Detecting DSM-5 Opioid and Methamphetamine Use Disorders With the UNCOPE Screen.

BACKGROUND: The most recent wave of the opioid epidemic has contributed to record number of drug overdoses. Most fatal outcomes are associated with opioids and methamphetamine; two substances that tend to be used at high rates among criminal justice populations. Despite the steady rise in the number of overdoses in local detention centers, many correctional facilities do not conduct routine screens for opioid and methamphetamine use disorders. This study examines the utility of the UNCOPE, a 6-item brief screen, to detect probable Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) diagnoses for these 2 specific substance use disorders (SUDs). The study also examines key indicators of these specific SUDs. METHODS: Data were collected from comprehensive substance use assessments conducted with 717 adults who were recently admitted to 4 county jails. RESULTS: Findings indicate that 3 positive UNCOPE responses accurately detected 99.8% of opioid use disorder diagnoses and 98.7% of methamphetamine use disorder diagnoses. Receiver operating characteristic curve results generate an area under the curve at 0.99 for severe opioid use cases and 0.98 for severe methamphetamine use cases. Subsequent analyses indicate 2 of the 6 items on the UNCOPE function to accurately identify 100% of cases classified with opioid use disorder and 99.6% of cases classified with methamphetamine use disorder. CONCLUSIONS: Evidence suggests that UNCOPE is a practical and efficient approach to identifying opioid and methamphetamine use disorders. In addition, 2 items can serve as an ultra-brief method to detecting these conditions at the time of admission to detention centers.

Anti-manic effect of deep brain stimulation of the ventral tegmental area in an animal model of mania induced by methamphetamine.

BACKGROUND: Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. AIM: The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph). METHODS: Wistar rats were given 14 days of m-amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low-frequency stimulation (LFS) or continuous high-frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open-field tests and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. RESULTS: M-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M-amph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. CONCLUSION: These results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects.

Parents' Knowledge, Attitude, and Practices toward Methamphetamine Abuse among Youth and its Risk Factors in Saudi Arabia.

Objective: The present study aimed to conduct an assessment of parents' knowledge, attitudes, and practices toward methamphetamine "shabu" abuse among youth and its risk factors. Materials and Methods: The present cross-sectional descriptive study was conducted on a sample of 1179 parents. Parents were assured that questionnaire content would stay classified and was given anonymously. It had 20 demographic, drug use, and addiction treatment questions. Statistical Package for Social Sciences v. 24 and Chi-Square test were used to examine the data after evaluating and coding it. Results: Out of a total of 1179 participants, only 11% had not heard about shabu, about 38% did not know the main symptoms of crystal addiction, and 46% did not know the long side effects of crystal addiction. The majority of participants mentioned that shabu is available in powder format (57%) or liquid (13%), while 27% did not know its form. Most of the participants (97%) think that the drug of shabu or crystal or ice is dangerous; about 60% of participants mentioned that there is an addict in the family. Conclusion: Parents have good knowledge levels regarding different aspects of methamphetamine or shabu abuse, symptoms, and its risk factors. Further in-depth studies are needed at whole Saudi Arabia.

Combining brief recall and ketamine treatment prevents stress-primed methamphetamine memory reinstatement via heightening mPFC GABA activity.

This study aimed to assess whether brief recall of methamphetamine (MA) memory, when combined with ketamine (KE) treatment, may prevent stress-primed MA memory reinstatement. Combining 3-min recall and KE facilitated MA memory extinction and resistance to subsequent stress-primed reinstatement. Such combination also produced glutamate metabotropic receptor 5 (mGluR5) upregulation in animals' medial prefrontal cortex (mPFC) γ-amino-butyric acid (GABA) neuron. Accordingly, chemogenetic methods were employed to bi-directionally modulate mPFC GABA activity. Following brief recall and KE-produced MA memory extinction, intra-mPFC mDlx-Gi-coupled-human-muscarinic-receptor 4 (hM4Di)-infused mice receiving compound 21 (C21) treatment showed eminent stress-primed reinstatement, while their GABA mGluR5 expression seemed to be unaltered. Intra-mPFC mDlx-Gq-coupled-human-muscarinic-receptor 3 (hM3Dq)-infused mice undergoing C21 treatment displayed MA memory extinction and resistance to stress-provoked reinstatement. These results suggest that combining a brief recall and KE treatment and exciting mPFC GABA neuron may facilitate MA memory extinction and resistance to stress-primed recall. mPFC GABA neuronal activity plays a role in mediating brief recall/KE-produced effects on curbing the stress-provoked MA seeking.

Transient receptor potential ankyrin 1 channel modulates the abuse-related mechanisms of methamphetamine through interaction with dopamine transporter.

BACKGROUND AND PURPOSE: Methamphetamine (METH) use disorder has risen dramatically over the past decade, and there are currently no FDA-approved medications due, in part, to gaps in our understanding of the pharmacological mechanisms related to METH action in the brain. EXPERIMENTAL APPROACH: Here, we investigated whether transient receptor potential ankyrin 1 (TRPA1) mediates each of several METH abuse-related behaviours in rodents: self-administration, drug-primed reinstatement, acquisition of conditioned place preference, and hyperlocomotion. Additionally, METH-induced molecular (i.e., neurotransmitter and protein) changes in the brain were compared between wild-type and TRPA1 knock-out mice. Finally, the relationship between TRPA1 and the dopamine transporter was investigated through immunoprecipitation and dopamine reuptake assays. KEY RESULTS: TRPA1 antagonism blunted METH self-administration and drug-primed reinstatement of METH-seeking behaviour. Further, development of METH-induced conditioned place preference and hyperlocomotion were inhibited by TRPA1 antagonist treatment, effects that were not observed in TRPA1 knock-out mice. Similarly, molecular studies revealed METH-induced increases in dopamine levels and expression of dopamine system-related proteins in wild-type, but not in TRPA1 knock-out mice. Furthermore, pharmacological blockade of TRPA1 receptors reduced the interaction between TRPA1 and the dopamine transporter, thereby increasing dopamine reuptake activity by the transporter. CONCLUSION AND IMPLICATIONS: This study demonstrates that TRPA1 is involved in the abuse-related behavioural effects of METH, potentially through its modulatory role in METH-induced activation of dopaminergic neurotransmission. Taken together, these data suggest that TRPA1 may be a novel therapeutic target for treating METH use disorder.

Challenges recruiting and retaining people at risk for HIV who use methamphetamine in a randomized PrEP adherence trial in Seattle, WA.

BACKGROUND: Methamphetamine is associated with increased HIV risk and suboptimal adherence to pre-exposure prophylaxis (PrEP). Interventions to support PrEP adherence for people who use methamphetamine are needed. METHODS: We evaluated peer navigation to support adherence among people initiating PrEP who use methamphetamine. The HIV Prevention in Methamphetamine Users (HMU!) study enrolled participants from May 2018-January 2022 in Seattle, WA, and followed them for 6 months. Surveys collected sociodemographic, drug use, and sexual behavior data at enrollment, month 3, and month 6. Dried blood spots (DBS) were collected at months 1, 3, and 6 to measure PrEP adherence. RESULTS: We enrolled 21 participants of a target sample of 40, of whom 20 were prescribed PrEP. Nine participants (43%) received peer navigation and 12 (57%) received standard of care or text messaging. At baseline, most participants reported at least weekly methamphetamine use (17, 81%) and condomless receptive anal intercourse (CRAI) (16, 76%). One-third reported CRAI with a partner with HIV. Among those who provided a DBS, 78% and 50% had results commensurate with ≥4 pills/week at the month 3 and 6 visit, respectively. More than half of those prescribed PrEP completed a month 6 visit (11, 55%). Retention was not associated with peer support compared to standard of care or text messaging (p = .20). CONCLUSIONS: We enrolled half our target sample size despite extensive recruitment efforts. As expected, participants had challenges with PrEP adherence and persistence. While peer navigation interventions should be studied further, additional interventions are likely needed to support PrEP uptake, adherence, and persistence among people who use methamphetamine.

Outcomes of substance use and sexual power among adolescent girls and young women in Cape Town: Implications for structural and cultural differences.

Adolescent girls and young women (AGYW) in South Africa experience contextual barriers to HIV risk reduction including incomplete schooling, unintended pregnancy, substance use, and gender-based violence. A cluster randomised trial in Cape Town allocated 24 Black and Coloured communities to a gender-focused HIV risk-reduction intervention or HIV testing, with 500 AGYW total enrolled. We evaluated intervention efficacy by comparing mean differences overall, by community population group (Black and Coloured) and among those with structural barriers based on neighbourhood, education, and employment (n = 406). Both arms reported reductions in alcohol, cannabis, and condomless sex, with no intervention efficacy overall. Among AGYW with barriers, intervention participants reported fewer days of methamphetamine use at 6 months (t(210) = 2·08, p = ·04). In population group analysis, we found intervention effects on alcohol and sexual communication. Intervention participants in Black communities had fewer days of alcohol use at 12 months (t(136) = 2·10, p = ·04). Sexual discussion (t(147) = -2·47, p = ·02) and condom negotiation (t(146) = -2·51, p = ·01) increased for intervention participants at 12 months in Coloured communities. Gender-focused interventions must address population group differences and intersecting barriers to decrease substance use and increase education, skills, and sexual health protection.

Motivation and context of concurrent stimulant and opioid use among persons who use drugs in the rural United States: a multi-site qualitative inquiry.

BACKGROUND: In recent years, stimulant use has increased among persons who use opioids in the rural U.S., leading to high rates of overdose and death. We sought to understand motivations and contexts for stimulant use among persons who use opioids in a large, geographically diverse sample of persons who use drugs (PWUD) in the rural settings. METHODS: We conducted semi-structured individual interviews with PWUD at 8 U.S. sites spanning 10 states and 65 counties. Content areas included general substance use, injection drug use, changes in drug use, and harm reduction practices. We used an iterative open-coding process to comprehensively itemize and categorize content shared by participants related to concurrent use. RESULTS: We interviewed 349 PWUD (64% male, mean age 36). Of those discussing current use of stimulants in the context of opioid use (n = 137, 39%), the stimulant most used was methamphetamine (78%) followed by cocaine/crack (26%). Motivations for co-use included: 1) change in drug markets and cost considerations; 2) recreational goals, e.g., seeking stronger effects after heightened opioid tolerance; 3) practical goals, such as a desire to balance or alleviate the effects of the other drug, including the use of stimulants to avoid/reverse opioid overdose, and/or control symptoms of opioid withdrawal; and 4) functional goals, such as being simultaneously energized and pain-free in order to remain productive for employment. CONCLUSION: In a rural U.S. cohort of PWUD, use of both stimulants and opioids was highly prevalent. Reasons for dual use found in the rural context compared to urban studies included changes in drug availability, functional/productivity goals, and the use of methamphetamine to offset opioid overdose. Education efforts and harm reduction services and treatment, such as access to naloxone, fentanyl test strips, and accessible drug treatment for combined opioid and stimulant use, are urgently needed in the rural U.S. to reduce overdose and other adverse outcomes.

Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats.

Previous research has demonstrated therapeutic potential for VMAT2 inhibitors in rat models of methamphetamine use disorder. Here, we report on the neurochemical and behavioral effects of 1-(2-methoxyphenethyl)-4-phenethypiperazine (JPC-141), a novel analog of lobelane. JPC-141 potently inhibited (Ki = 52 nM) [3H]dopamine uptake by VMAT2 in striatal vesicles with 50 to 250-fold greater selectivity for VMAT2 over dopamine, norepinephrine and serotonin plasmalemma transporters. Also, JPC-141 was 57-fold more selective for inhibiting VMAT2 over [3H]dofetilide binding to hERG channels expressed by HEK293, suggesting relatively low potential for cardiotoxicity. When administered in vivo to rats, JPC-141 prevented the METH-induced reduction in striatal dopamine content when given either prior to or after a high dose of METH, suggesting a reduction in METH-induced dopaminergic neurotoxicity. In behavioral assays, JPC-141 decreased METH-stimulated locomotor activity in METH-sensitized rats at doses of JPC-141 which did not alter locomotor activity in the saline control group. Moreover, JPC-141 specifically decreased iv METH self-administration at doses that had no effect on food-maintained responding. These findings support the further development of VMAT2 inhibitors as pharmacotherapies for individuals with methamphetamine use disorder.

Preventing Overdoses Involving Stimulants: The POINTS Study Protocol.

Background: In recent years, overdoses involving illicit cocaine, methamphetamine, and other stimulants have increased in the U.S. The unintentional consumption of stimulants containing illicit fentanyl is a major risk factor for overdoses, particularly in Massachusetts and Rhode Island. Understanding the drug use patterns and strategies used by people who use stimulants (PWUS) to prevent overdose is necessary to identify risk and protective factors for stimulant-involved overdoses. Mixed-methods research with people who distribute drugs (PWDD) can also provide critical information into the mechanisms through which fentanyl may enter the stimulant supply, and the testing of drug samples can further triangulate PWUS and PWDD perspectives regarding the potency and adulteration of the drug supply. These epidemiological methods can inform collaborative intervention development efforts with community leaders to identify feasible, acceptable, and scalable strategies to prevent fatal and non-fatal overdoses in high-risk communities. Methods: Our overall objective is to reduce stimulant and opioid-involved overdoses in regions disproportionately affected by the overdose epidemic. To meet this long-term objective, we employ a multi-pronged approach to identify risk and protective factors for unintentional stimulant and opioid-involved overdoses among PWUS, and use these findings to develop a package of locally tailored intervention strategies that can be swiftly implemented to prevent overdoses. Specifically, this study aims to [1] Carry out mixed-methods research with incarcerated and non-incarcerated people who use or distribute illicit stimulants to identify risk and protective factors for stimulant and opioid-involved overdoses; [2] Conduct drug checking to examine the presence and relative quantity of fentanyl and other adulterants in the stimulant supply; and [3] Convene a series of working groups with community stakeholders involved in primary and secondary overdose prevention in Massachusetts and Rhode Island to contextualize our mixed-methods findings and identify multilevel intervention strategies to prevent stimulant-involved overdoses. Discussion: Completion of this study will yield a rich understanding of the social epidemiology of stimulant and opioid-involved overdoses in addition to community-derived intervention strategies that can be readily implemented and scaled to prevent such overdoses in two states disproportionately impacted by the opioid and overdose crises: Massachusetts and Rhode Island.

Methamphetamine Enhancement of HIV-1 gp120-Mediated NLRP3 Inflammasome Activation and Resultant Proinflammatory Responses in Rat Microglial Cultures.

Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders (HANDs) remain prevalent in HIV-1-infected individuals despite the evident success of combined antiretroviral therapy (cART). The mechanisms underlying HAND prevalence in the cART era remain perplexing. Ample evidence indicates that HIV-1 envelope glycoprotein protein 120 (gp120), a potent neurotoxin, plays a pivotal role in HAND pathogenesis. Methamphetamine (Meth) abuse exacerbates HANDs, but how this occurs is not fully understood. We hypothesize that Meth exacerbates HANDs by enhancing gp120-mediated neuroinflammation. To test this hypothesis, we studied the effect of Meth on gp120-induced microglial activation and the resultant production of proinflammatory cytokines in primary rat microglial cultures. Our results show that Meth enhanced gp120-induced microglial activation, as revealed by immunostaining and Iba-1 expression, and potentiated gp120-mediated NLRP3 expression and IL-1ß processing and release, as assayed by immunoblotting and ELISA. Meth also augmented the co-localization of NLRP3 and caspase-1, increased the numbers of NLRP3 puncta and ROS production, increased the levels of iNOS expression and NO production, and increased the levels of cleaved gasderminD (GSDMD-N; an executor of pyroptosis) in gp120-primed microglia. The Meth-associated effects were attenuated or blocked by MCC950, an NLRP3 inhibitor, or Mito-TEMPO, a mitochondrial superoxide scavenger. These results suggest that Meth enhances gp120-associated microglial NLRP3 activation and the resultant proinflammatory responses via mitochondria-dependent signaling.

Mapping structural covariance networks of emotional withdrawal symptoms in males with methamphetamine use disorder during abstinence.

Individuals with methamphetamine use disorder (MUD) often experience anxiety and depressive symptoms during abstinence, which can worsen the likelihood of relapse. Thus, it is essential to understand the neuro-mechanism behind methamphetamine use and its associated emotional withdrawal symptoms in order to develop effective clinical strategies. This study aimed to evaluate associations between emotional withdrawal symptoms and structural covariance networks (SCNs) based on cortical thickness (CTh) across the brain. The CTh measures were obtained from Tl-weighted MRI data from a sample of 48 males with MUD during abstinence and 48 male healthy controls. The severity of anxiety and depressive symptoms was assessed by the Hamilton Anxiety Scale (HAMA) and depression (HAMD) scales. Two important nodes belonging to the brain reward system, the right rostral anterior cingulate cortex (rACC) and medial prefrontal cortex (medPFC), were selected as seeds to conduct SCNs and modulation analysis by emotional symptoms. MUDs showed higher structural covariance between the right rACC and regions in the dorsal attention, right frontoparietal, auditory, visual and limbic networks. They also displayed higher structural covariance between the right medPFC and regions in the limbic network. Moreover, the modulation analysis showed that higher scores on HAMA were associated with increased covariance between the right rACC and the left parahippocampal and isthmus cingulate cortex in the default mode network. These outcomes shed light on the complex neurobiological mechanisms underlying methamphetamine use and its associated emotional withdrawal symptoms and may provide new insights into the development of effective treatments for MUD.

The 3,4-methylenedioxymethamphetamine enhances early visual processing for salient socio-emotional stimuli.

The 3,4-methylenedioxymethamphetamine (MDMA) has long been used non-medically, and it is currently under investigation for its potential therapeutic benefits. Both uses may be related to its ability to enhance empathy, sociability, emotional processing and its anxiolytic effects. However, the neural mechanisms underlying these effects, and their specificity to MDMA compared to other stimulants, are not yet fully understood. Here, using electroencephalography (EEG), we investigated the effects of MDMA and a prototypic stimulant, methamphetamine (MA), on early visual processing of socio-emotional stimuli in an oddball emotional faces paradigm. Specifically, we examined whether MDMA or MA enhance the processing of facial expressions, compared to placebo, during the early stages of visual perception. MDMA enhanced an event-related component that is sensitive to detecting faces (N170), specifically for happy and angry expressions compared to neutral faces. MA did not affect this measure, and neither drug altered other components of the response to emotional faces. These findings provide novel insights into the neural mechanisms underlying the effects of MDMA on socio-emotional processing and may have implications for the therapeutic use of MDMA in the treatment of social anxiety and other psychiatric disorders.

Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms.

BACKGROUND: The orexin system has been implicated as a mechanism underlying insomnia and methamphetamine-induced sleep disruptions, with a potential role for OX2 receptors in the sleep-modulating effects of orexin. The aim of the present study was to investigate the extent to which orexin receptors mediate the effects of acute methamphetamine administration on actigraphy-based sleep in female rhesus monkeys. METHODS: Actigraphy-based sleep measures were obtained in female rhesus monkeys (n=5) under baseline and acute test conditions. First, morning (10h) i.m. injections of methamphetamine (0.03 - 0.56mg/kg) were administered to determine the effects of methamphetamine alone. Then, saline or methamphetamine (0.3mg/kg) were administered at 10h, and evening (17h30) oral treatments with vehicle, the non-selective orexin receptor antagonist suvorexant (1 - 10mg/kg, p.o.), or the OX2-selective orexin receptor antagonist MK-1064 (1 - 10mg/kg, p.o.) were given. The ability of suvorexant and MK-1064 (10mg/kg, p.o.) to improve actigraphy-based sleep was also assessed in a group of female monkeys quantitatively identified with "short-duration sleep" (n=4). RESULTS: Methamphetamine dose-dependently disrupted actigraphy-based sleep parameters. Treatment with either suvorexant or MK-1064 dose-dependently improved actigraphy-based sleep in monkeys treated with methamphetamine. Additionally, both suvorexant and MK-1064 promoted actigraphy-based sleep in a group of monkeys with baseline short actigraphy-based sleep. CONCLUSIONS: These findings suggest that orexin-mediated mechanisms play a role in the effects of methamphetamine on actigraphy-based sleep in female monkeys. Targeting the orexin system, in particular OX2 receptors, could be an effective option for treating sleep disruptions observed in individuals with methamphetamine use disorder.

Co-administration of naloxone and dexmedetomidine to simultaneously reverse acute effects of fentanyl and methamphetamine in rats.

BACKGROUND: The incidence of combination methamphetamine (METH)-opioid overdose has substantially increased in recent years. While agitation is uncommon after the naloxone (NLX) reversal of opioids, it is a major clinical concern in acute METH intoxication and can be physiologically antagonized by opioid-induced sedation. This study aimed to perform initial preclinical analysis of the safety and efficacy of dexmedetomidine (DEXMED) co-administered with NLX to attenuate METH-induced locomotor activity, as a rat model of agitation, after the reversal of fentanyl (FENT)-induced sedation. METHODS: Male Sprague Dawley rats were administered subcutaneous (SC) 0.1mg/kg FENT ± 1mg/kg METH. Fifteen min later, SC 0.1mg/kg NLX ± an increasing (0, 0.032, 0.056, and 0.1mg/kg) DEXMED dose was administered prior to the measurement of locomotor activity. After a washout period, the FENT ± METH and NLX ± DEXMED administration with the highest dose of DEXMED was administered for measurement of blood oxygen saturation and heart rate. RESULTS: After the NLX reversal of FENT-induced sedation, adjunct DEXMED substantially and significantly reduced METH-induced locomotor activity (p<0.05) at all doses tested. While the addition of DEXMED did not significantly reduce blood oxygenation in METH treated rats, it did so in the absence of METH. Also, DEXMED significantly reduced heart rate compared to non-DEXMED treated groups and resulted in further significant reductions in the animals not exposed to METH (p<0.05). CONCLUSIONS: These data provide preclinical evidence that DEXMED may be a safe and effective chemical restraint for METH-induced agitation after NLX opioid reversal.

Chemical cousins with contrasting behavioural profiles: MDMA users and methamphetamine users differ in social-cognitive functions and aggression.

Methamphetamine (METH, "Crystal Meth") and 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") share structural-chemical similarities but have distinct psychotropic profiles due to specific neurochemical actions. Previous research has suggested that their impact on social cognitive functions and social behaviour may differ significantly, however, direct comparisons of METH and MDMA users regarding social cognition and interaction are lacking. Performances in cognitive and emotional empathy (Multifaceted Empathy Test) and emotion sensitivity (Face Morphing Task), as well as aggressive social behaviour (Competitive Reaction Time Task) were assessed in samples of n = 40 chronic METH users, n = 39 chronic MDMA users and n = 86 stimulant-naïve controls (total N = 165). Self-reports and hair samples were used to obtain subjective and objective estimates of substance use patterns. METH users displayed diminished cognitive and emotional empathy towards positive stimuli, elevated punitive social behaviour regardless of provocation, and self-reported heightened trait anger relative to controls. MDMA users diverged from the control group only by exhibiting a distinct rise in punitive behaviour when faced with provocation. Correlation analyses indicated that both higher hair concentrations of MDMA and METH may be associated with reduced cognitive empathy. Moreover, greater lifetime MDMA use correlated with increased punitive behaviour among MDMA users. Our findings confirm elevated aggression and empathy deficits in chronic METH users, while chronic MDMA users only displayed more impulsive aggression. Dose-response correlations indicate that some of these deficits might be a consequence of use. Specifically, the dopaminergic mechanism of METH might be responsible for social-cognitive deficits.

Point-of-care testing of methamphetamine and cocaine utilizing wearable sensors.

The imperative for the point-of-care testing of methamphetamine and cocaine in drug abuse prevention necessitates innovative solutions. To address this need, we have introduced a multi-channel wearable sensor harnessing CRISPR/Cas12a system. A CRISPR/Cas12a based system, integrated with aptamers specific to methamphetamine and cocaine, has been engineered. These aptamers function as signal-mediated intermediaries, converting methamphetamine and cocaine into nucleic acid signals, subsequently generating single-stranded DNA to activate the Cas12 protein. Additionally, we have integrated a microfluidic system and magnetic separation technology into the CRISPR system, enabling rapid and precise detection of cocaine and methamphetamine. The proposed sensing platform demonstrated exceptional sensitivity, achieving a detection limit as low as 0.1 ng/mL. This sensor is expected to be used for on-site drug detection in the future.

Effects of systemic pretreatment with the NAALADase inhibitor 2-PMPA on oral methamphetamine reinforcement in C57BL/6J mice.

Introduction: Repeated exposure to methamphetamine (MA) in laboratory rodents induces a sensitization of glutamate release within the corticoaccumbens pathway that drives both the rewarding and reinforcing properties of this highly addictive drug. Such findings argue the potential for pharmaceutical agents inhibiting glutamate release or its postsynaptic actions at glutamate receptors as treatment strategies for MA use disorder. One compound that may accomplish both of these pharmacological actions is the N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA). 2-PMPA elevates brain levels of the endogenous agonist of glutamate mGluR3 autoreceptors, N-acetyl-aspartatylglutamate (NAAG), while potentially acting as an NMDA glutamate receptor antagonist. Of relevance to treating psychomotor stimulant use disorders, 2-PMPA is reported to reduce indices of both cocaine and synthetic cathinone reward, as well as cocaine reinforcement in preclinical rodent studies. Method: Herein, we conducted three experiments to pilot the effects of systemic pretreatment with 2-PMPA (0-100 mg/kg, IP) on oral MA self-administration in C57BL/6J mice. The first experiment employed female mice with a prolonged history of MA exposure, while the mice in the second (females) and third (males and females) experiment were MA-naïve prior to study. In all experiments, mice were trained daily to nose-poke for delivery of unadulterated MA solutions until responding stabilized. Then, mice were pretreated with 2-PMPA prior to operant-conditioning sessions in which nose-poking behavior was reinforced by delivery of 120 mg/L or 200 mg/L MA (respectively, in Experiments 1 and 2/3). Results: Contrary to our expectations, 30 mg/kg 2-PMPA pretreatment altered neither appetitive nor consummatory measures related to MA self-administration. In Experiment 3, 100 mg/kg 2-PMPA reduced responding in the MA-reinforced hole, as well as the number of reinforcers earned, but did not significantly lower drug intake. Discussion: These results provide mixed evidenced related to the efficacy of this NAALADase inhibitor for reducing oral MA reinforcement in female mice.

Neonatal brain inflammation enhances methamphetamine-induced reinstated behavioral sensitization in adult rats analyzed with explainable machine learning.

Neonatal brain inflammation produced by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) results in long-lasting brain dopaminergic injury and motor disturbances in adult rats. The goal of the present work is to investigate the effect of neonatal systemic LPS exposure (1 or 2 mg/kg, i.p. injection in postnatal day 5, P5, male rats)-induced dopaminergic injury to examine methamphetamine (METH)-induced behavioral sensitization as an indicator of drug addiction. On P70, subjects underwent a treatment schedule of 5 once daily subcutaneous (s.c.) administrations of METH (0.5 mg/kg) (P70-P74) to induce behavioral sensitization. Ninety-six hours following the 5th treatment of METH (P78), the rats received one dose of 0.5 mg/kg METH (s.c.) to reintroduce behavioral sensitization. Hyperlocomotion is a critical index caused by drug abuse, and methamphetamine administration has been shown to produce remarkable locomotor-enhancing effects. Therefore, a random forest model was used as the detector to extract the feature interaction patterns among the collected high-dimensional locomotor data. Our approaches identified neonatal systemic LPS exposure dose and METH-treated dates as features significantly associated with METH-induced behavioral sensitization, reinstated behavioral sensitization, and perinatal inflammation in this experimental model of drug addiction. Overall, the analysis suggests that the implementation of machine learning strategies is sensitive enough to detect interaction patterns in locomotor activity. Neonatal LPS exposure also enhanced METH-induced reduction of dopamine transporter expression and [3H]dopamine uptake, reduced mitochondrial complex I activity, and elevated interleukin-1ß and cyclooxygenase-2 concentrations in the P78 rat striatum. These results indicate that neonatal systemic LPS exposure produces a persistent dopaminergic lesion leading to a long-lasting change in the brain reward system as indicated by the enhanced METH-induced behavioral sensitization and reinstated behavioral sensitization later in life. These findings indicate that early-life brain inflammation may enhance susceptibility to drug addiction development later in life, which provides new insights for developing potential therapeutic treatments for drug addiction.