and peripheral circulation. Disruption of the NVU by the human immunodeficiency virus-1 (HIV-1) induces dysfunction of the BBB and triggers inflammatory responses, which can lead to the development of neurocognitive impairments collectively known as HIV-1-associated neurocognitive disorders (HAND). Methamphetamine (METH) use disorder is a frequent comorbidity among individuals infected with HIV-1. METH use may be associated not only with rapid HIV-1 disease progression but also with accelerated onset and increased severity of HAND. However, the molecular mechanisms of METH-induced neuronal injury and cognitive impairment in the context of HIV-1 infection are poorly understood. In this review, we summarize recent progress in the signaling pathways mediating synergistic impairment of the BBB and neuronal injury induced by METH and HIV-1, potentially accelerating the onset or severity of HAND in HIV-1-positive METH abusers. We also discuss potential therapies to limit neuroinflammation and NVU damage in HIV-1-infected METH abusers.

Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior.

Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose-response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.

Hippocampal neurogenesis interferes with extinction and reinstatement of methamphetamine-associated reward memory in mice.

Drugs of abuse, including morphine and cocaine, can reduce hippocampal neurogenesis (HN). Whereas promotion of HN is being increasingly recognized as a promising strategy for treating morphine and cocaine addiction. The present study is focused on exploring the changes of HN during methamphetamine (METH) administration and further clarify if HN is involved in METH-associated reward memory. After successfully establishing the conditioned place preference (CPP) paradigm to simulate the METH-associated reward memory in C57BL/6 mice, we observed that HN was significantly inhibited during METH (2 mg/kg, i. p.) administration and returned to normal after the extinction of METH CPP, as indicated by the immunostaining of bromodeoxyuridine (BrdU) and doublecortin (DCX) in the hippocampus. To promote/inhibit HN levels, 7,8-dihydroxyflavone (DHF), a small tyrosine kinase receptor B (TrkB) agonist and temozolomide (TMZ), an alkylating agent, were administered intraperitoneally (i.p.), respectively. The data showed that either DHF (5 mg/kg, i. p.) or TMZ (25 mg/kg, i. p.) pre-treatment before METH administration could significantly prolong extinction and enhance reinstatement of the reward memory. Notably, DHF treatment after METH administration significantly facilitated extinction and inhibited METH reinstatement, while TMZ treatment resulted in opposite effects. The present study indicated that METH administration could induce a temporal inhibitory effect on HN. More importantly, promotion of HN after the acquisition of METH-associated reward memory, but not inhibition of HN or promotion of HN before the acquisition of reward memory, could facilitate METH extinction and inhibit METH reinstatement, indicating the beneficial effect of HN on METH addiction by erasing the according reward memory.

Behavioural and biochemical responses to methamphetamine are differentially regulated by mGlu2 and mGlu3 metabotropic glutamate receptors in male mice.

Group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) shape mechanisms of methamphetamine addiction, but the individual role played by the two subtypes is unclear. We measured methamphetamine-induced conditioned place preference (CPP) and motor responses to single or repeated injections of methamphetamine in wild-type, mGlu2-/-, and mGlu3-/-mice. Only mGlu3-/-mice showed methamphetamine preference in the CPP test. Motor response to the first methamphetamine injection was dramatically reduced in mGlu2-/-mice, unless these mice were treated with the mGlu5 receptor antagonist, MTEP. In contrast, methamphetamine-induced sensitization was increased in mGlu3-/-mice compared to wild-type mice. Only mGlu3-/-mice sensitized to methamphetamine showed increases in phospho-ERK1/2 levels in the nucleus accumbens (NAc) and free radical formation in the NAc and medial prefrontal cortex. These changes were not detected in mGlu2-/-mice. We also measured a series of biochemical parameters related to the mechanism of action of methamphetamine in naïve mice to disclose the nature of the differential behavioural responses of the three genotypes. We found a reduced expression and activity of dopamine transporter (DAT) and vesicular monoamine transporter-2 in the NAc and striatum of mGlu2-/-and mGlu3-/-mice, whereas expression of the DAT adaptor, syntaxin 1A, was selectively increased in the striatum of mGlu3-/-mice. Methamphetamine-stimulated dopamine release in striatal slices was largely reduced in mGlu2-/-, but not in mGlu3-/-, mice. These findings suggest that drugs that selectively enhance mGlu3 receptor activity or negatively modulate mGlu2 receptors might be beneficial in the treatment of methamphetamine addiction and associated brain damage.

Impaired Learning From Negative Feedback in Stimulant Use Disorder: Dopaminergic Modulation.

BACKGROUND: Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments. METHODS: We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. RESULTS: Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients. CONCLUSION: Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function.

Untargeted metabolomics analysis by gas chromatography/time-of-flight mass spectrometry of human serum from methamphetamine abusers.

Methamphetamine (METH) abuse has become a global public health problem. However, the potential mechanisms involving METH-induced metabolic disorders have thus far remained poorly understood. Metabolomics can provide a clue for the cause of apparent changes and consequently be used to investigate the METH-induced dysregulation of metabolite expression and the mechanism of metabolic disorder mechanism. This laboratory investigation included 80 METH abusers and 80 healthy people. The serum metabolites were detected and analysed by gas chromatography/time-of-flight mass spectrometry. Raw data were processed with the software MS DIAL, which includes deconvolution, peak alignment and compound identification. The data matrix was processed by univariate and multivariate analyses for significant metabolite screening with the criteria of variable importance in projection values > 1, fold change > 1.5 and the t test (p value < 0.05). Significant differences in 16 metabolites (deoxycholic acid, cholic acid, hydroxylamine, etc.) in serum were found between the METH abuse group and the control group. Energy metabolic pathways and several amino acid metabolic pathways (alanine, aspartic acid and glutamate metabolism and tryptophan metabolism) were primarily involved. Further analysis indicated that the area under the receiver operating characteristic curve (AUC) was 0.998 for these 16 metabolites. Among the metabolites, three carbohydrates (d-ribose, cellobiose and maltotriose) had an AUC of 0.975, which were determined as potential markers of abuse. We observed metabolic disturbances in METH abusers, particularly perturbation in energy metabolism and amino acid metabolism, which can provide new insights into the search for biomarkers and the mechanisms underlying the adverse effects of METH on human health.