RESUMEN
Methamphetamine addiction poses a growing public health challenge in Sri Lanka, yet limited research explores its impacts on the addicted population. This study aimed to assess the severity, patterns, and perceived impacts of methamphetamine addiction among adult patients at the National Institute of Mental Health (NIMH), Angoda, Sri Lanka. An analytical cross-sectional study was conducted among adult clients (aged >18 years) diagnosed with methamphetamine use disorder according to DSM-5 criteria at NIMH, Sri Lanka. A sample of 427 participants was recruited through purposive sampling. Data were collected using a structured, self-developed, validated, interviewer-administered questionnaire covering sociodemographic details, addiction severity (DSM-5 criteria), consumption patterns, impacts, and reasons for use. Descriptive statistics were analyzed using SPSS version 26. All participants (100%) responded to the survey. Among participants, 93.7% were male, and 65.3% were aged 18-30 years. The majority resided in urban (57.9%) or semi-urban (36.1%) areas. Addiction severity was categorized as mild (29%), moderate (38.6%), and severe (32.3%). Most (65.3%) initiated methamphetamine use between 21-30 years. Smoking (52.7%) and snorting (44.9%) were common methods of use, with peer pressure (48.9%) cited as the primary reason for initiation. The most cited physical impacts were weight loss (38.8%) and loss of appetite (37.2%), while irritability (28.8%) and interpersonal relationship problems (50.8%) were cited as common mental and social perceived impacts, respectively. Findings reveal that young urban males are predominantly affected by methamphetamine addiction, with moderate to severe dependence common. methamphetamine addiction severity was associated with living arrangement, monthly income, living area, age of onset, frequency of consumption, method of consumption, and accessibility (p < 0.05). Peer influence and easy accessibility were significant contributing factors. The physical, mental, and social health impacts emphasize the urgent need for comprehensive intervention strategies focusing on prevention, early detection, and integrated rehabilitation services at the national level.
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Trastornos Relacionados con Anfetaminas , Metanfetamina , Humanos , Masculino , Adulto , Femenino , Sri Lanka/epidemiología , Estudios Transversales , Metanfetamina/efectos adversos , Trastornos Relacionados con Anfetaminas/epidemiología , Trastornos Relacionados con Anfetaminas/psicología , Adulto Joven , Adolescente , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Methamphetamine (Meth) exposure leads to cognitive dysfunction and neurodegeneration in the hippocampus. Considering exosome therapy as a new treatment approach for neurological diseases, the current study proposed to investigate the effects of mesenchymal stem cell (MSC)-derived exosomes on hippocampal angiogenesis, inflammation, and cognitive function in Meth-treated mice. Meth (5 mg/kg) was injected daily for 30 days, and MSC-derived exosomes (100 µg per dose) were administered intravenously for three consecutive days after the Meth exposure. The Y-maze and Novel Object Recognition Test (NORT) evaluated spatial and recognition memory, while motor function was assessed through the Open Field Test (OFT). Results showed that exosome therapy improved both spatial and recognition memory. Additionally, the time spent in the center of the open field and the distance traveled significantly increased following treatment in Meth-exposed animals. Furthermore, exosome therapy promoted hippocampal angiogenesis and neurogenesis, as indicated by increased expression levels of HIF-1α, VEGF, and DCX, respectively, and also reduced Meth-induced hippocampal inflammation, evidenced by decreased TNF-α expression. These findings demonstrate that exosome therapy enhances cognitive function, encourages hippocampal angiogenesis, and diminishes inflammation in the hippocampus of Meth-treated mice.
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Estimulantes del Sistema Nervioso Central , Exosomas , Hipocampo , Metanfetamina , Animales , Metanfetamina/toxicidad , Metanfetamina/administración & dosificación , Exosomas/trasplante , Exosomas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Masculino , Proteína Doblecortina , Neurogénesis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/toxicidad , Células Madre Mesenquimatosas/metabolismo , Inflamación/inducido químicamenteRESUMEN
BACKGROUND: Cocaine- and methamphetamine (METH)-induced mitochondrial dysfunction and oxidative stress are key contributors to the neuropathology of psychostimulant addiction. These effects are often accompanied by epigenetic alterations, mitochondrial damage, and the accumulation of reactive oxygen species (ROS). Methionine synthase (MS) plays a critical role in epigenetic regulation and neuronal survival and may offer neuroprotection against psychostimulant-induced toxicity. We hypothesize that SA-31, a novel thiourea-based analog of TEMPOL, will attenuate cocaine or METH induced decrease in antioxidant, anti-inflammatory, and MS activities in neuronal cells. METHODS: SA-31 was synthesized and characterized via 1H NMR and mass spectrometry. Human SH-SY5Y dopaminergic neural cells were exposed to tertbutyl hydrogen peroxide (TBHP), cocaine hydrochloride, or methamphetamine (METH), with or without co-treatment with SA-31 for 24 h. Cell viability was measured using MTT assays. MS activity, IL-1ß, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase levels were assessed via ELISA. Mitochondrial function was evaluated using Seahorse-based oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) assays. RESULTS: SA-31 (10-100 µM) significantly protected cells from TBHP-, cocaine-, and METH-induced cytotoxicity. TBHP and METH reduced MS activity, which was significantly restored by SA-31. The compound also reversed cocaine-induced reductions in SOD, GPx, and catalase and lowered pro-inflammatory IL-1ß levels. Additionally, SA-31 (1-100 µM) enhanced mitochondrial respiration and glycolytic activity. CONCLUSION: These findings suggest that SA-31 confers neuroprotection by enhancing MS activity, upregulating antioxidant defenses, and improving mitochondrial function. Further studies in rodent models of addiction are planned to evaluate its therapeutic potential for psychostimulant use disorders and related neurodegenerative conditions.
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Antioxidantes , Estimulantes del Sistema Nervioso Central , Fármacos Neuroprotectores , Síndromes de Neurotoxicidad , Tiourea , Humanos , Fármacos Neuroprotectores/farmacología , Supervivencia Celular/efectos de los fármacos , Cocaína/toxicidad , Línea Celular Tumoral , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estimulantes del Sistema Nervioso Central/toxicidad , Estrés Oxidativo/efectos de los fármacos , Metanfetamina/toxicidad , Tiourea/farmacología , Tiourea/análogos & derivados , Antioxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Síndromes de Neurotoxicidad/metabolismoRESUMEN
The article provides an overview of key substance use and addictive behaviors in Vietnam, alongside the development of addiction science, drawing from a synthesis of literature and the authors' perspectives. Over the last two decades, the primary illicit drug of concern has shifted from heroin to methamphetamine and other psychoactive substances. Tobacco use has declined but remains widespread while alcohol consumption is high compared with other countries in the region with common binge drinking. Studies on behavioral addictions in Vietnam are limited. While the impacts of opioid addiction are well documented, reports on the societal impacts of methamphetamine use remain scarce. Public discourse has often framed substance use negatively, fueling stigmatization and supporting abstinence-oriented policies. Vietnam's drug policy reflects a tension between abstinence-focused and harm reduction approaches. The nationwide expansion of methadone treatment is a significant achievement. However, the country's responses to the new epidemic of methamphetamine and other psychoactive substances are still evolving. International cooperation has continued to play an important role in advancing research and surveillance as well as adapting evidence-based interventions. There are promising signs that Vietnam will strengthen public awareness and expand workforce training and policy innovation to address the issue of substance use in the population.
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Conducta Adictiva , Trastornos Relacionados con Sustancias , Vietnam/epidemiología , Humanos , Trastornos Relacionados con Sustancias/epidemiología , Conducta Adictiva/epidemiología , Metanfetamina , Reducción del DañoRESUMEN
The highly addictive psychostimulant methamphetamine increases the release of dopamine in the brain's reward circuitry, where it also promotes the release of cytokines, including TNF-α, that contribute to neuroinflammation associated with methamphetamine abuse. Here, we found a dynamic interplay between methamphetamine and TNF-α in facilitating dopamine transmission within the ventral tegmental area (VTA) in mice. In ex vivo mouse brain slices and dopaminergic neurons, methamphetamine or TNF-α treatment increased dopamine release, intracellular Ca2+ concentrations, and the firing activity of VTA dopaminergic neurons. These effects depended on the activity of dopamine transporter (DAT) and L-type voltage-gated Ca2+ channels. Pharmacological inhibition of either DAT or TNF-α signaling mitigated these effects, suggesting that methamphetamine-induced alterations in VTA dopaminergic neurons are partially TNF-α dependent. These results underscore the role of neuroimmune signaling in modulating the dopaminergic circuitry and may inform therapeutic strategies for addressing methamphetamine addiction and its associated neuroinflammatory disorders.
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Canales de Calcio Tipo L , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Dopamina , Neuronas Dopaminérgicas , Metanfetamina , Transducción de Señal , Factor de Necrosis Tumoral alfa , Animales , Metanfetamina/farmacología , Ratones , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Dopamina/metabolismo , Transducción de Señal/efectos de los fármacos , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Canales de Calcio Tipo L/metabolismo , Masculino , Ratones Endogámicos C57BL , Calcio/metabolismo , Estimulantes del Sistema Nervioso Central/farmacologíaRESUMEN
BACKGROUND Methamphetamine use has dramatically increased among young adults worldwide, contributing to a surge in cardiovascular complications. While typically associated with QT prolongation, nonspecific ST-T wave abnormalities, and tachyarrhythmias, high-grade atrio-ventricular (AV) blocks are exceedingly rare. Methamphetamine's sympathomimetic effects usually enhance AV nodal conduction, making bradyarrhythmia an unusual presentation. CASE REPORT A 40-year-old man with methamphetamine dependence presented with dyspnea, bilateral lower-extremity edema, and intermittent chest pain. He admitted to recent methamphetamine use earlier that day and requested detoxification. Initial vital signs revealed sinus tachycardia (123 bpm) and systolic blood pressure in the 130 s to 150 s mmHg. A physical exam showed an S3 gallop, a displaced point of maximal impulse, and a soft systolic murmur. Continuous telemetry monitoring later revealed a 2: 1 AV block. Subsequent electrocardiogram captured a transient 3: 1 AV block preceded by PR prolongation, following a period of sinus tachycardia and coinciding with apnea and oxygen desaturation for both events. Echocardiography showed severe global hypokinesis and a left ventricular ejection fraction (LVEF) of 20%. Cardiac MRI demonstrated severe biventricular dilation and dysfunction, prominent trabeculations, and a suspected LV thrombus without late gadolinium enhancement. Nuclear imaging was negative for amyloidosis. The patient underwent dual-chamber implantable cardioverter-defibrillator (ICD) placement for primary prevention of sudden cardiac death and pacing support and was discharged in stable condition. CONCLUSIONS This case illustrates the potential for methamphetamine toxicity to unmask distal conduction system disease. Early recognition is critical, as such presentations can progress to complete heart block requiring permanent pacing.
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Trastornos Relacionados con Anfetaminas , Bloqueo Atrioventricular , Estimulantes del Sistema Nervioso Central , Metanfetamina , Humanos , Masculino , Metanfetamina/efectos adversos , Adulto , Bloqueo Atrioventricular/inducido químicamente , Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/terapia , Trastornos Relacionados con Anfetaminas/complicaciones , Electrocardiografía , Estimulantes del Sistema Nervioso Central/efectos adversosRESUMEN
Far-infrared radiation (FIR) induces glutathione peroxidase-1 (GPx-1) expression and enhances microcirculation by upregulating endothelial nitric oxide synthase (eNOS). However, the role of eNOS in FIR-mediated neuroprotection remains unclear. Here, we investigated whether FIR upregulates eNOS and extracellular signal-regulated kinase (ERK) signaling to mitigate recognition memory impairment caused by methamphetamine (MA). FIR significantly reduced MA-induced oxidative stress, which was primarily associated with GPx-1 inhibition. FIR or genetic overexpression of GPx-1 (GPx-1 TG) in mice significantly attenuated the MA-induced reduction in phospho-eNOS (p-eNOS) and phospho-ERK (p-ERK). Triple-label immunostaining revealed colocalization of p-eNOS, p-ERK, and GPx-1 within the same cellular populations in the prefrontal cortex. In non-transgenic (non-TG) mice, FIR exposure improved MA-induced cholinergic and memory deficits. However, FIR did not provide additional cognitive benefits in GPx-1 TG mice, and the GPx-1 inhibitor mercaptosuccinate blocked FIR-mediated cholinergic effects. Inhibitors of eNOS (i.e. L-NAME) and ERK (i.e. U0126) also significantly blocked the FIR-driven memory-enhancing effects in non-TG mice. Unlike L-NAME, which inhibits phosphorylation of both eNOS and ERK, U0126 did not affect FIR-induced eNOS phosphorylation, suggesting that eNOS is an upstream molecule for ERK signaling. Our finding suggests that GPx-1 is an essential mediator of FIR-induced memory enhancement, and that FIR exposure attenuates MA-induced cognitive impairments via cholinergic upregulation associated with GPx-1/eNOS/ERK signaling.
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Glutatión Peroxidasa , Rayos Infrarrojos , Trastornos de la Memoria , Metanfetamina , Óxido Nítrico Sintasa de Tipo III , Animales , Ratones , Óxido Nítrico Sintasa de Tipo III/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa GPX1 , Metanfetamina/toxicidad , Masculino , Trastornos de la Memoria/inducido químicamente , Transducción de Señal/efectos de la radiación , Sistema de Señalización de MAP Quinasas/efectos de la radiación , Ratones Endogámicos C57BL , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Memoria/efectos de los fármacos , Memoria/efectos de la radiaciónRESUMEN
BACKGROUND: Heroin and methamphetamine are two widely abused drugs that have profound effects on brain morphology and functioning. This study aims to (1) identify brain structural differences between heroin and methamphetamine users; (2) examine how these drugs differentially affect the topology and functional connectivity of key brain networks; and (3) characterize associations between morphological alterations and clinical symptoms, including anxiety and depression. METHODS: In this study, we collected T1-weighted magnetic resonance imaging data from 26 heroin-abstinent (HA) patients, 24 methamphetamine-abstinent (MA) patients, and 32 healthy controls (HC). All participants were in early abstinence (< 6 months) to minimize acute intoxication and withdrawal confounds while capturing residual brain alterations. Four surface-based morphological features, including cortical thickness (CT), fractal dimension (FD), gyrification index (GI), and sulcal depth (SD), were analyzed, and morphological brain networks were constructed using Jensen-Shannon divergence with 210 cortical regions from the Brainnetome Atlas. RESULTS: Both patient groups showed brain tissue thinning in hearing-related areas (temporal cortex) and reduced depth in visual processing regions. Heroin users specifically exhibited atrophy in somatosensory cortex regions associated with touch sensation whereas methamphetamine users demonstrated distinctive cortical folding alterations in motor cortex areas related to movement control. Network analysis revealed that heroin users had widespread connection problems affecting brain communication efficiency, while methamphetamine users showed localized damage in specific brain hubs important for memory, attention, and visual processing. Clinical correlations revealed that morphological changes were significantly associated with drug use patterns (frequency and dosage) and psychological symptoms, with anxiety scores negatively correlating with SD in heroin users and depression scores positively correlating with morphological measures in methamphetamine users. CONCLUSIONS: Our findings demonstrate distinct neurobiological signatures of heroin and methamphetamine addiction that persist during early abstinence. Heroin primarily causes widespread network disruption, while methamphetamine leads to focal hub damage. The observed associations between brain morphology and clinical symptoms indicate the practical importance of these structural alterations. These distinct patterns may inform the development of substance-specific treatment approaches.
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Trastornos Relacionados con Anfetaminas , Encéfalo , Dependencia de Heroína , Heroína , Metanfetamina , Red Nerviosa , Humanos , Masculino , Adulto , Metanfetamina/efectos adversos , Metanfetamina/farmacología , Femenino , Encéfalo/patología , Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Imagen por Resonancia Magnética/métodos , Heroína/efectos adversos , Heroína/farmacología , Dependencia de Heroína/patología , Dependencia de Heroína/fisiopatología , Dependencia de Heroína/diagnóstico por imagen , Trastornos Relacionados con Anfetaminas/patología , Trastornos Relacionados con Anfetaminas/fisiopatología , Trastornos Relacionados con Anfetaminas/diagnóstico por imagen , Red Nerviosa/patología , Red Nerviosa/efectos de los fármacos , Persona de Mediana Edad , Vías Nerviosas/patología , Vías Nerviosas/efectos de los fármacos , Trastornos Relacionados con Sustancias/patología , Adulto JovenRESUMEN
Methamphetamine (METH) is a highly addictive synthetic psychostimulant that can induce severe neurotoxicity, leading to neurodegeneration similar to neurodegenerative diseases. The endocytosis of glial cell line-derived neurotrophic factor (GDNF) and its family receptor alpha 1 (GFRα1), regulated by transmembrane receptor tyrosine kinase (RET), has been shown to resist neurodegeneration. Specifically, the endocytosis of GDNF-GFRα1 mediated by RET is crucial in protecting neurons. Although many molecular mechanisms of METH induced neurotoxicity have been explored, the obstacles to the neuroprotective effect of GDNF in the context of METH induced neurotoxicity are still unclear. In this study, an increase in cell apoptosis and GDNF expression was observed in the hippocampus of METH abusers. METH also induces cell degeneration, cytotoxicity, and GDNF expression and release in hippocampal neuronal (HT-22) cells in a concentration-dependent manner (0.25, 0.5, 1, 2, and 4 mM) and time-dependent manner (3, 6, 12, 24, and 48 h). Meanwhile, after 24 h of exposure to METH (2mM), apoptosis, impaired endocytosis of GDNF-GFRα1, and decreased expression of RET were observed in HT-22 cells and organotypic hippocampal slices of mice. More notably, overexpression of RET weakened METH induced cell degeneration, apoptosis, and disruption of GDNF-GFRα1 endocytosis in HT-22 cells. This study suggests that RET is a key molecule for METH to disrupt GDNF-mediated neuroprotective signaling, and targeting RET-mediated endocytosis of GDNF-GFRα1 may be a potential therapeutic approach for METH induced neurotoxicity and neurodegeneration.
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Endocitosis , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial , Factor Neurotrófico Derivado de la Línea Celular Glial , Metanfetamina , Síndromes de Neurotoxicidad , Proteínas Proto-Oncogénicas c-ret , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Animales , Metanfetamina/toxicidad , Metanfetamina/efectos adversos , Endocitosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-ret/metabolismo , Proteínas Proto-Oncogénicas c-ret/genética , Ratones , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Apoptosis/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Masculino , Línea Celular , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patologíaRESUMEN
Objective: This study evaluated whether depressive symptom severity improved early with extended-release naltrexone and bupropion combination (naltrexone bupropion) compared to a placebo in individuals with moderate/severe methamphetamine use disorder and predicted subsequent use of methamphetamine.Methods: This secondary analysis from the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial, which was conducted from May 23, 2017-July 25, 2019, included 326 individuals with a 9-item Patient Health Questionnaire (PHQ-9) score ≥5 at baseline. Repeated-measures mixed model analyses evaluated early (baseline-to-week-4) changes in depressive symptom severity with naltrexone-bupropion versus placebo and provided slope estimates for PHQ-9 change. Additional depression outcomes included response (≥50% reduction in PHQ-9 from baseline) and remission (PHQ-9 ≤4). Methamphetamine treatment response was ascribed if 3 out of 4 urine drug screens were negative during weeks 5 and 6. Logistic regression analyses evaluated whether changes in depression predicted methamphetamine treatment response. Covariates included age, sex, race, ethnicity, and baseline PHQ-9.Results: There was a greater reduction in PHQ-9 scores at week 4 with naltrexone-bupropion versus placebo (estimate = -2.52; standard error = 0.81). At week 4, depression response (odds ratio [OR] = 2.54; 95% confidence limit [CL], 1.42-4.55) and remission (OR = 3.04; 95% CL, 1.57-5.87) were more likely with naltrexone-bupropion versus placebo. Greater baseline-to-week 4 reduction in PHQ-9 was associated with a higher likelihood of methamphetamine treatment response (OR = 3.74, 95% CL, 1.28-10.93) and explained 24.8% (95% CI, 6.7%-60.3%) of the effect of naltrexone-bupropion on methamphetamine treatment response.Conclusion: Use of naltrexone bupropion was associated with early reduction in depressive symptom severity compared to a placebo, which was associated with a higher likelihood of reduction in subsequent methamphetamine use.Trial Registration: ClinicalTrials.gov identifier: NCT03078075.
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Trastornos Relacionados con Anfetaminas , Bupropión , Depresión , Metanfetamina , Naltrexona , Humanos , Naltrexona/administración & dosificación , Naltrexona/uso terapéutico , Naltrexona/farmacología , Bupropión/administración & dosificación , Bupropión/uso terapéutico , Bupropión/farmacología , Masculino , Femenino , Metanfetamina/efectos adversos , Trastornos Relacionados con Anfetaminas/tratamiento farmacológico , Trastornos Relacionados con Anfetaminas/complicaciones , Adulto , Índice de Severidad de la Enfermedad , Quimioterapia Combinada , Persona de Mediana Edad , Depresión/tratamiento farmacológico , Depresión/diagnóstico , Preparaciones de Acción Retardada , Antagonistas de Narcóticos/administración & dosificación , Combinación de Medicamentos , Método Doble Ciego , Resultado del TratamientoRESUMEN
Methamphetamine (Meth) is a psychoactive and neurotoxic chemical. Selective antibodies against Meth molecules have been examined for the treatment of Meth abuse through immunization. Antibodies with high affinity for Meth can capture Meth molecules and reduce Meth response. We previously reported that intraperitoneal administration of adeno-associated virus serotype vector serotype 8 carrying Meth-specific monoclonal antibody transgene (AAV8-MethAb, 2.5 × 1010 VGC per mouse) induced long-term and stable expression of Meth-antibody in the peripheral. Mice receiving AAV8-MethAb had a lower Meth level in the blood and brain and attenuated Meth-induced locomotor activity after an acute dose of Meth. The effect of AAV-MethAb in animals receiving repeated Meth administration was still not known. In this study, we first investigated the tropism of AAV serotypes in rat primary dopaminergic (DA) neuronal culture. We found that AAV6 is an optimal gene carrier for MethAb. AAV6-MethAb or AAV6-mCherry was used in cellular and animal models of chronic Meth use. In primary DA neuronal culture, repeated Meth administration increased the dendritic branching of DA neurons, which was antagonized by AAV6-MethAb. AAV6-MethAb or AAV6-mCherry was stereotaxically administered to the nucleus accumbens (NAc) of adult CD1 mice. Two weeks after the viral injection, animals were stimulated with a daily dose of Meth for 7 days. Repeat Meth administrations led to a progressive increase in locomotor activity or behaviour sensitization. This response was significantly attenuated in mice receiving AAV6-MethAb. Using qRTPCR and Western analysis, we demonstrated that MethAb mRNA and protein were expressed in the NAc. Previous reports indicated that Meth sensitization was associated with upregulation of tyrosine hydroxylase (TH) in the NAc. Using Western blot analysis, we found that AAV6-MethAb significantly reduced TH protein levels in Meth-sensitized mice. Taken together, our data support that intracerebral administration of AAV6-MethAb reduced Meth sensitization. Our data support a novel antibody gene therapy for Meth abuse.
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Trastornos Relacionados con Anfetaminas , Anticuerpos Monoclonales , Conducta Animal , Estimulantes del Sistema Nervioso Central , Dependovirus , Metanfetamina , Animales , Metanfetamina/farmacología , Metanfetamina/inmunología , Dependovirus/genética , Ratones , Estimulantes del Sistema Nervioso Central/farmacología , Anticuerpos Monoclonales/genética , Masculino , Ratas , Neuronas Dopaminérgicas/efectos de los fármacos , Vectores Genéticos , Conducta Animal/efectos de los fármacos , Trastornos Relacionados con Anfetaminas/terapia , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacosRESUMEN
Methamphetamine abuse among women of reproductive age is a growing concern, necessitating investigation of its intrauterine effects on offspring. In this study, we examined the induction of oxidative stress and apoptosis in the ovaries of rat offspring following maternal methamphetamine exposure. Pregnant Wistar rats received methamphetamine (2 mg/kg or 5 mg/kg) from gestational day 10 until delivery. Control rats received 0.9% saline (1 mL/kg) on the same schedule. Female offspring were raised to puberty and their ovaries were examined, compared to controls. Protein expression levels of FASL and TRAIL were assessed by immunohistochemistry, and antioxidant enzyme levels (superoxide dismutase, SOD) and oxidative stress marker levels (malondialdehyde, MDA) were evaluated by ELISA1. Histological examination of the ovaries was performed using H&E staining. Maternal methamphetamine treatment significantly increased ovarian FASL and TRAIL protein expression in the pubertal offspring (p ≤ 0.001). In utero methamphetamine exposure led to a dose-dependent increase in ovarian MDA levels and a corresponding decrease in SOD activity (p ≤ 0.05). Histologically, exposed offspring showed a reduction in the number of primordial, primary, secondary, and Graafian follicles, as well as a reduction in corpora lutea, compared to controls (p < 0.05). Conversely, the number of atretic follicles increased significantly in a dose-dependent manner (p < 0.05). Prenatal methamphetamine exposure induces oxidative stress and promotes apoptosis in the ovaries of offspring, leading to reduced ovarian follicle reserves. These findings raise concerns that methamphetamine use during pregnancy may impair female reproductive health in offspring.
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Apoptosis , Metanfetamina , Ovario , Estrés Oxidativo , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Metanfetamina/efectos adversos , Metanfetamina/toxicidad , Estrés Oxidativo/efectos de los fármacos , Embarazo , Apoptosis/efectos de los fármacos , Ovario/efectos de los fármacos , Ovario/metabolismo , Ovario/patología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Proteína Ligando Fas/metabolismo , Malondialdehído/metabolismoRESUMEN
Non-muscle myosin II (NMII), a molecular motor that regulates critical processes such as cytokinesis and neuronal plasticity, has substantial therapeutic potential. However, translating this potential to in vivo use has been hampered by a lack of selective tools. The most prototypical non-selective inhibitor inactivates both NMII and cardiac muscle myosin II (CMII), a key regulator of heart function. Using rational drug design, we developed a series of NMII inhibitors that markedly improve tolerability by selectively targeting NMII over CMII, including MT-228 and clinical candidate MT-110. MT-228 and MT-110 have excellent properties, including high brain penetration and efficacy in preclinical models of methamphetamine use disorder (MUD), which has no current FDA-approved therapies. The structure of MT-228 bound to myosin II provides insight into its selectivity for NMII over CMII. The broad therapeutic windows of these NMII inhibitors provide valuable tools for the scientific community and a promising clinical candidate for the treatment of MUD.
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Miosina Tipo II , Bibliotecas de Moléculas Pequeñas , Animales , Humanos , Miosina Tipo II/antagonistas & inhibidores , Miosina Tipo II/metabolismo , Ratones , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , MetanfetaminaRESUMEN
Purpose: Given the evidence of a link between methamphetamine (METH) exposure and retinal vascular abnormalities, this study aims to investigate the molecular and cellular mechanisms underlying METH-induced retinal angiogenesis using a unique self-administration rat model and primary rat retinal microvascular endothelial cells (RRMECs). Method: To model the impact of compulsive use of METH, rats underwent an 8-week METH long-access self-administration protocol, with retinal tissues analyzed using whole retinal flatmount imaging and vascular network quantification. Proteomic analysis via liquid chromatography/tandem mass spectrometry identified differentially expressed proteins, while RRMECs were treated with METH to assess molecular changes through immunoblotting and quantitative RT-PCR. Results: Consistent with compulsive use of METH in humans and our previous experience with this model, rats self-administered high levels of METH. METH self-administration elevated dopamine levels in the vitreous humor and increased vascular density in both superficial and deep capillary layers across central, mid-peripheral, and peripheral retina regions. Proteomic analysis revealed 148 differentially expressed retinal proteins, with gene ontology enrichment highlighting pathways related to abiotic stimuli, hypoxia, and ischemia. Increased hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor a (VEGFa) expression confirmed a hypoxia-driven angiogenesis process, further supported by in vitro experiments showing enhanced endothelial cell proliferation and HIF-1α/VEGFa expression. Additionally, TAAR-1 upregulation in both the retina and endothelial cells was observed, with TAAR-1 antagonism reducing METH-induced endothelial cell proliferation and modulating HIF-1α/VEGFa signaling. Conclusions: METH self-administration leads to significant retinal vascular changes and angiogenesis, driven by upregulation of hypoxia-related pathways. TAAR-1 plays a critical role in endothelial cell proliferation through the HIF-1α/VEGFa pathway, potentially contributing to pathological retinal conditions.
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Estimulantes del Sistema Nervioso Central , Metanfetamina , Neovascularización Retiniana , Vasos Retinianos , Animales , Metanfetamina/administración & dosificación , Metanfetamina/toxicidad , Ratas , Neovascularización Retiniana/inducido químicamente , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/patología , Masculino , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/patología , Vasos Retinianos/metabolismo , Autoadministración , Proteómica , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/toxicidad , Cromatografía Liquida , Células Cultivadas , Espectrometría de Masas en Tándem , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , AngiogénesisRESUMEN
Anxiety disorders, commonly observed during methamphetamine (METH) withdrawal, are important negative reinforcement factors that contribute to relapse.The lateral habenula (LHb) serves as a negative reinforcement center, however its role in METH withdrawal-induced anxiety remains unclear. Here, we used the open field test (OFT) and elevated plus maze (EPM) to assess anxiety-like behaviors in METH-withdrawn male mice, combined with c-Fos immunofluorescence and chemogenetics approach. Our results showed that METH-withdrawn mice exhibited anxiety-like behaviors, along with activation of LHb neurons. Furthermore, suppressing LHb neurons activity in METH-withdrawn mice alleviated the anxiety-like behaviors. In normal (naïve) mice, activation of LHb also induced anxiety-like behaviors, highlighting the importance of LHb activity homeostasis in emotional regulation. Taken together, our findings provide evidence for the role of LHb in METH withdrawal-induced anxiety, demonstrating that maintaining the homeostasis of LHb activity is crucial for preventing maladaptive behaviors associated with anxiety.
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Ansiedad , Estimulantes del Sistema Nervioso Central , Habénula , Metanfetamina , Síndrome de Abstinencia a Sustancias , Animales , Habénula/efectos de los fármacos , Habénula/metabolismo , Habénula/fisiopatología , Síndrome de Abstinencia a Sustancias/fisiopatología , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/psicología , Metanfetamina/efectos adversos , Masculino , Ansiedad/fisiopatología , Ansiedad/metabolismo , Ansiedad/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Estimulantes del Sistema Nervioso Central/efectos adversos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacosRESUMEN
Methamphetamine (METH) addiction involves escalating intake with strong cue reactivity, and high relapse risk, yet its neural mechanism remains unclear. Using c-Fos mapping and machine learning, we identified the claustrum (CLA), a subcortical region reciprocally connected with the anterior cingulate cortex (ACC), as key mediators of both METH taking and seeking in self-administering male rats. Chemogenetic inhibition of CLA suppressed both drug consumption and cue-induced reinstatement, while ACC inhibition selectively reduced drug-seeking. Circuit tracing and manipulation revealed that the CLA-ACC circuit supported drug-taking, whereas the ACC-CLA circuit was specifically recruited during drug-seeking. Activity-dependent labeling showed that ACC ensembles activated by cues overlapped with those engaged during prior drug use. These findings suggest that CLA drives METH reward through the ACC, while the ACC gains cue salience and feeds back to CLA, reinforcing relapse. Targeting this bidirectional CLA-ACC circuit may provide novel therapeutic strategies for treating METH addiction.
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Trastornos Relacionados con Anfetaminas , Ganglios Basales , Comportamiento de Búsqueda de Drogas , Giro del Cíngulo , Metanfetamina , Animales , Metanfetamina/administración & dosificación , Metanfetamina/farmacología , Giro del Cíngulo/fisiología , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/fisiopatología , Masculino , Comportamiento de Búsqueda de Drogas/fisiología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Ratas , Señales (Psicología) , Autoadministración , Ganglios Basales/fisiología , Ganglios Basales/efectos de los fármacos , Ganglios Basales/fisiopatología , Recompensa , Trastornos Relacionados con Anfetaminas/fisiopatología , Ratas Sprague-Dawley , Vías Nerviosas , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Drug addiction is characterized by compulsive drug use despite significant negative consequences. N-acetyltransferase 10 (NAT10), a member of the Gcn5-related N-acetyltransferases (GNAT) family, has been associated with depression, anxiety-like behaviors, and cognitive dysfunction. However, its role in addiction remains largely unknown. In the present study, we observed increased expression of NAT10 in the nucleus accumbens (NAc) of mice treated either singly or repeatedly with 2 mg/kg methamphetamine (METH). To assess the role of NAT10 in addiction-related behaviors, we established mouse models of conditioned place preference (CPP) and hyperlocomotion. Using intraperitoneal administration of 0.1 mg/kg SCH23390, a dopamine D1 receptor (D1R) antagonist, we found that D1R antagonism significantly suppressed the METH-induced upregulation of NAT10 in the NAc and inhibited hyperlocomotion. Furthermore, stereotaxic delivery of a short hairpin RNA (shRNA)-based adeno-associated virus (AAV-shNAT10) into the NAc reduced both METH-induced hyperlocomotion and CPP. AAV-shNAT10 also inhibited METH-induced upregulation of PSD95 and preserved dendritic morphology in the NAc. These findings suggest that NAT10 contributes to the development of METH-induced reward-related behaviors by modulating dendritic plasticity in the NAc.
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Acetiltransferasas , Condicionamiento Psicológico , Hipercinesia , Locomoción , Metanfetamina , Núcleo Accumbens , Animales , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/enzimología , Metanfetamina/farmacología , Metanfetamina/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Acetiltransferasas/metabolismo , Acetiltransferasas/biosíntesis , Locomoción/efectos de los fármacos , Locomoción/fisiología , Hipercinesia/inducido químicamente , Hipercinesia/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiologíaRESUMEN
BACKGROUND: The coinjection of methamphetamine and opioids, known as "goofballing," is an emerging practice among people who inject drugs. This combination poses significant clinical challenges due to the opposing pharmacological effects of stimulants and depressants. The increasing prevalence of this practice, particularly in North America, raises significant concerns regarding its impact on public health and patient management. MATERIAL AND METHODS: The authors report the case of a 48-year-old man admitted to the intensive care unit with suspected sepsis after intravenous heroin use. During methadone substitution therapy, the patient developed hyperthermia, diffuse myalgia, and mild somnolence. Physical investigation revealed no evidence of infection. Toxicological analyses were conducted on blood and urine samples using targeted and nontargeted screening methods. RESULTS: Toxicological analyses revealed the presence of methamphetamine, amphetamine (a metabolite of methamphetamine), morphine, codeine, methadone, and EDDP in both blood and urine. The presence of 6-acetylmorphine in the urine confirmed recent heroin exposure. No other substances were detected in any sample. The patient was later treated for coinjection of heroin and methamphetamine, which supported the diagnosis of goofballing-induced hyperthermia rather than sepsis. CONCLUSIONS: This case highlights the diagnostic challenges associated with the "goofball" phenomenon. The coadministration of methamphetamine and heroin can lead to severe atypical toxicological symptoms. Health care providers should be aware of this emerging practice to ensure rapid diagnosis and appropriate management. Public health initiatives should focus on harm reduction strategies to mitigate associated risks.
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Dependencia de Heroína , Metanfetamina , Abuso de Sustancias por Vía Intravenosa , Humanos , Masculino , Persona de Mediana Edad , Metanfetamina/efectos adversos , Metanfetamina/sangre , Metanfetamina/administración & dosificación , Abuso de Sustancias por Vía Intravenosa/complicaciones , Metadona , Dependencia de Heroína/complicaciones , Heroína/efectos adversos , Hipertermia/inducido químicamente , Sepsis , Analgésicos Opioides/efectos adversos , Tratamiento de Sustitución de OpiáceosRESUMEN
Background and Objectives: Methamphetamine (METH) is a potent psychostimulant known to induce neurotoxicity and neurodegeneration, leading to cognitive impairment. This study aimed to explore cubebin's potential neuroprotective effects against METH-induced cognitive deficits by investigating its ability to suppress lipid peroxidation and pro-inflammatory markers and modulate neurotransmitter levels. Material and Methods: A total of 30 rats were taken and randomly grouped into five groups: group I-control; group II-METH 100 mg/kg/i.p.; group III-METH + cubebin (10 mg/kg/p.o.); group IV-METH + cubebin (20 mg/kg/p.o.); and group V-cubebin per os at 20 mg/kg. After a 14-day oral regimen, behavioral activities were assessed utilizing the Morris water maze (MWM). Biochemical analysis included neurotransmitters, including dopamine (DA), norepinephrine (NE), and gamma-aminobutyric acid (GABA); oxidative stress markers (malondialdehyde (MDA); nitric oxide (NO), catalase (CAT), reduced glutathione (GSH)); inflammatory cytokines [interleukin (IL-1ß), IL-6, tumor necrosis factor-α (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)]; neurotrophic factors (BDNF, CREB); and apoptotic markers (caspase-3 and caspase-9). Furthermore, molecular docking and simulation studies were conducted. Results: Treatment with cubebin led to a marked reduction in latency during the MWM task. It significantly modulated the oxidative stress markers (SOD, GSH, CAT, MDA, and NO), inflammatory cytokines (IL-6, IL-1ß, TNF-α), neurotrophic factors (CREB, BDNF), apoptotic markers (NFkB, caspase-3, caspase-9), and neurotransmitters (NE, DA, and GABA) in METH-induced memory-impaired rats. The results of molecular dynamics simulation (MDS) provided insight into the mechanisms that associate proteins CREB, BDNF, and caspase-3 in conformational dynamics upon binding to cubebin. Conclusions: In conclusion, cubebin administration improved cognitive function in rats by modulating antioxidant enzyme activity, reducing pro-inflammatory cytokines, and regulating neurotransmitter levels, demonstrating its potential neuroprotective effects against MA-induced neurodegeneration.
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Metanfetamina , Síndromes de Neurotoxicidad , Animales , Metanfetamina/toxicidad , Metanfetamina/efectos adversos , Ratas , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/análisis , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Caspasa 3/efectos de los fármacos , Caspasa 3/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/análisis , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Ratas Wistar , Simulación por Computador , Modelos Animales de EnfermedadRESUMEN
BACKGROUND AND AIMS: Sexual minority men (SMM) in the US experience high rates of methamphetamine use and are disproportionately affected by HIV. Unlike prior studies among treatment-seeking populations, this study examined associations between methamphetamine use, smoking, and mortality in a community-based cohort of SMM, half of whom have HIV. Using time-varying survival models, we assessed how dynamic patterns of substance use impact mortality risk over time. DESIGN AND SETTING: This longitudinal cohort study followed N = 541 SMM in Los Angeles from two community-based sites (2014-2023). Substance use and health outcomes data were collected biannually through behavioral surveys and clinical evaluations. Deaths were defined using the Los Angeles Medical Examiner Database or direct reports from participants' family or friends. We used Cox proportional hazards regression with time-varying covariates to assess the association between methamphetamine use, cigarette smoking, and mortality risk. FINDINGS: There were N = 19 observed deaths in our cohort. Daily methamphetamine use (aHR=4.45, 95 % CI 1.33-14.9), weekly methamphetamine use (aHR=3.32, 95 % CI 1.09-10.1) and smoking more than ½ pack of cigarettes per day (aHR=3.28, 95 % CI 1.07-10.0) were significantly and independently associated with increased risk of mortality, after adjusting for confounders. CONCLUSIONS: Findings confirm that consistent methamphetamine use and cigarette smoking above a threshold frequency of use significantly increase mortality risk among otherwise healthy SMM. Comprehensive interventions including behavioral therapies and risk screening are warranted to mitigate early mortality and improve health outcomes among SMM.