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2.
Zhonghua Yi Xue Za Zhi ; 102(35): 2779-2785, 2022 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-36124350

RESUMO

Objective: To explore the value of MRI diffusion tensor imaging (DTI) in the white matter changes of short-term methamphetamine (MA) abstinence. Methods: The data of DTI, demographics features, general information of addiction and impulsivity scale eleven (BIS-11) of 55 short-term MA addicts who were from Changsha, Zhuzhou and Yueyang compulsory detoxification centers in Hunan province, including 40 males and 15 females, aged 14-45 (37.24±7.31) years old, and 52 healthy controls, including 40 males and 12 females aged 18-59 (40.3±9.1) years were collected prospectively from August 2017 to December 2018. The differences of DTI indicators between the two groups were compared by tract-based spatial statistics (TBSS), and then the correlation between the different indicators and the age of first MA use, time of MA use, daily dose used, BIS-11 score were performed. Results: There were significant differences in BIS total score(P<0.001), BIS motivational impulsivity(P<0.001) and BIS attentional impulsivity(P=0.003) between MA group and healthy control group in short-term withdrawal. And compared with the healthy control group, the fractional anisotropy (FA) (0.58±0.02 vs 0.56±0.02,0.77±0.02 vs 0.75±0.04,0.79±0.04 vs 0.76±0.06; all P<0.05), axial diffusivity (AD) (0.57±0.01 vs 0.56±0.02,P=0.001) and mean diffusivity (MD) (0.66±0.02 vs 0.65±0.02,0.52±0.07 vs 0.51±0.06; both P<0.05)values in the MA group were all increased (P<0.05), but there was no significant difference in the radial diffusivity (RD) value (P>0.05). The white matter areas with increased FA value were located in the knee and body of corpus callosum, bilateral anterior corona radiata and left superior corona radiata; the areas with increased AD value were located in the knee, body and pressure of corpus callosum, bilateral anterior limb of internal capsule, posterior limb of internal capsule, anterior, superior and posterior corona radiata, external capsule and superior longitudinal fasciculus; and the areas with increased MD value were mainly located in the right superior longitudinal fasciculus, anterior and posterior limb of internal capsule. The corpus callosum, where there was a difference in FA between the two groups, was positively correlated with the daily dose of MA (r=0.301, P=0.026). Conclusion: MA addicted individuals with short-term withdrawal have white matter edema and damage, and the degree of corpus callosum damage is positively correlated with the daily dose of MA,which is helpful to understand the pathophysiological process of white matter damage in the nervous system and the potential mechanism of neuropsychiatric symptoms in short-term withdrawal MA addicted individuals.


Assuntos
Metanfetamina , Substância Branca , Adulto , Anisotropia , Corpo Caloso , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Masculino , Metanfetamina/efeitos adversos
4.
J Opioid Manag ; 18(4): 361-375, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052933

RESUMO

OBJECTIVE: Clinicians and policymakers have been wrestling with the appropriateness and safety of opioid therapy during the opioid crisis. Policy and clinical decisions have often been made without much current data on trends in drug use in patients with pain. Thus, we evaluated definitive urine drug test (UDT) results in patients being treated for pain to see if those taking their prescribed opioids were less likely to be positive for the primary illicit drugs currently driving overdose deaths: cocaine, heroin, fentanyl, and methamphetamine. DESIGN, SETTING, AND PATIENTS: A cross-sectional study of UDT results from January 1, 2015 to September 30, 2021, from 600,000 patient specimens submitted for testing by pain management specialists. INTERVENTIONS: UDT by liquid chromatography-tandem mass spectrometry as ordered by the treating clinician. MAIN OUTCOME MEASURES: Presence of other substances stratified by whether a patient's prescribed opioid was found. RESULTS: The presence of cocaine, heroin, fentanyl, and methamphetamine for the total population was low (<5 percent). Of the 347,092 patients prescribed opioids, 76 percent (n = 264,961) were positive on UDT for their prescribed opioid ("consistent"). Compared to patients without their prescribed opioid present ("inconsistent"), patients consistent with therapy were 54 percent (incidence rate ratio (IRR) 1.54, 95 percent confidence interval (CI) 1.47-1.59) less likely to be positive for cocaine, 47 percent [IRR 1.47, 95 percent CI 1.34-1.57] less likely to be positive for heroin, and 35 percent [IRR 1.35, 95 percent CI 1.24-1.45] less likely to be positive for methamphetamine, p < 0.001. Differences between the groups for fentanyl were not significant. CONCLUSIONS: Overall positivity rates for cocaine, heroin, fentanyl, and methamphetamine were low. Patients with prescribed opioid present were less likely to be positive for cocaine, heroin, or methamphetamine. Patterns of substance use within this pain management population should be used to inform ongoing policy decisions.


Assuntos
Cocaína , Overdose de Drogas , Metanfetamina , Transtornos Relacionados ao Uso de Substâncias , Analgésicos Opioides/uso terapêutico , Cocaína/efeitos adversos , Estudos Transversais , Overdose de Drogas/tratamento farmacológico , Fentanila/efeitos adversos , Heroína , Humanos , Metanfetamina/efeitos adversos , Dor/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
5.
Int J Mol Sci ; 23(17)2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36077488

RESUMO

Perturbations in striatal dopamine (DA) homeostasis might underlie the behavioral and pathobiological consequences of METH use disorder in humans. To identify potential consequences of long-term METH exposure, we modeled the adverse consequence DSM criterion of substance use disorders by giving footshocks to rats that had escalated their intake of METH during a drug self-administration procedure. Next, DA D1 receptor antagonist, SCH23390 was injected. Thereafter, rats were euthanized to measure several indices of the striatal dopaminergic system. Footshocks split the METH rats into two phenotypes: (i) shock-sensitive that decreased their METH-intake and (ii) shock-resistant that continued their METH intake. SCH23390 caused substantial dose-dependent reduction of METH taking in both groups. Stopping SCH23390 caused re-emergence of compulsive METH taking in shock-resistant rats. Compulsive METH takers also exhibited greater incubation of METH seeking than non-compulsive rats during withdrawal from METH SA. Analyses of DA metabolism revealed non-significant decreases (about 35%) in DA levels in resistant and sensitive rats. However, striatal contents of the deaminated metabolites, DOPAL and DOPAC, were significantly increased in sensitive rats. VMAT2 and DAT protein levels were decreased in both phenotypes. Moreover, protein expression levels of the D1-like DA receptor, D5R, and D2-like DA receptors, D3R and D4R, were significantly decreased in the compulsive METH takers. Our results parallel findings in post-mortem striatal tissues of human METH users who develop Parkinsonism after long-term METH intake and support the use of this model to investigate potential therapeutic interventions for METH use disorder.


Assuntos
Metanfetamina , Animais , Corpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Humanos , Ratos , Ratos Sprague-Dawley , Autoadministração
6.
Front Immunol ; 13: 952183, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059515

RESUMO

HIV-associated neurocognitive impairment (HIV-NCI) persists in 15-40% of people with HIV (PWH) despite effective antiretroviral therapy. HIV-NCI significantly impacts quality of life, and there is currently no effective treatment for it. The development of HIV-NCI is complex and is mediated, in part, by the entry of HIV-infected mature monocytes into the central nervous system (CNS). Once in the CNS, these cells release inflammatory mediators that lead to neuroinflammation, and subsequent neuronal damage. Infected monocytes may infect other CNS cells as well as differentiate into macrophages, thus contributing to viral reservoirs and chronic neuroinflammation. Substance use disorders in PWH, including the use of methamphetamine (meth), can exacerbate HIV neuropathogenesis. We characterized the effects of meth on the transcriptional profile of HIV-infected mature monocytes using RNA-sequencing. We found that meth mediated an upregulation of gene transcripts related to viral infection, cell adhesion, cytoskeletal arrangement, and extracellular matrix remodeling. We also identified downregulation of several gene transcripts involved in pathogen recognition, antigen presentation, and oxidative phosphorylation pathways. These transcriptomic changes suggest that meth increases the infiltration of mature monocytes that have a migratory phenotype into the CNS, contributing to dysregulated inflammatory responses and viral reservoir establishment and persistence, both of which contribute to neuronal damage. Overall, our results highlight potential molecules that may be targeted for therapy to limit the effects of meth on HIV neuropathogenesis.


Assuntos
Infecções por HIV , Metanfetamina , Humanos , Macrófagos/metabolismo , Metanfetamina/farmacologia , Monócitos , Qualidade de Vida
7.
eNeuro ; 9(5)2022.
Artigo em Inglês | MEDLINE | ID: mdl-35995558

RESUMO

Accumulating evidence indicates significant consequences for astrocytes associated with drug abuse. For example, reductions in structural features and synaptic colocalization of male rat nucleus accumbens (NAc) astrocytes are observed following short-access (ShA; 2 h/d) self-administration and extinction from cocaine, methamphetamine, and heroin. However, it is unknown whether these observations extend to other rodent models of drug abuse, how enduring these effects may be, and whether similar effects are observed in female rats. Here, we assess the effects of long-access (LgA; 6 h/d) cocaine self-administration and abstinence on NAc astrocytes separately in male and female rats, employing a commonly used behavioral approach to investigate the incubation of cocaine craving. NAc astrocytes from male rats exhibit extensive (∼40%) reductions in surface area, volume, and postsynaptic colocalization 45 d but not 24 h after the last self-administration session. In contrast, no effect of self-administration and abstinence was observed in astrocytes from female rats. Moreover, no effect of LgA self-administration and abstinence was observed on NAc GLT-1 expression in female rats, an effect that has been well described in males. These results indicate striking and sexually dimorphic effects of abstinence subsequent to LgA self-administration on astrocytes. Taken together, these results indicate a pivotal role of prolonged abstinence in the effects of cocaine self-administration on NAc astrocytes, and extend a growing body of evidence regarding sex differences in the cellular consequences of drug self-administration in the brain.


Assuntos
Cocaína , Metanfetamina , Animais , Astrócitos , Cocaína/farmacologia , Feminino , Heroína/farmacologia , Masculino , Metanfetamina/farmacologia , Núcleo Accumbens/metabolismo , Ratos , Autoadministração
8.
J Am Heart Assoc ; 11(16): e023663, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35912709

RESUMO

Background Methamphetamine misuse affects 27 million people worldwide and is associated with cardiovascular disease (CVD); however, risk factors for CVD among users have not been well studied. Methods and Results We studied hospitalized patients in California, captured by the Healthcare Cost and Utilization Project database, between 2005 and 2011. We studied the association between methamphetamine use and CVD (pulmonary hypertension, heart failure, stroke, and myocardial infarction). Among 20 249 026 persons in the Healthcare Cost and Utilization Project, 66 199 used methamphetamines (median follow-up 4.58 years). Those who used were more likely younger (33 years versus 45 years), male (63.3% versus 44.4%), smoked, misused alcohol, and had depression and anxiety compared with nonusers. Methamphetamine use was associated with the development of heart failure (hazard ratio [HR], 1.53 [95% CI, 1.45-1.62]) and pulmonary hypertension (HR, 1.42 [95% CI, 1.26-1.60]). Among users, male sex (HR, 1.73 [95% CI, 1.37-2.18]) was associated with myocardial infarction. Chronic kidney disease (HR, 2.38 [95% CI, 1.74-3.25]) and hypertension (HR, 2.26 [95% CI, 2.03-2.51]) were strong risk factors for CVD among users. When compared with nonuse, methamphetamine use was associated with a 32% significant increase in CVD, alcohol abuse with a 28% increase, and cocaine use with a 47% increase in CVD. Conclusions Methamphetamine use has a similar magnitude of risk of CVD compared with alcohol and cocaine. Prevention and treatment could be focused on those with chronic kidney disease, hypertension, and mental health disorders.


Assuntos
Doenças Cardiovasculares , Cocaína , Insuficiência Cardíaca , Hipertensão Pulmonar , Hipertensão , Metanfetamina , Infarto do Miocárdio , Insuficiência Renal Crônica , Doenças Cardiovasculares/etiologia , Insuficiência Cardíaca/complicações , Humanos , Hipertensão/complicações , Hipertensão Pulmonar/complicações , Masculino , Metanfetamina/efeitos adversos , Infarto do Miocárdio/complicações , Insuficiência Renal Crônica/complicações , Fatores de Risco
9.
Ann Behav Med ; 56(9): 900-908, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36039526

RESUMO

BACKGROUND: Social genomics has demonstrated altered inflammatory and type I interferon (IFN) gene expression among people experiencing chronic social adversity. Adverse social experiences such as discrimination and violence are linked to stimulant misuse and HIV, conditions that dysregulate inflammatory and innate antiviral responses, leading to increased HIV viral replication and risk of chronic diseases. PURPOSE: We aimed to determine whether methamphetamine (MA) use, unsuppressed HIV viral load (VL) (≥200 c/mL), and experienced intimate partner violence (IPV) (past 12 months) predicted inflammatory and type I IFN gene expression in HIV-positive Black and Latinx men who have sex with men (MSM). METHODS: Participants were 147 HIV-positive Black and Latinx MSM recruited from the mSTUDY, a cohort of 561 MSM aged 18-45 in Los Angeles, CA, of whom half are HIV-positive and substance-using. Transcriptomic measures of inflammatory and type I IFN activity were derived from RNA sequencing of peripheral blood mononuclear cells and matched to urine drug tests, VL, and survey data across two time points 12 months apart. Analysis used linear random intercept modeling of MA use, unsuppressed VL, and experienced IPV on inflammatory and type I IFN expression. RESULTS: In adjusted models, MA use predicted 27% upregulated inflammatory and 31% upregulated type I IFN expression; unsuppressed VL predicted 84% upregulated type I IFN but not inflammatory expression; and experienced IPV predicted 31% upregulated inflammatory and 26% upregulated type I IFN expression. CONCLUSIONS: In Black and Latinx MSM with HIV, MA use, unsuppressed VL, and experienced IPV predicted upregulated social genomic markers of immune functioning.


Assuntos
Infecções por HIV , Metanfetamina , Minorias Sexuais e de Gênero , Genômica , Homossexualidade Masculina , Humanos , Leucócitos Mononucleares , Masculino , Metanfetamina/efeitos adversos , Carga Viral
10.
Psychiatry Res ; 316: 114790, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35987070

RESUMO

The adenosine A2A receptor (ADORA2A) is highly expressed in the central nervous system and plays vital roles in drug addiction. In this study, we aimed to explore the susceptibility of ADORA2A to methamphetamine use disorder (MUD) and the craving degree based on a two-stage association analysis. A total of 3,542 (1,216 patients with MUD and 2,326 controls) and 1,740 participants (580 patients with MUD and 1,160 controls) were recruited in discovery and replication stage, respectively. Significant SNPs identified in the discovery stage were genotyped in the replication samples. Serum levels of ADORA2A were measured using enzyme-linked immunosorbent assay kits. The genetic association signal of each SNP was examined using Plink. A linear model was fitted to investigate the relationship between craving scores and genotypes of significant SNPs. SNP rs5751876 was significantly associated with MUD in the discovery samples and this association signal was then further replicated in the replication samples. Significant associations were also identified between serum levels of ADORA2A and the genotypes of rs5751876 (P = 0.0002). The craving scores in patients with MUD were strongly correlated with rs5751876 genotypes. Our results suggest that polymorphisms of the ADORA2A gene could affect the susceptibility to MUD and its craving degree.


Assuntos
Metanfetamina , Receptor A2A de Adenosina , Fissura , Humanos , Metanfetamina/efeitos adversos , Polimorfismo de Nucleotídeo Único/genética , Receptor A2A de Adenosina/genética , Fatores de Risco
11.
Int J Mol Sci ; 23(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35955676

RESUMO

The trace amine-associated receptor 1 (TAAR1) is a Gs protein-coupled, intracellularly located metabotropic receptor. Trace and classic amines, amphetamines, act as agonists on TAAR1; they activate downstream signal transduction influencing neurotransmitter release via intracellular phosphorylation. Our aim was to check the effect of the catecholaminergic activity enhancer compound ((-)BPAP, (R)-(-)-1-(benzofuran-2-yl)-2-propylaminopentane) on neurotransmitter release via the TAAR1 signaling. Rat striatal slices were prepared and the resting and electrical stimulation-evoked [3H]dopamine release was measured. The releaser (±)methamphetamine evoked non-vesicular [3H]dopamine release in a TAAR1-dependent manner, whereas (-)BPAP potentiated [3H]dopamine release with vesicular origin via TAAR1 mediation. (-)BPAP did not induce non-vesicular [3H]dopamine release. N-Ethylmaleimide, which inhibits SNARE core complex disassembly, potentiated the stimulatory effect of (-)BPAP on vesicular [3H]dopamine release. Subsequent analyses indicated that the dopamine-release stimulatory effect of (-)BPAP was due to an increase in PKC-mediated phosphorylation. We have hypothesized that there are two binding sites present on TAAR1, one for the releaser and one for the enhancer compounds, and they activate different PKC-mediated phosphorylation leading to the evoking of non-vesicular and vesicular dopamine release. (-)BPAP also increased VMAT2 operation enforcing vesicular [3H]dopamine accumulation and release. Vesicular dopamine release promoted by TAAR1 evokes activation of D2 dopamine autoreceptor-mediated presynaptic feedback inhibition. In conclusion, TAAR1 possesses a triggering role in both non-vesicular and vesicular dopamine release, and the mechanism of action of (-)BPAP is linked to the activation of TAAR1 and the signal transduction attached.


Assuntos
Dopamina , Metanfetamina , Animais , Corpo Estriado/metabolismo , Dopamina/metabolismo , Dopaminérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Metanfetamina/farmacologia , Ratos , Receptores Acoplados a Proteínas G/metabolismo
12.
Addict Biol ; 27(5): e13204, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001418

RESUMO

Individuals with methamphetamine use disorder (MUD) commonly exhibit socially problematic behaviours. Investigating the prosocial decision-making of individuals with MUD could enable a better understanding of their impaired social functioning and help improve their social relationships. We conducted two studies to examine the performance of individuals with MUD and healthy controls on a modified dictator game. In Study 1, 55 male individuals with MUD and 34 healthy male participants made a series of choices between two pairs of monetary prizes for themselves and for others. In Study 2, 62 male individuals with MUD and 31 healthy male participants made the same choices as in Study 1 after a brief exposure to methamphetamine-related pictures. In both studies, we consistently found a context dependency of decreased prosociality in individuals with MUD. That is, individuals with MUD made fewer prosocial choices than healthy individuals in disadvantageous contexts (but not advantageous contexts). The results of the computational model suggested that the lower prosociality of individuals with MUD in disadvantageous contexts could be attributed to the lower weight placed on others' benefits. Moreover, when exposed to methamphetamine-related pictures, individuals with MUD showed less caution and slower encoding/motor speed than healthy individuals, and individuals with MUD with a longer history of methamphetamine use tended to respond less cautiously. Our findings provide evidence that in disadvantageous contexts, individuals with MUD show reduced prosociality and less consideration of others' benefits. Identifying the origin of the alterations in prosocial decision-making has implications for diagnosis and treatment.


Assuntos
Metanfetamina , Humanos , Relações Interpessoais , Masculino
13.
Addict Biol ; 27(5): e13212, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36001437

RESUMO

The high-drinking-in-the-dark (HDID) lines of mice were selectively bred for achieving high blood alcohol levels in the drinking-in-the-dark (DID) task and have served as a unique genetic risk model for binge-like alcohol intake. However, little is known about their willingness to consume other addictive drugs. Here, we examined (a) whether the HDID-1 and HDID-2 lines of mice would voluntarily consume midazolam, methamphetamine, morphine and nicotine in a DID test and (b) whether the HDID lines differ from their founders, heterogeneous stock/Northport (HS/NPT), in consumption levels of these drugs at the concentrations tested. Separate groups of HDID-1, HDID-2 and HS/NPT mice were given 4 days of access to each drug, using the single-bottle, limited-access DID paradigm. Male and female mice of both HDID lines consumed all four offered drugs. We observed no genotype differences in 40 µg/ml methamphetamine intake, but significant differences in nicotine, midazolam and morphine intake. Both HDID lines drank significantly more (150 µg/ml) midazolam than their founders, providing strong support for a shared genetic contribution to binge ethanol and midazolam intake. HDID-2 mice, but not HDID-1 mice, consumed more morphine (700 µg/ml) and more nicotine across a range of concentrations than HS/NPT mice. These results demonstrate that the HDID mice can be utilized for tests of voluntary drug consumption other than ethanol and highlight potentially important differences between HDID lines in risk for elevated drug intake.


Assuntos
Metanfetamina , Nicotina , Consumo de Bebidas Alcoólicas/genética , Animais , Etanol , Feminino , Masculino , Metanfetamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Midazolam/farmacologia , Morfina/farmacologia , Nicotina/farmacologia
14.
Psychopharmacology (Berl) ; 239(9): 2903-2919, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35920922

RESUMO

INTRODUCTION: Methamphetamine (METH, "ice") is a potent and addictive psychostimulant. Abuse of METH perturbs neurotransmitter systems and induces neurotoxicity; however, the neurobiological mechanisms which underlie addiction to METH are not fully understood, limiting the efficacy of available treatments. Here we investigate METH-induced changes to neuronal nitric oxide synthase (nNOS), parvalbumin and calretinin-expressing GABAergic interneuron populations within the nucleus accumbens (NAc), prefrontal cortex (PFC) and orbitofrontal cortex (OFC). We hypothesise that dysfunction or loss of these GABAergic interneuron populations may disrupt the excitatory/inhibitory balance within the brain. METHODS: Male Long Evans rats (N = 32) were trained to lever press for intravenous METH or received yoked saline infusions. Following 14 days of behavioural extinction, animals were given a non-contingent injection of saline or METH (1 mg/kg, IP) to examine drug-primed reinstatement to METH-seeking behaviours. Ninety minutes post-IP injection, animals were culled and brain sections were analysed for Fos, nNOS, parvalbumin and calretinin immunoreactivity in eight distinct subregions of the NAc, PFC and OFC. RESULTS: METH exposure differentially affected GABAergic populations, with METH self-administration increasing nNOS immunoreactivity at distinct locations in the prelimbic cortex and decreasing parvalbumin immunoreactivity in the NAc. METH self-administration triggered reduced calretinin immunoreactivity, whilst acute METH administration produced a significant increase in calretinin immunoreactivity. As expected, non-contingent METH-priming treatment increased Fos immunoreactivity in subregions of the NAc and PFC. CONCLUSION: Here we report that METH exposure in this model may alter the function of GABAergic interneurons in more subtle ways, such as alterations in neuronal firing or synaptic connectivity.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Ácido gama-Aminobutírico/metabolismo , Animais , Calbindina 2 , Estimulantes do Sistema Nervoso Central/farmacologia , Interneurônios , Masculino , Metanfetamina/farmacologia , Núcleo Accumbens , Parvalbuminas , Córtex Pré-Frontal , Ratos , Ratos Long-Evans , Autoadministração
15.
Hum Exp Toxicol ; 41: 9603271221124092, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36036424

RESUMO

This study examined the association between clock gene expression and the effect of methamphetamine (MA) on drug-metabolizing enzymes from the perspective of drug metabolism. The relationship between expression of the clock genes BMAL1 and PER2 and the drug-metabolizing enzymes CYP3A4 and CYP2D6 was investigated using livers from autopsy cases of MA-intoxication deaths. Additionally, the effect of MA exposure on various genes was examined in HepG2 human hepatocellular carcinoma cells. Comparisons of the expression of various genes in MA users according to blood MA concentration revealed that CYP3A4 expression was similar to that of PER2, and CYP2D6 expression was similar to that of BMAL1. In cultured cell experiments, BMAL1 and CYP2D6 expression decreased depending on the time elapsed after MA addition, and PER2 and CYP3A4 expression increased slightly in a concentration-dependent manner. These results were consistent with the findings of autopsy examinations. Expression of CYP3A4 and CYP2D6 under BMAL1 and PER2 suppression, but not CYP2D6 under PER2 suppression alone, was upregulated in response to MA. These results suggest that CYPs are regulated via the clock genes BMAL1 and PER2 during MA metabolism.


Assuntos
Fatores de Transcrição ARNTL , Metanfetamina , Citocromo P-450 CYP3A , Humanos
16.
JAMA Netw Open ; 5(8): e2225593, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35939303

RESUMO

Importance: Overdose is one of the leading causes of death in the US; however, surveillance data lag considerably from medical examiner determination of the death to reporting in national surveillance reports. Objective: To automate the classification of deaths related to substances in medical examiner data using natural language processing (NLP) and machine learning (ML). Design, Setting, and Participants: Diagnostic study comparing different natural language processing and machine learning algorithms to identify substances related to overdose in 10 health jurisdictions in the US from January 1, 2020, to December 31, 2020. Unstructured text from 35 433 medical examiner and coroners' death records was examined. Exposures: Text from each case was manually classified to a substance that was related to the death. Three feature representation methods were used and compared: text frequency-inverse document frequency (TF-IDF), global vectors for word representations (GloVe), and concept unique identifier (CUI) embeddings. Several ML algorithms were trained and best models were selected based on F-scores. The best models were tested on a hold-out test set and results were reported with 95% CIs. Main Outcomes and Measures: Text data from death certificates were classified as any opioid, fentanyl, alcohol, cocaine, methamphetamine, heroin, prescription opioid, and an aggregate of other substances. Diagnostic metrics and 95% CIs were calculated for each combination of feature extraction method and machine learning classifier. Results: Of 35 433 death records analyzed (decedent median age, 58 years [IQR, 41-72 years]; 24 449 [69%] were male), the most common substances related to deaths included any opioid (5739 [16%]), fentanyl (4758 [13%]), alcohol (2866 [8%]), cocaine (2247 [6%]), methamphetamine (1876 [5%]), heroin (1613 [5%]), prescription opioids (1197 [3%]), and any benzodiazepine (1076 [3%]). The CUI embeddings had similar or better diagnostic metrics compared with word embeddings and TF-IDF for all substances except alcohol. ML classifiers had perfect or near perfect performance in classifying deaths related to any opioids, heroin, fentanyl, prescription opioids, methamphetamine, cocaine, and alcohol. Classification of benzodiazepines was suboptimal using all 3 feature extraction methods. Conclusions and Relevance: In this diagnostic study, NLP/ML algorithms demonstrated excellent diagnostic performance at classifying substances related to overdoses. These algorithms should be integrated into workflows to decrease the lag time in reporting overdose surveillance data.


Assuntos
Cocaína , Overdose de Drogas , Metanfetamina , Analgésicos Opioides , Benzodiazepinas , Overdose de Drogas/epidemiologia , Feminino , Fentanila , Heroína , Humanos , Masculino , Pessoa de Meia-Idade , Processamento de Linguagem Natural
17.
JAMA Netw Open ; 5(8): e2226544, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35969400

RESUMO

Importance: Overdoses continue to increase in the US, but the contribution of methamphetamine use is understudied in rural communities. Objective: To estimate the prevalence of methamphetamine use and its correlates among people who use drugs (PWUD) in rural US communities and to determine whether methamphetamine use is associated with increased nonfatal overdoses. Design, Setting, and Participants: From January 2018 through March 2020, the National Rural Opioid Initiative conducted cross-sectional surveys of PWUD in rural communities in 10 states (Illinois, Kentucky, New Hampshire, Massachusetts, North Carolina, Ohio, Oregon, Vermont, West Virginia, and Wisconsin). Participants included rural PWUD who reported any past-30-day injection drug use or noninjection opioid use to get high. A modified chain-referral sampling strategy identified seeds who referred others using drugs. Data analysis was performed from May 2021 to January 2022. Exposures: Use of methamphetamine alone, opioids alone, or both. Main Outcomes and Measures: Unweighted and weighted prevalence of methamphetamine use, any past-180-day nonfatal overdose, and number of lifetime nonfatal overdoses. Results: Among the 3048 participants, 1737 (57%) were male, 2576 (85%) were White, and 225 (7.4%) were American Indian; the mean (SD) age was 36 (10) years. Most participants (1878 of 2970 participants with any opioid or methamphetamine use [63%]) reported co-use of methamphetamine and opioids, followed by opioids alone (702 participants [24%]), and methamphetamine alone (390 participants [13%]). The estimated unweighted prevalence of methamphetamine use was 80% (95% CI, 64%-90%), and the estimated weighted prevalence was 79% (95% CI, 57%-91%). Nonfatal overdose was greatest in people using both methamphetamine and opioids (395 of 2854 participants with nonmissing overdose data [22%]) vs opioids alone (99 participants [14%]) or methamphetamine alone (23 participants [6%]). Co-use of methamphetamine and opioids was associated with greater nonfatal overdose compared with opioid use alone (adjusted odds ratio, 1.45; 95% CI, 1.08-1.94; P = .01) and methamphetamine use alone (adjusted odds ratio, 3.26; 95% CI, 2.06-5.14; P < .001). Those with co-use had a mean (SD) of 2.4 (4.2) (median [IQR], 1 [0-3]) lifetime overdoses compared with 1.7 (3.5) (median [IQR], 0 [0-2]) among those using opioids alone (adjusted rate ratio, 1.20; 95% CI, 1.01-1.43; P = .04), and 1.1 (2.9) (median [IQR], 0 [0-1]) among those using methamphetamine alone (adjusted rate ratio, 1.81; 95% CI, 1.45-2.27; P < .001). Participants with co-use most often reported having tried and failed to access substance use treatment: 827 participants (44%) for both, 117 participants (30%) for methamphetamine alone, and 252 participants (36%) for opioids alone (χ22 = 33.8; P < .001). Only 66 participants (17%) using methamphetamine alone had naloxone. Conclusions and Relevance: These findings suggest that harm reduction and substance use disorder treatment interventions must address both methamphetamine and opioids to decrease overdose in rural communities.


Assuntos
Overdose de Drogas , Metanfetamina , Transtornos Relacionados ao Uso de Opioides , Adulto , Analgésicos Opioides/uso terapêutico , Estudos Transversais , Overdose de Drogas/epidemiologia , Feminino , Humanos , Masculino , Transtornos Relacionados ao Uso de Opioides/epidemiologia , População Rural
18.
Biomed Pharmacother ; 154: 113591, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36007276

RESUMO

Methamphetamine (MA) is a extremely addictive psychostimulant drug with a significant abuse potential. Long-term MA exposure can induce neurotoxic effects through oxidative stress, mitochondrial functional impairment, endoplasmic reticulum stress, the activation of astrocytes and microglial cells, axonal transport barriers, autophagy, and apoptosis. However, the molecular and cellular mechanisms underlying MA-induced neurotoxicity remain unclear. MA abuse increases the chances of developing neurotoxic conditions such as Parkinson's disease (PD), Alzheimer's disease (AD) and other neurotoxic diseases. MA increases the risk of PD by increasing the expression of alpha-synuclein (ASYN). Furthermore, MA abuse is linked to high chances of developing AD and subsequent neurodegeneration due to biological variations in the brain region or genetic and epigenetic variations. To date, there is no Food and Drug Administration (FDA)-approved therapy for MA-induced neurotoxicity, although many studies are being conducted to develop effective therapeutic strategies. Most current studies are now focused on developing therapies to diminish the neurotoxic effects of MA, based on the underlying mechanism of neurotoxicity. This review article highlights current research on several therapeutic techniques targeting multiple pathways to reduce the neurotoxic effects of MA in the brain, as well as the putative mechanism of MA-induced neurotoxicity.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Estimulantes do Sistema Nervoso Central , Metanfetamina , Síndromes Neurotóxicas , Doença de Parkinson , Transtornos Relacionados ao Uso de Anfetaminas/complicações , Transtornos Relacionados ao Uso de Anfetaminas/terapia , Astrócitos , Estimulantes do Sistema Nervoso Central/toxicidade , Humanos , Metanfetamina/toxicidade , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/terapia
19.
Vaccine ; 40(41): 5882-5891, 2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36041942

RESUMO

BACKGROUND: Methamphetamine (METH) addiction is a major public health concern globally with limited management options. The development of a METH vaccine through hapten design has received significant attention as a promising platform for the potential treatment of METH addiction and overdose, however there is yet to be a successful candidate in human trials. RESEARCH DESIGN AND METHODS: In this study, we developed a novel conjugated METH vaccine using oxidized mannan (a polymannose) as an immunogenic carrier. A METH hapten was synthesized by using amphetamine and conjugated to mannan with a (Lysine-Glycine-Lysine-Glycine-lysine-Glycine-Lysine-Glycine-Lysine-Glycine) (KG)5 peptide linker. RESULTS: The reaction between amphetamine and (KG)5, oxidation of mannan, and conjugation of amphetamine-(KG)5 with oxidized mannan were confirmed by color tests, Fourier-transform infrared spectroscopy, gas and liquid chromatography mass spectrometry, thin-layer chromatography, and ultraviolet spectrophotometer. Additionally, the ability of the vaccine to generate antibodies was confirmed in C57BL/6 mice. CONCLUSIONS: The successful development and characterization of the METH-mannan conjugate vaccine, provides a potential therapeutic intervention to curb METH substance use disorders. Each step of vaccine development was characterized to aid in future research on these vaccines, and the immunogenicity shown in the animal models supports future evaluation of the approach. Future studies of the conjugated METH vaccine should evaluate the efficacy in animal models of acute and chronic METH to pave the way for human studies.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Metanfetamina , Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Transtornos Relacionados ao Uso de Anfetaminas/prevenção & controle , Animais , Glicina/uso terapêutico , Haptenos , Humanos , Lisina/uso terapêutico , Mananas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Vacinas Conjugadas
20.
Behav Brain Res ; 435: 114064, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-35987306

RESUMO

Repeated methamphetamine exposure impairs reversal learning in laboratory animals and downregulates dopamine D2 receptor expression. In the present study, we tested the possibility that repeated exposure to the dopamine D2 antagonist, eticlopride, would increase D2 receptor expression, improve behavioral flexibility and restore behavioral flexibility that was disrupted by exposure to methamphetamine in rats. Male Sprague-Dawley rats received repeated daily pretreatment with the dopamine D2 antagonist, eticlopride (0.0 or 0.3 mg/kg/day, 14 days). Three days after the last treatment, whole brain (minus olfactory bulbs and cerebellum) dopamine D2 receptor expression was measured using flow cytometry in one group and reversal learning performance was measured in another group. Reversal learning was also measured in other groups prior to and after methamphetamine exposure (0.0 or 2.0 mg/kg, 4 injections, 2 h apart, 1 day) followed by repeated eticlopride (0.0 or 0.3 mg/kg, 14 days) treatment. Eticlopride treatment increased D2 receptor expression and improved reversal learning performance. Methamphetamine impaired reversal learning performance and eticlopride treatment reversed the deficit. These results suggest that repeated administration of eticlopride can restore behavioral flexibility and that upregulation of D2 receptors might be an effective adjunct to treatment of methamphetamine misuse.


Assuntos
Metanfetamina , Animais , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Metanfetamina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Salicilamidas/farmacologia
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