Ten-year cardiovascular disease risk and related factors in lifetime marijuana use with comorbid methamphetamine-associated psychotic disorder: a QRISK®3 study.

BACKGROUND: Methamphetamine use and related direct and indirect problems are increasing all over the world. The coexistence of lifetime marijuana use (LMU) and methamphetamine use disorder (MUD) may also be accompanied by psychotic symptoms (MAP). Methamphetamine and marijuana use are known to pose risks for cardiovascular diseases (CVDs). However, ten-year CVD risk and inflammation markers of LMU-MUD (non-psychosis group) and LMU-MAP (psychosis group) subjects and the relationship of various sociodemographic and clinical variables with these markers have not yet been examined. METHODS: Thirty-two male subjects were included in non-psychosis group and 72 male subjects in psychosis group. Sociodemographic and clinical characteristics were recorded. Psychotic symptom severity of psychosis group subjects was measured. The ten-year CVD risk was calculated using QRISK®3 model. RESULTS: Age, cigarettes/pack-years, alcohol use onset age, drug use onset age, methamphetamine use onset age, duration of methamphetamine use, education and marital status of the groups were similar (p > 0.05). There was a statistical difference between the non-psychosis and psychosis groups in terms of self-mutilation history (p < 0.001), suicidal attempt history (p = 0.007), homicidal attempt history (p = 0.002), psychiatric hospitalization history (p = 0.010). Ten-year QRISK®3 score was 4.90 ± 9.30 in the psychosis group, while it was 1.60 ± 1.43 in the non-psychosis group (p = 0.004). The mean heart age of the psychosis group was 14 years higher than their chronological age, while the mean heart age of the non-psychosis group was 8 years higher. Neutrophil to lymphocyte ratio (NLR) (p = 0.003) was higher in the psychosis group. A significant correlation was detected between ten-year QRISK®3 and positive psychotic symptoms in the psychosis group (r = 0.274, p = 0.020). Regression analysis showed that self-mutilation history, NLR and relative risk obtained from QRISK®3 can be used to distinguish non-psychosis group and psychosis group subjects (sensitivity = 91.7; Nagelkerke R2 0.438; p = 0.001). CONCLUSIONS: This study is important as it demonstrates for the first time that among the subjects using marijuana and methamphetamine, those with psychotic symptoms have a higher NLR and ten-year CVD risk.

Development and evaluation of portable NIR technology for the identification and quantification of Australian illicit drugs.

The efficient and accurate analysis of illicit drugs remains a constant challenge in Australia given the high volume of drugs trafficked into and around the country. Portable drug testing technologies facilitate the decentralisation of the forensic laboratory and enable analytical data to be acted upon more efficiently. Near-infrared (NIR) spectroscopy combined with chemometric modelling (machine learning algorithms) has been highlighted as a portable drug testing technology that is rapid and accurate. However, its effectiveness depends upon a database of chemically relevant specimens that are representative of the market. There are chemical differences between drugs in different countries that need to be incorporated into the database to ensure accurate chemometric model prediction. This study aimed to optimise and assess the implementation of NIR spectroscopy combined with machine learning models to rapidly identify and quantify illicit drugs within an Australian context. The MicroNIR (Viavi Solutions Inc.) was used to scan 608 illicit drug specimens seized by the Australian Federal Police comprising of mainly crystalline methamphetamine hydrochloride (HCl), cocaine HCl, and heroin HCl. A number of other traditional drugs, new psychoactive substances and adulterants were also scanned to assess selectivity. The 3673 NIR scans were compared to the identity and quantification values obtained from a reference laboratory in order to assess the proficiency of the chemometric models. The identification of crystalline methamphetamine HCl, cocaine HCl, and heroin HCl specimens was highly accurate, with accuracy rates of 98.4 %, 97.5 %, and 99.2 %, respectively. The sensitivity of these three drugs was more varied with heroin HCl identification being the least sensitive (methamphetamine = 96.6 %, cocaine = 93.5 % and heroin = 91.3 %). For these three drugs, the NIR technology provided accurate quantification, with 99 % of values falling within the relative uncertainty of ±15 %. The MicroNIR with NIRLAB infrastructure has demonstrated to provide accurate results in real-time with clear operational applications. There is potential to improve informed decision-making, safety, efficiency and effectiveness of frontline and proactive policing within Australia.

U.S. trends in methamphetamine-involved psychiatric hospitalizations in the United States, 2015-2019.

BACKGROUND: In the U.S., overdose deaths and substance treatment admissions related to methamphetamine are rising. This study aims to measure and compare U.S. temporal trends in methamphetamine-involved psychiatric hospitalizations. METHODS: We conducted a population-based, trend analysis of U.S. psychiatric hospitalizations and calculated quarterly (Q) rates per 100,000 population of substance-involved psychiatric hospitalizations. We assessed U.S. regional quarterly percentage hospitalization rate changes using Joinpoint regression. RESULTS: From Q4 2015-Q4 2019, there were 963,202 psychiatric hospitalizations, 50,223 (5.2 %) involved methamphetamine and 102,877 (10.7 %) involved opioids and/or cocaine without methamphetamine. Methamphetamine-involved psychiatric hospitalization rates increased by 68.0 %, psychiatric hospitalizations rates involving opioid and/or cocaine without methamphetamine decreased by 22 %, while nonsubstance-involved psychiatric hospitalizations rates remained unchanged. The largest significant increases in methamphetamine-involved psychiatric hospitalization rates were among people >61 years old, males, and Midwesterners. Methamphetamine-involved psychiatric hospitalization rates doubled among Black patients. The largest average percent increase among methamphetamine-involved psychiatric hospitalizations was 10.2 % from Q4 2015-Q2 2017 in the Midwest. CONCLUSION AND RELEVANCE: Most psychiatric hospitalizations did not involve substances. Methamphetamine-involved psychiatric hospitalizations greatly increased while opioid-involved psychiatric hospitalizations decreased, but involved more total encounters. Greater access to harm reduction services, contingency management programs, and mental health services is urgently needed.

Prenatal methamphetamine hydrochloride exposure downregulates miRNA-151-3p and CACNA1C in testis rats' offspring.

Due to the widespread use of methamphetamine (METH) among reproductive-aged women, the effects of intrauterine exposure to METH need to be investigated, as previous studies on this topic have been limited. The goal of this study is to examine the influence of two regulatory genes (miRNA-151-3p and CACNA1C) on the intrauterine life of mice exposed to METH. Pregnant mice received doses of 2 and 5 mg/kg of METH and saline from day 10 of pregnancy until the end. Their offspring were then evaluated for miRNA-151-3p and CACNA1C gene expression levels using real-time PCR. The findings indicated that exposure to METH reduced the expression levels of both miRNA-151-3p and CACNA1C genes in offspring compared to the control group (p≤0.001). In conclusion, intrauterine exposure to METH leads to a decrease in expression levels of both miRNA-151-3p and CACNA1C genes, potentially disrupting regulatory pathways involving these genes and having an impact on male reproductive health.

Associations between childbirth, gang exposure and substance use among young women in Cape Town, South Africa.

The prevalence and influence of gangs on adolescents and young adults remain a concern in Western Cape, South Africa-particularly as they have one of the largest gang presence. While less attention has been focused on young women, there is a need to elucidate the relationship between gang exposure and health behaviors, such substance use, in addition to understanding whether becoming a caregiver impacts this relationship. This study uses baseline data from 496 participants enrolled in a NIDA-funded R01 trial that recruited young women aged 16 to 19 who were out of school and reported recent alcohol or other drug use and sexual risk behavior. At enrollment, a risk behavior survey was administered, and urine drug screening was conducted. Multivariable logistic regression analyses were conducted to examine baseline associations between childbirth, a gang exposure index based on eight items, and positive drug screens of the most prevalent drugs in the Western Cape (marijuana, methaqualone, and methamphetamine). At enrollment, approximately 39% of the sample had a positive urine screen for marijuana, 17% for methaqualone, and 11% for methamphetamine. Additionally, 28% had ever given birth. While only 6% reported ever being a member of a gang, most reported exposure to gangs through their physical and social environments. For all three drugs, gang exposure was associated with statistically significantly higher odds of a positive screen. Every one-point increase in the gang exposure index was associated with a 31% increase in the odds of a positive marijuana screen (p < .001), a 26% increase for methaqualone (p = 0.005) and a 37% increase in the odds of a positive methamphetamine screen (p < .001). Ever given birth was associated with lower odds of marijuana use (adjusted odds ratio [AOR]: 0.63; 95% CI: 0.42-0.96), but it was not associated with methaqualone or methamphetamine use. The findings suggest that exposure to gangs through young women's social and physical environment is positively associated with drug use. Childbirth was also protective for marijuana use, indicating there may be something unique about this type of drug, such as one's ability to more easily stop use. Although very few young women reported gang membership, a majority reported some exposure, indicating the need to address how pervasive this exposure is and the potential risk.

Midlife and Older Age Methamphetamine Poisoning Deaths in Hawai'i.

Unintentional and undetermined intent drug overdose fatality records from the State Unintentional Drug Overdose Reporting System (SUDORS) for Hawai'i from July 1, 2020, to December 31, 2021 revealed that 58.2% of decedents were aged 50-75. The main substance associated with cause of death for those aged 50-75 years was methamphetamine, followed by a combination of mixed drugs. Of those aged 50 and older, 25.5% died from cardiovascular or neurological complications which were likely to be associated with chronic, long-term methamphetamine use. Based on death investigator narrative reports, 76.5% of the older decedents had a history of substance abuse, suggesting possible long-term substance use starting at a young age. The trajectory of substance use over the life course is often influenced by life events and transitions, which can be stressors. Hawai'i kupuna (older adults) should be screened for substance use and dependence to ensure that there is treatment if needed, for the entirety of this use trajectory.Also, barriers to kupuna seeking treatment, such as stigma towards drug use should be addressed.

In vitro biotransformation of 3-methylmethcathinone (3-MMC) through incubation with human liver microsomes and cytosol and application to in vivo samples.

Synthetic cathinones are the second largest group of new psychoactive substances (NPS) monitored by the European Monitoring Centre for Drugs and Drug Addiction. Although 3-methylmethcathinone (3-MMC, C11H15NO) is legally banned in many countries, it is readily available for purchase online and on the street. Due to the scarcity of information regarding the pharmacokinetic and toxicological profile of 3-MMC, understanding its biotransformation pathways is crucial in determining its potential toxicity in humans and in the development of analytical methods for screening of human matrices. To gain more insight, Phase I and Phase II in vitro biotransformation of 3-MMC was investigated using human liver microsomes and human liver cytosol. Suspect and non-target screening approaches were employed to identify metabolites. To confirm in vitro results in an in vivo setting, human matrices (i.e., plasma, urine, saliva and hair) positive for 3-MMC (n=31) were screened. In total three biotransformation products were identified in vitro: C11H15NO2 (a hydroxylated derivate), C11H17NO (a keto-reduced derivate) and C10H13NO (an N-desmethyl derivate). All three were confirmed as human metabolites in respectively 16 %, 52 % and 42 % of the analysed human samples. In total, 61 % of the analysed samples were positive for at least one of the three metabolites. Interestingly, three urine samples were positive for all three metabolites. The presence of 3-MMC in saliva and hair indicates its potential applicability in specific settings, e.g., roadside testing or chronic consumption analysis. To our knowledge, C11H17NO was not detected before in vivo. Although some of these metabolites have been previously suggested in vitro or in a single post mortem case report, a wide in vivo confirmation including the screening of four different human matrices was performed for the first time. These metabolites could serve as potential human biomarkers to monitor human 3-MMC consumption effectively.

Effect of a Smartphone App (S-Check) on Actual and Intended Help-Seeking and Motivation to Change Methamphetamine Use Among Adult Consumers of Methamphetamine in Australia: Randomized Waitlist-Controlled Trial.

BACKGROUND: Interventions are required that address delays in treatment-seeking and low treatment coverage among people consuming methamphetamine. OBJECTIVE: We aim to determine whether a self-administered smartphone-based intervention, the "S-Check app" can increase help-seeking and motivation to change methamphetamine use, and determine factors associated with app engagement. METHODS: This study is a randomized, 28-day waitlist-controlled trial. Consenting adults residing in Australia who reported using methamphetamine at least once in the last month were eligible to download the app for free from Android or iOS app stores. Those randomized to the intervention group had immediate access to the S-Check app, the control group was wait-listed for 28 days before gaining access, and then all had access until day 56. Actual help-seeking and intention to seek help were assessed by the modified Actual Help Seeking Questionnaire (mAHSQ), modified General Help Seeking Questionnaire, and motivation to change methamphetamine use by the modified readiness ruler. χ2 comparisons of the proportion of positive responses to the mAHSQ, modified General Help Seeking Questionnaire, and modified readiness ruler were conducted between the 2 groups. Logistic regression models compared the odds of actual help-seeking, intention to seek help, and motivation to change at day 28 between the 2 groups. Secondary outcomes were the most commonly accessed features of the app, methamphetamine use, feasibility and acceptability of the app, and associations between S-Check app engagement and participant demographic and methamphetamine use characteristics. RESULTS: In total, 560 participants downloaded the app; 259 (46.3%) completed eConsent and baseline; and 84 (32.4%) provided data on day 28. Participants in the immediate access group were more likely to seek professional help (mAHSQ) at day 28 than those in the control group (n=15, 45.5% vs n=12, 23.5%; χ21=4.42, P=.04). There was no significant difference in the odds of actual help-seeking, intention to seek help, or motivation to change methamphetamine use between the 2 groups on the primary logistic regression analyses, while in the ancillary analyses, the imputed data set showed a significant difference in the odds of seeking professional help between participants in the immediate access group compared to the waitlist control group (adjusted odds ratio 2.64, 95% CI 1.19-5.83, P=.02). For participants not seeking help at baseline, each minute in the app increased the likelihood of seeking professional help by day 28 by 8% (ratio 1.08, 95% CI 1.02-1.22, P=.04). Among the intervention group, a 10-minute increase in app engagement time was associated with a decrease in days of methamphetamine use by 0.4 days (regression coefficient [ß] -0.04, P=.02). CONCLUSIONS: The S-Check app is a feasible low-resource self-administered intervention for adults in Australia who consume methamphetamine. Study attrition was high and, while common in mobile health interventions, warrants larger studies of the S-Check app. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619000534189; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377288&isReview=true.

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.

Psychometric validation of the Chinese Version of the stimulant relapse risk scale (SRRS) in patients with methamphetamine use disorder.

BACKGROUND: Evaluating the risk of relapse is a pivotal step in the treatment of patients with methamphetamine use disorder (MUD). The 30-item Stimulant Relapse Risk Scale (SRRS) was originally developed in Japan to meet the demand. This study examined the reliability, validity, and factor structure of the Chinese version of the SRRS for patients with MUD. METHODS: 247 patients with MUD self-rated the Chinese version of the SRRS. Cronbach's alpha coefficients and inter-item correlation analysis were used to assess the internal consistency reliability. Construct validity was determined through confirmatory factor analysis (CFA), and concurrent validity was examined using the visual analogue scale (VAS) for drug craving and the severity of dependence scale (SDS). We followed the participants for 1 year and assessed the predictive validity based on the correlation of the scores of the Chinese version of the SRRS with the relapse rate within 3, 6, and 12 months of follow-up. RESULTS: CFA revealed satisfactory model fit estimates for the 22-item Chinese version of the SRRS that consisted of four subscales. The four-factored 22-item Chinese version of the SRRS had adequate internal consistency with Cronbach's alphas ranging from 0.76 to 0.92. The 22-item Chinese version of the SRRS scores were significantly correlated with the VAS and SDS scores as well as the relapse rate within 3, 6, and 12 months, indicating good concurrent and predictive validity of this scale. The receiver operating characteristic curve revealed a cutoff score of 40 could discriminate between participants with (SDS score ≥ 4) and without (SDS score < 4) methamphetamine dependence (area under the curve = 0.71, p < 0.01). CONCLUSIONS: The 22-item Chinese version of the SRRS that consists of four subscales is a valid and reliable instrument to assess the relapse risk in patients with MUD.

Cellular and circuit architecture of the lateral septum for reward processing.

The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.

Nationwide assessment of illicit drug consumption patterns in South Korea using wastewater-based epidemiology during the COVID-19 pandemic (2020-2022).

Illicit drugs have become a crucial global social issue, with South Korea experiencing a continuous increase in the number of offenders and drug smuggling. This study employed wastewater-based epidemiology to investigate consumption patterns of 8 illicit drugs and their 7 metabolites during the COVID-19 pandemic (2020-2022) in South Korea. Ten compouds were detected in the wastewater influent. Methamphetamine (METH) was prevalent in samples, followed by amphetamine and ecstasy (MDMA). Interestingly, MDMA and ketamine (KET), which were not detected in previous Korean studies conducted before COVID-19 pandemic, were detected in this study. METH exhibited the highest consumption rates, decreasing from 16.6 to 12.4 mg/day/1000 people between 2020 and 2022, while MDMA increased over the three years (mean: 1.16, 1.24, and 1.62 mg/day/1000 people in 2020, 2021, and 2022, respectively) (p < 0.05). Significant correlations were identified between regional income levels and the consumption rates of METH (p < 0.01), MDMA (p < 0.01), and KET (p < 0.05). Furthermore, METH and MDMA consumption rates in cities were positively correlated with the number of drug offenders arrested and local clubs in those cities. The findings of this study provide valuable insights into shaping regulatory policies related to illicit drugs and future studies.

Assessing daily patterns in stimulant use during the COVID-19 pandemic in Melbourne, Australia using wastewater analysis.

During the COVID-19 pandemic, one of Australia's biggest cities, Melbourne, experienced three major isolation ("lockdown") periods in 2020 (160 days) and in 2021 (111 days) which makes it one of the most locked down cities world-wide. This study assessed how the pandemic affected temporal trends in methamphetamine, MDMA and cocaine consumption using wastewater-based epidemiology. Daily samples were collected for most of 2020 and 2021 (n = 660 days). Concentrations were measured using direct-injection LC-MS/MS and back-calculated to consumption estimates. Results indicate that methamphetamine use was increasing before the first lockdown and decreased after the end of the first lockdown in 2020. Methamphetamine trends appeared to have remained steady throughout the second lockdown period before increasing steeply after it ended. For most of 2020, cocaine use remained steady, with an increase after the second lockdown. MDMA use decreased after the start of the first lockdown and remained steady throughout most of 2020 and 2021. In comparison to 2020, trends in 2021 were less variable and stimulant use did not appear to be as associated with COVID-19 restrictions. Overall, this study was able to show the impact of lockdown periods and the related social restrictions on illicit stimulant use. ENVIRONMENTAL IMPLICATION: Illicit drugs are hazardous chemicals, of concern both to humans and the environment. While studies have been undertaken to understand their temporal trends, this work utilizes wastewater-based epidemiology and daily sampling to provide a comprehensive understanding of the impact of the COVID-19 pandemic on the use of methamphetamine, MDMA and cocaine on one of the most locked-down cities in the world. Understanding the consequences of this significant intervention on illicit drug use could provide valuable insights into its potential environmental impact.

Worsening trends in the frequency of methamphetamine and other stimulant use between treatment admission and discharge.

BACKGROUND: Treatment for methamphetamine and other stimulants can be effective but treatment attrition and continued use are very high. Abstinence is the conventional outcome used to evaluate treatment success, but defining treatment success in this way misses opportunities to promote improved health even when abstinence is not achieved. Reducing methamphetamine and stimulant use without abstinence is associated with many positive outcomes. However, little is known about drug use patterns during treatment or trends in use over time. METHODS: We used the Treatment Episode Dataset-Discharges (TEDS-D) to identify treatment episodes that had a stimulant drug indicated as the primary substance of use (2017-2021; N=251,841; methamphetamine, cocaine, other amphetamines, or other stimulants). Our outcome was the change in the frequency of drug use between admission and discharge (decreased use with abstinence, decreased use without abstinence, increased use). We used multiple logistic regression to model a change in drug use frequency, predicted by year, stimulant type, and their interaction. RESULTS: Nearly two-thirds of the sample (60 %) had methamphetamine indicated as the primary stimulant of use. There was a decrease in the predicted rate of abstinence over time and worsening trends were strongest among those using methamphetamine. Daily and periodic drug use at both admission and discharge (no change in use) became worse over time, particularly for those using methamphetamine. CONCLUSION: Treatment outcomes worsened over time and declined fastest among those reporting methamphetamine. Abstinence was rare and most treatment clients did not change their drug use behavior. We recommend a renewed focus on evidence-based harm reduction while the nation's treatment systems continue grappling with the stimulant crises.

Clustering of methamphetamine users based on personality characteristics and self-efficacy in the west of Iran.

With the substantial increase in the use of stimulants, especially methamphetamine, in recent years, the present study aimed to cluster methamphetamine users based on personality traits and self-efficacy, and compare their mental health, sleep quality, and the risk of relapse in the identified clusters. This cross-sectional study was conducted through convenience sampling on 501 methamphetamine users in addiction treatment centers in Kermanshah, western Iran. The data were collected using the Schwarzer General Self-Efficacy Scale, Zuckerman-Kuhlman Personality Questionnaire, Goldberg and Hiller General Health Questionnaire (GHQ), Zuckerman-Kuhlman Personality Questionnaire, and Stimulant Relapse Risk Scale (SRRS). A total of 501 methamphetamine users were distinguished into three clusters with frequencies of 111 (22.2%), 298 (59.5%), and 92 (18.4%) members through hierarchical cluster analysis. The participants in the first cluster were characterized by low self-efficacy, high neuroticism, sensation seeking, and aggressiveness, along with low extroversion and activity, low positive health, high negative health, low sleep quality, and high risk of drug relapse. The participants in the second cluster reported moderate levels of self-efficacy, neuroticism, sensation seeking, activity, and aggressiveness, high extroversion, and moderate levels of mental health, sleep quality, and the risk of relapse. Moreover, the participants in the third cluster reported the highest level of self-efficacy, the lowest level of neuroticism, sensation seeking, and aggressiveness, moderate extroversion and high activity, low relapse risk, high sleep quality, as well as high positive and low negative health symptoms. The third cluster was significantly different from the other two clusters in terms of the mentioned factors. The findings of this study suggest that low self-efficacy and the presence of neuroticism, sensation seeking, and high aggressiveness contribute to reduced mental health and sleep quality, as well as an increased risk of relapse in methamphetamine users.

Pathological polarizations from microglia to astrocyte contributes to spatial memory deficit in methamphetamine abstinence mice.

Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.

Degradation of perineuronal nets in the medial prefrontal cortex promotes extinction and reduces reinstatement of methamphetamine-induced conditioned place preference in female mice.

The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories.

Clavulanic acid inhibits methamphetamine locomotor sensitization in mice and normalizes methamphetamine-induced changes in glutaminase mRNA levels in the nucleus accumbens.

Clavulanic acid (CLAV) is a component of Augmentin® that preserves antibiotic efficacy by inhibiting ß-lactamase activity. It also enhances cellular glutamate uptake and is a potential CNS therapeutic. Because increased glutamate transmission in brain reward circuits facilitates methamphetamine (METH) locomotor activation and sensitization, we tested the hypothesis that CLAV inhibits acute and sensitized locomotor responses to METH in mice and investigated effects of CLAV on METH-induced changes in glutaminase, the major glutamate-producing enzyme in the brain. Acute METH (3 mg/kg) produced hyperlocomotion that was reduced by CLAV (20 mg/kg but not 10 mg/kg). Mice injected with METH (3 mg/kg) every other day for 9 d and then challenged with METH 27 d later displayed locomotor sensitization. CLAV (10 mg/kg), when injected 15 min before each METH injection during the 9-d exposure interval, blocked locomotor sensitization induced by METH challenge. In METH-sensitized mice, mRNA levels of both isoforms of glutaminase (GLS and GLS2) were altered in the nucleus accumbens compared to mice exposed to a single injection of METH (i.e., GLS decreased and GLS2 increased). CLAV normalized the METH-induced GLS deficit but not the increase in GLS2. In summary, CLAV reduced acute and sensitized locomotor responses to METH and normalized the METH-induced reduction of GLS gene expression in the NAC. Given that glutaminases belong to the ß-lactamase superfamily and CLAV is a ß-lactamase inhibitor, our data point toward studying glutaminase as a therapeutic target of CLAV.

A systematic approach to the analysis of illicit drugs for DNA with an overview of the problems encountered.

Due to the restricted nature of illicit drugs, it is difficult to conduct research surrounding the analysis of this drug material for any potential DNA in sufficient quantities acceptable for high numbers of replicates. Therefore, the current research available in peer reviewed journals thus far regarding analysing illicit drugs for DNA has been performed under varying experimental conditions, often using surrogate chemicals in place of illicit drugs. The data presented within this study originated from the analysis of genuine illicit drugs prepared both in controlled environments and those seized at the Australian border (and therefore from an uncontrolled environment) to determine if DNA can be obtained from this type of material. This study has been separated into three main parts (total n=114 samples): firstly, methamphetamine synthesised within a controlled environment was spiked with both saliva and trace DNA to determine the yield following DNA extraction; secondly, methamphetamine also synthesised in a controlled environment but on a larger scale was tested for the amount of DNA added incidentally throughout the synthesis, including the additional steps of recrystallising, homogenising and "cutting" the drug material to simulate preparation for distribution; and thirdly, the detection of human DNA within samples of cocaine and heroin seized at the Australian border. The DNA Fast Flow Microcon Device was utilised to concentrate all replicates from the same source into one combined extract to improve the DNA profiles for the samples where no DNA spiking occurred. Full STR profiles were successfully obtained from drug samples spiked with both saliva and trace DNA. Methamphetamine was present in the final DNA extracts and caused incompatibilities with the quantification of DNA using Qubit. The yields of DNA from drugs not spiked with DNA sources were much lower, resulting in 36 % of samples yielding alleles where all others did not. These results were not unexpected given these were realistic drug samples where the history of the drug material was unknown. This is the first study to obtain DNA profiles from genuine illicit drug material in both controlled and uncontrolled environments and indicates that the analysis of illicit drugs for DNA is an avenue worth pursuing to provide information which can in turn assist with disrupting the supply of these drugs. Given that DNA profiling is carried out worldwide using essentially the same systems as described within this study, the potential for impact is on a national and international scale.

Adaptive Changes in Group 2 Metabotropic Glutamate Receptors Underlie the Deficit in Recognition Memory Induced by Methamphetamine in Mice.

Cognitive dysfunction is associated with methamphetamine use disorder (MUD). Here, we used genetic and pharmacological approaches to examine the involvement of either Group 2 metabotropic glutamate (mGlu2) or mGlu3 receptors in memory deficit induced by methamphetamine in mice. Methamphetamine treatment (1 mg/kg, i.p., once a day for 5 d followed by 7 d of withdrawal) caused an impaired performance in the novel object recognition test in wild-type mice, but not in mGlu2-/- or mGlu3-/- mice. Memory deficit in wild-type mice challenged with methamphetamine was corrected by systemic treatment with selectively negative allosteric modulators of mGlu2 or mGlu3 receptors (compounds VU6001966 and VU0650786, respectively). Methamphetamine treatment in wild-type mice caused large increases in levels of mGlu2/3 receptors, the Type 3 activator of G-protein signaling (AGS3), Rab3A, and the vesicular glutamate transporter, vGlut1, in the prefrontal cortex (PFC). Methamphetamine did not alter mGlu2/3-mediated inhibition of cAMP formation but abolished the ability of postsynaptic mGlu3 receptors to boost mGlu5 receptor-mediated inositol phospholipid hydrolysis in PFC slices. Remarkably, activation of presynaptic mGlu2/3 receptors did not inhibit but rather amplified depolarization-induced [3H]-D-aspartate release in synaptosomes prepared from the PFC of methamphetamine-treated mice. These findings demonstrate that exposure to methamphetamine causes changes in the expression and function of mGlu2 and mGlu3 receptors, which might alter excitatory synaptic transmission in the PFC and raise the attractive possibility that selective inhibitors of mGlu2 or mGlu3 receptors (or both) may be used to improve cognitive dysfunction in individuals affected by MUD.