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1.
Adv Pharmacol ; 99: 169-216, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467481

RESUMO

Parental exposure to drugs of abuse induces changes in the germline that can be transmitted across subsequent generations, resulting in enduring effects on gene expression and behavior. This transgenerational inheritance involves a dynamic interplay of environmental, genetic, and epigenetic factors that impact an individual's vulnerability to neuropsychiatric disorders. This chapter aims to summarize recent research into the mechanisms underlying the inheritance of gene expression and phenotypic patterns associated with exposure to drugs of abuse, with an emphasis on cocaine. We will first define the epigenetic modifications such as DNA methylation, histone post-translational modifications, and expression of non-coding RNAs that are impacted by parental cocaine use. We will then explore how parental cocaine use induces heritable epigenetic changes that are linked to alterations in neural circuitry and synaptic plasticity within reward-related circuits, ultimately giving rise to potential behavioral vulnerabilities. This discussion will consider phenotypic differences associated with gestational as well as both maternal and paternal preconception drug exposure and will emphasize differences based on offspring sex. In this context, we explore the complex interactions between genetics, epigenetics, environment, and biological sex. Overall, this chapter consolidates the latest developments in the multigenerational effects and long-term consequences of parental substance abuse.


Assuntos
Cocaína , Humanos , Cocaína/efeitos adversos , Epigênese Genética/genética , Metilação de DNA/genética , Fenótipo
2.
Adv Pharmacol ; 99: 35-59, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467486

RESUMO

The dopamine transporter (DAT) is a key site of action for cocaine and amphetamines. Dysfunctional DAT is associated with aberrant synaptic dopamine transmission and enhanced drug-seeking and taking behavior. Studies in cultured cells and ex vivo suggest that DAT function is sensitive to membrane cholesterol content. Although it is largely unknown whether psychostimulants alter cholesterol metabolism in the brain, emerging evidence indicates that peripheral cholesterol metabolism is altered in patients with psychostimulant use disorder and circulating cholesterol levels are associated with vulnerability to relapse. Cholesterol interacts with sphingolipids forming lipid raft microdomains on the membrane. These cholesterol-rich lipid raft microdomains serve to recruit and assemble other lipids and proteins to initiate signal transduction. There are two spatially and functionally distinct populations of the DAT segregated by cholesterol-rich lipid raft microdomains and cholesterol-scarce non-raft microdomains on the plasma membrane. These two DAT populations are differentially regulated by DAT blockers (e.g. cocaine), substrates (e.g. amphetamine), and protein kinase C providing distinct cholesterol-dependent modulation of dopamine uptake and efflux. In this chapter, we summarize the impact of depletion and addition of membrane cholesterol on DAT conformational changes between the outward-facing and the inward-facing states, lipid raft-associated DAT localization, basal and induced DAT internalization, and DAT function. In particular, we focus on how the interactions of the DAT with cocaine and amphetamine are influenced by membrane cholesterol. Lastly, we discuss the therapeutic potential of cholesterol-modifying drugs as a new avenue to normalize DAT function and dopamine transmission in patients with psychostimulant use disorder.


Assuntos
Cocaína , Proteínas da Membrana Plasmática de Transporte de Dopamina , Humanos , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Dopamina/metabolismo , Anfetamina/farmacologia , Cocaína/farmacologia , Colesterol/química , Colesterol/metabolismo
4.
Health Promot Chronic Dis Prev Can ; 44(3): 77-88, 2024 Mar.
Artigo em Inglês, Francês | MEDLINE | ID: mdl-38501679

RESUMO

INTRODUCTION: Substance-related acute toxicity deaths (ATDs) are a public health crisis in Canada. Youth are often at higher risk for substance use due to social, environmental and structural factors. The objectives of this study were to understand the characteristics of youth (aged 12-24 years) dying of accidental acute toxicity in Canada and examine the substances contributing to and circumstances surrounding youth ATDs. METHODS: Data from a national chart review study of coroner and medical examiner data on ATDs that occurred in Canada between 2016 and 2017 were used to conduct descriptive analyses with proportions, mortality rates and proportionate mortality rates. Where possible, youth in the chart review study were compared with youth in the general population and youth who died of all causes, using census data. RESULTS: Of the 732 youth who died of accidental acute toxicity in 2016-2017, most (94%) were aged 18 to 24 years. Youth aged 20 to 24 who were unemployed, unhoused or living in collective housing were overrepresented among accidental ATDs. Many of the youth aged 12 to 24 who died of accidental acute toxicity had a documented history of substance use. Fentanyl, cocaine and methamphetamine were the most common substances contributing to death, and 38% of the deaths were witnessed or potentially witnessed. CONCLUSION: The findings of this study point to the need for early prevention and harm reduction strategies and programs that address mental health, exposure to trauma, unemployment and housing instability to reduce the harms of substance use on Canadian youth.


Assuntos
Cocaína , Transtornos Relacionados ao Uso de Substâncias , Humanos , Adolescente , Médicos Legistas , Canadá/epidemiologia , Fentanila
5.
Health Promot Chronic Dis Prev Can ; 44(3): 89-100, 2024 Mar.
Artigo em Inglês, Francês | MEDLINE | ID: mdl-38501680

RESUMO

INTRODUCTION: Limited research exists on substance-related acute toxicity deaths (ATDs) in older adults (≥60 years) in Canada. This study aims to examine and describe the sociodemographic characteristics, health histories and circumstances of death for accidental ATDs among older adults. METHODS: Following a retrospective descriptive analysis of all coroner and medical examiner files on accidental substance-related ATDs in older adults in Canada from 2016 to 2017, proportions and mortality rates for coroner and medical examiner data were compared with general population data on older adults from the 2016 Census. Chisquare tests were conducted for categorical variables where possible. RESULTS: From 2016 to 2017, there were 705 documented accidental ATDs in older adults. Multiple substances contributed to 61% of these deaths. Fentanyl, cocaine and ethanol (alcohol) were the most common substances contributing to death. Heart disease (33%), chronic pain (27%) and depression (26%) were commonly documented. Approximately 84% of older adults had contact with health care services in the year preceding their death. Only 14% were confirmed as having their deaths witnessed. CONCLUSIONS: Findings provide insight into the demographic, contextual and medical history factors that may influence substance-related ATDs in older adults and suggest key areas for prevention.


Assuntos
Dor Crônica , Cocaína , Overdose de Drogas , Humanos , Idoso , Estudos Retrospectivos , Fentanila , Etanol
6.
Sci Rep ; 14(1): 6509, 2024 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-38499566

RESUMO

Cocaine disrupts dopamine (DA) and kappa opioid receptor (KOR) system activity, with long-term exposure reducing inhibiton of DA uptake by cocaine and increasing KOR system function. Single treatment therapies have not been successful for cocaine use disorder; therefore, this study focuses on a combination therapy targeting the dopamine transporter (DAT) and KOR. Sprague Dawley rats self-administered 5 days of cocaine (1.5 mg/kg/inf, max 40 inf/day, FR1), followed by 14 days on a progressive ratio (PR) schedule (0.19 mg/kg/infusion). Behavioral effects of individual and combined administration of phenmetrazine and nBNI were then examined using PR. Additionally, ex vivo fast scan cyclic voltammetry was then used to assess alterations in DA and KOR system activity in the nucleus accumbens before and after treatments. Chronic administration of phenmetrazine as well as the combination of phenmetrazine and nBNI-but not nBNI alone-significantly reduced PR breakpoints. In addition, the combination of phenmetrazine and nBNI partially reversed cocaine-induced neurodysregulations of the KOR and DA systems, indicating therapeutic benefits of targeting the DA and KOR systems in tandem. These data highlight the potential benefits of the DAT and KOR as dual-cellular targets to reduce motivation to administer cocaine and reverse cocaine-induced alterations of the DA system.


Assuntos
Cocaína , Receptores Opioides kappa , Ratos , Animais , Receptores Opioides kappa/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Motivação , Dopamina/farmacologia , Ratos Sprague-Dawley , Fenmetrazina/farmacologia , Cocaína/farmacologia , Núcleo Accumbens/metabolismo , Autoadministração
7.
Psychiatry Res ; 334: 115821, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38432116

RESUMO

Substance addiction (SA) is a risk factor of suicidal thoughts and behaviors (STB), although it is still unclear which SAs are reliably associated with increased risk for suicidal ideation, planning, and attempt. The current study aimed to meet this goal using data from the National Survey on Drug Use and Health (NSDUH) referring to years from 2008 to 2020. The information extracted included sociodemographic and contextual information, eleven SAs (e.g., nicotine, alcohol, marijuana, cocaine, pain relievers, heroin, inhalants, hallucinogens, sedatives, stimulants, and tranquillizers), and STB. The analysis revealed that SAs for alcohol, pain relievers, marijuana, and cocaine were stable and reliable predictors for STB (e.g., suicidal ideation, planning, and attempt), while cocaine was not a stable predictor for suicide attempt. The selected SAs model showed a greater predictive accuracy than only sociodemographic and contextual factors as well as not selected SAs. Moreover, selected SAs showed comparable predictive accuracy to the full model. Furthermore, SA to alcohol showed to be an extremely effective predictor of STB, having a comparable predictive accuracy to all the other ten SAs together. In conclusion, SAs to pain relievers, alcohol, marijuana, and cocaine can be considered as important risk factors for concurrent STB.


Assuntos
Cannabis , Cocaína , Alucinógenos , Transtornos Relacionados ao Uso de Substâncias , Humanos , Ideação Suicida , Etanol , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Acetaminofen , Agonistas de Receptores de Canabinoides , Estudos Epidemiológicos , Dor
8.
Eur J Pharmacol ; 969: 176466, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38431243

RESUMO

The chronic use of the novel synthetic cathinone mexedrone, like other psychoactive drugs, can be considered addictive, with a high potential for abuse and the ability to cause psychological dependence in certain users. However, little is known about the neurobehavioral effects of mexedrone in association with its potential for abuse. We investigated the abuse potential for mexedrone abuse through multiple behavioral tests. In addition, serotonin transporter (SERT) levels were measured in the synaptosome of the dorsal striatum, and serotonin (5-HT) levels were measured in the dorsal striatum of acute mexedreone (50 mg/kg)-treated mice. To clarify the neuropharmacological mechanisms underlying the locomotor response of mexedrone, the 5-HT2A receptor antagonist M100907 (0.5 or 1.0 mg/kg) was administered prior to the acute injection of mexedrone in the locomotor activity experiment in mice. Mexedrone (10-50 mg/kg) produced a significant place preference in mice and mexedrone (0.1-0.5 mg/kg/infusion) maintained self-administration behavior in rats in a dose-dependent manner. In the drug discrimination experiment, mexedrone (5.6-32 mg/kg) was fully substituted for the discriminative stimulus effects of cocaine in rats. Mexedrone increased locomotor activity, and these effects were reversed by pretreatment with M100907. Acute mexedrone significantly increased c-Fos expression in the dorsal striatum and decreased SERT levels in the synaptosome of the dorsal striatum of mice, resulting in an elevation of 5-HT levels. Taken together, our results provide the possibility that mexedrone has abuse potential, which might be mediated, at least in part, by the activation of the serotonergic system in the dorsal striatum.


Assuntos
Cocaína , Fluorbenzenos , Metanfetamina/análogos & derivados , Piperidinas , Catinona Sintética , Ratos , Camundongos , Masculino , Animais , Ratos Sprague-Dawley , Serotonina/metabolismo , Cocaína/farmacologia , Relação Dose-Resposta a Droga
9.
Brain Behav ; 14(3): e3457, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38450910

RESUMO

INTRODUCTION: Repeated exposure to cocaine induces microglial activation. Cocaine exposure also induces a release of high mobility group box-1 (HMGB1) from neurons into the extracellular space in the nucleus accumbens (NAc). HMGB1 is an important late inflammatory mediator of microglial activation. However, whether the secretion of HMGB1 acts on microglia or contributes to cocaine addiction is largely unknown. METHODS: Rats were trained by intraperitoneal cocaine administration and cocaine-induced conditioned place preference (CPP). Expression of HMGB1 was regulated by viral vectors. Activation of microglia was inhibited by minocycline. Interaction of HMGB1 and the receptor for advanced glycation end products (RAGE) was disrupted by peptide. RESULTS: Cocaine injection facilitated HMGB1 signaling, together with the delayed activation of microglia concurrently in the NAc. Furthermore, the inhibition of HMGB1 or microglia activation attenuated cocaine-induced CPP. Box A, a specific antagonist to interrupt the interaction of HMGB1 and RAGE, abolished the expression of cocaine reward memory. Meanwhile, the inhibition of HMGB1-RAGE interaction suppressed cocaine-induced microglial activation, as well as the consolidation of cocaine-induced memory. CONCLUSION: All above results suggest that the neural HMGB1 induces activation of microglia through RAGE, which contributes to the consolidation of cocaine reward memory. These findings offer HMGB1-RAGE axis as a new target for the treatment of drug addiction.


Assuntos
Cocaína , Proteína HMGB1 , Animais , Ratos , Núcleo Accumbens , Microglia , Receptor para Produtos Finais de Glicação Avançada , Cocaína/farmacologia
10.
BMC Oral Health ; 24(1): 185, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317147

RESUMO

BACKGROUND: The study aimed to investigate the association between maternal cocaine abuse during pregnancy and the prevalence of cleft lip/palate (CL/P) in offspring, synthesizing existing evidence through a systematic review and meta-analysis. CL/P is a congenital craniofacial anomaly with complex etiology, and prior research has suggested potential links between maternal cocaine use and CL/P. However, these associations remain inconclusive. METHODS: A comprehensive literature search was conducted to identify relevant studies published up to the study's cutoff date in September 2021. Several databases were systematically searched using predefined search terms. Inclusion criteria were set to encompass studies reporting on the prevalence of CL/P in infants born to mothers with a history of cocaine use during pregnancy, with a comparison group of non-cocaine-using mothers. Data were extracted, and a meta-analysis was performed using a random-effects model to calculate pooled odds ratios (OR) and relative risks (RR) with their respective 95% confidence intervals (CI). RESULTS: The review included data from 4 studies that met the inclusion criteria. The combined OR from two studies was 0.05 (95% CI: 0.00, 4.41), which does not suggest a statistically significant association between prenatal cocaine exposure and the incidence of CL/P due to the confidence interval crossing the null value. Additionally, the combined RR was 0.17 (95% CI: 0.04, 0.66), indicating a statistically significant decrease in the risk of CL/P associated with prenatal cocaine exposure. These results, with an OR that is not statistically significant and an RR suggesting decreased risk, should be interpreted with caution due to considerable heterogeneity and variability among the included studies' findings. Further research is needed to clarify these associations. CONCLUSION: The findings from this systematic review and meta-analysis suggest that maternal cocaine use during pregnancy is not a statistically significant independent risk factor for the development of CL/P in offspring. These results underscore the multifactorial nature of CL/P etiology and emphasize the importance of considering other genetic, environmental, and nutritional factors in understanding the condition's origins. While the study provides important insights, limitations such as data heterogeneity and potential confounders should be acknowledged. Future research should adopt rigorous study designs and explore a broader range of potential risk factors to comprehensively elucidate CL/P development.


Assuntos
Fenda Labial , Fissura Palatina , Transtornos Relacionados ao Uso de Cocaína , Cocaína , Lactente , Gravidez , Feminino , Humanos , Fenda Labial/etiologia , Fenda Labial/genética , Fissura Palatina/etiologia , Fissura Palatina/genética , Incidência , Transtornos Relacionados ao Uso de Cocaína/complicações , Transtornos Relacionados ao Uso de Cocaína/epidemiologia , Pais , Cocaína/efeitos adversos
11.
Transl Psychiatry ; 14(1): 101, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38374108

RESUMO

G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆9-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.


Assuntos
Canabidiol , Cocaína , Receptores de Canabinoides , Transtornos Relacionados ao Uso de Substâncias , Animais , Camundongos , Ratos , Canabidiol/análogos & derivados , Cocaína/farmacologia , Neurônios Dopaminérgicos/metabolismo , Ácido Glutâmico/metabolismo , Camundongos Knockout , Nicotina/farmacologia , Preparações Farmacêuticas/metabolismo , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas G/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo
12.
Drug Alcohol Depend ; 256: 111078, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38309089

RESUMO

BACKGROUND: This study tested an adaptive intervention for optimizing abstinence outcomes over phases of treatment for cocaine use disorder using a SMART design. Phase 1 assessed whether 4 weeks of contingency management (CM) improved response with the addition of Acceptance and Commitment Therapy (ACT). Phase 2 assessed pharmacological augmentation with modafinil (MOD) vs. placebo (PLA) for individuals not achieving abstinence during Phase 1. METHOD: For Phase 1 of treatment, participants (N=118) were randomly allocated to ACT+CM or Drug Counseling (DC+CM), the comparison condition. At week 4, treatment response was defined as the submission of six consecutive cocaine-negative urine drug screens (UDS). Phase 1 non-responders were re-randomized to MOD or PLA as adjunct to their initial treatment. Phase 1 responders continued receiving their initial treatment. Primary outcomes included response rate and proportion of cocaine-negative UDS for Phase 1 and 2. Analyses used Bayesian inference with 80% pre-specified as the posterior probability (PP) threshold constituting moderate evidence that an effect exists. RESULTS: Phase 1 response was higher in the ACT+CM group (24.5%) compared to the DC+CM group (17.5%; PP = 84.5%). In Phase 2, the proportion of cocaine-negative UDS among Phase 1 responders did not differ by initial treatment (PP = 61.8%) but remained higher overall compared to Phase 1 non-responders (PPs > 99%). No evidence of an effect favoring augmentation with MOD was observed. DISCUSSION: Adding ACT to CM increased abstinence initiation. Initial responders were more likely to remain abstinent compared to initial non-responders, for whom modafinil was not an effective pharmacotherapy augmentation strategy.


Assuntos
Terapia de Aceitação e Compromisso , Transtornos Relacionados ao Uso de Cocaína , Cocaína , Humanos , Teorema de Bayes , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/psicologia , Resultado do Tratamento , Cocaína/uso terapêutico , Modafinila/uso terapêutico , Poliésteres/uso terapêutico
13.
Acta Psychiatr Scand ; 149(4): 340-349, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38378931

RESUMO

BACKGROUND AND OBJECTIVES: Bipolar disorder is a chronic condition affecting millions of people worldwide. Currently, there is some evidence to suggest that cannabis use during adolescence may be an environmental risk factor for its onset, however inconsistencies have been observed across the literature. Considering this, we aimed to assess whether early lifetime cannabis is associated with subsequent bipolar disorder in young adults between 18 and 22 years of age. METHODS: Using data from the 1993 Pelotas (Brazil) birth cohort (n = 5249), cannabis exposure was examined at age 18 by self-report, and bipolar disorder diagnosis was measured at age 22 using the Mini International Neuropsychiatric Interview (MINI). In order to control the analysis, we considered socioeconomic status index, sex, skin color, physical abuse by parents and lifetime cocaine use. RESULTS: A total of 3781 individuals were evaluated in 2015 aged 22 years, of whom 87 were diagnosed with the bipolar disorder onset after the age of 18. Lifetime cannabis use predicted bipolar disorder onset at 22 years old (OR 1.82, 95% CI [1.10, 2.93]), and the effect remained after adjusting for socioeconomic status, sex, skin color, and physical abuse by parents (OR 2.00, 95% CI [1.20, 3.25]). However, this association was attenuated to statistically non-significant after further adjustment for all available covariates, including lifetime cocaine use (OR 1.79, 95% CI [0.95, 3.19]). We also found similar results for early cocaine use, where the association with bipolar disorder onset did not maintain significance in the multivariate model (OR 1.35, 95% CI [0.62, 2.86]). Otherwise, when we considered cannabis or cocaine lifetime use as a unique feature, our findings showed that the adolescent exposure to cannabis or cocaine increased the odds by 1.95 times of developing bipolar disorder at 22 years age, even when controlling for all other study variables (OR 2.14, 95% CI [1.30, 3.47]). Finally, our models suggest that cocaine use may potentially exert a major influence on the effect of lifetime cannabis use on bipolar disorder onset, and that physical abuse by parents and sex may modify the effect of cannabis use for later bipolar disorder onset. CONCLUSION: Based on our findings, early cannabis exposure predicted bipolar disorder onset in young adults, but this association was confounded by cocaine use. Contrary to schizophrenia, cannabis as a sole exposure was not associated with bipolar disorder onset after adjusting for control variables.


Assuntos
Transtorno Bipolar , Cannabis , Cocaína , Alucinógenos , Adolescente , Adulto Jovem , Humanos , Adulto , Cannabis/efeitos adversos , Estudos de Coortes , Brasil/epidemiologia , Transtorno Bipolar/epidemiologia
14.
Transl Psychiatry ; 14(1): 120, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409093

RESUMO

It has been previously established that paternal development of a strong incentive motivation for cocaine can predispose offspring to develop high cocaine-seeking behavior, as opposed to sole exposure to the drug that results in drug resistance in offspring. However, the adaptive changes of the reward circuitry have not been fully elucidated. To infer the key nuclei and possible hub genes that determine susceptibility to addiction in offspring, rats were randomly assigned to three groups, cocaine self-administration (CSA), yoked administration (Yoke), and saline self-administration (SSA), and used to generate F1. We conducted a comprehensive transcriptomic analysis of the male F1 offspring across seven relevant brain regions, both under drug-naïve conditions and after cocaine self-administration. Pairwise differentially expressed gene analysis revealed that the orbitofrontal cortex (OFC) exhibited more pronounced transcriptomic changes in response to cocaine exposure, while the dorsal hippocampus (dHip), dorsal striatum (dStr), and ventral tegmental area (VTA) exhibited changes that were more closely associated with the paternal voluntary cocaine-seeking behavior. Consistently, these nuclei showed decreased dopamine levels, elevated neuronal activation, and elevated between-nuclei correlations, indicating dopamine-centered rewiring of the midbrain circuit in the CSA offspring. To determine if possible regulatory cascades exist that drive the expression changes, we constructed co-expression networks induced by paternal drug addiction and identified three key clusters, primarily driven by transcriptional factors such as MYT1L, POU3F4, and NEUROD6, leading to changes of genes regulating axonogenesis, synapse organization, and membrane potential, respectively. Collectively, our data highlight vulnerable neurocircuitry and novel regulatory candidates with therapeutic potential for disrupting the transgenerational inheritance of vulnerability to cocaine addiction.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Ratos , Masculino , Animais , Dopamina , Cocaína/efeitos adversos , Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Recompensa , Perfilação da Expressão Gênica , Autoadministração
15.
Addict Biol ; 29(2): e13381, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38357782

RESUMO

Cocaine use disorder (CUD) is a worldwide public health condition that is suggested to induce pathological changes in macrostructure and microstructure. Repetitive transcranial magnetic stimulation (rTMS) has gained attention as a potential treatment for CUD symptoms. Here, we sought to elucidate whether rTMS induces changes in white matter (WM) microstructure in frontostriatal circuits after 2 weeks of therapy in patients with CUD and to test whether baseline WM microstructure of the same circuits affects clinical improvement. This study consisted of a 2-week, parallel-group, double-blind, randomized controlled clinical trial (acute phase) (sham [n = 23] and active [n = 27]), in which patients received two daily sessions of rTMS on the left dorsolateral prefrontal cortex (lDLPFC) as an add-on treatment. T1-weighted and high angular resolution diffusion-weighted imaging (DWI-HARDI) at baseline and 2 weeks after served to evaluate WM microstructure. After active rTMS, results showed a significant increase in neurite density compared with sham rTMS in WM tracts connecting lDLPFC with left and right ventromedial prefrontal cortex (vmPFC). Similarly, rTMS showed a reduction in orientation dispersion in WM tracts connecting lDLPFC with the left caudate nucleus, left thalamus, and left vmPFC. Results also showed a greater reduction in craving Visual Analogue Scale (VAS) after rTMS when baseline intra-cellular volume fraction (ICVF) was low in WM tracts connecting left caudate nucleus with substantia nigra and left pallidum, as well as left thalamus with substantia nigra and left pallidum. Our results evidence rTMS-induced WM microstructural changes in fronto-striato-thalamic circuits and support its efficacy as a therapeutic tool in treating CUD. Further, individual clinical improvement may rely on the patient's individual structural connectivity integrity.


Assuntos
Cocaína , Transtornos Relacionados ao Uso de Substâncias , Humanos , Estimulação Magnética Transcraniana/métodos , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Córtex Pré-Frontal Dorsolateral , Método Duplo-Cego , Resultado do Tratamento
16.
Water Sci Technol ; 89(3): 823-837, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38358505

RESUMO

Quinoline inevitably remains in the effluent of coking wastewater treatment plants due to its bio-refractory nature, which might cause unfavorable effects on human and ecological environments. In this study, MnCexOy was consciously synthesized by α-MnO2 doped with Ce3+ (Ce:Mn = 1:10) and employed as the ozonation catalyst for quinoline degradation. After that, the removal efficiency and mechanism of quinoline were systematically analyzed by characterizing the physicochemical properties of MnCexOy, investigating free radicals and monitoring the solution pH. Results indicated that the removal rate of quinoline was greatly improved by the prepared MnCexOy catalyst. Specifically, the removal efficiencies of quinoline could be 93.73, 62.57 and 43.76%, corresponding to MnCexOy, α-MnO2 and single ozonation systems, respectively. The radical scavenging tests demonstrated that •OH and •O2- were the dominant reactive oxygen species in the MnCexOy ozonation system. Meanwhile, the contribution levels of •OH and •O2- to quinoline degradation were about 42 and 35%, respectively. The abundant surface hydroxyl groups and oxygen vacancies of the MnCexOy catalyst were two important factors for decomposing molecular O3 into more •OH and •O2-. This study could provide scientific support for the application of the MnCexOy/O3 system in degrading quinoline in bio-treated coking wastewater.


Assuntos
Cocaína , Coque , Ozônio , Quinolinas , Humanos , Compostos de Manganês , Óxidos , Catálise , Oxigênio
17.
Sci Rep ; 14(1): 4182, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378969

RESUMO

Organisms must regulate their behavior flexibly in the face of environmental challenges. Failure can lead to a host of maladaptive behavioral traits associated with a range of neuropsychiatric disorders, including attention deficit hyperactivity disorder, autism, and substance use disorders. This maladaptive dysregulation of behavior is influenced by genetic and environmental factors. For example, environmental enrichment produces beneficial neurobehavioral effects in animal models of such disorders. The present study determined the effects of environmental enrichment on a range of measures related to behavioral regulation using a large cohort of male, outbred heterogeneous stock (HS) rats as subjects. Subjects were reared from late adolescence onwards either in pairs in standard housing with minimal enrichment (n = 200) or in groups of 16 in a highly enriched environment consisting of a large multi-level cage filled with toys, running wheels, and shelters (n = 64). Rats were subjected to a battery of tests, including: (i) locomotor response to novelty, (ii) light reinforcement, (iii) social reinforcement, (iv) reaction time, (v) a patch-depletion foraging test, (vi) Pavlovian conditioned approach, (vii) conditioned reinforcement, and (viii) cocaine conditioned cue preference. Results indicated that rats housed in the enriched environment were able to filter out irrelevant stimuli more effectively and thereby regulate their behavior more efficiently than standard-housing rats. The dramatic impact of environmental enrichment suggests that behavioral studies using standard housing conditions may not generalize to more complex environments that may be more ethologically relevant.


Assuntos
Cocaína , Humanos , Ratos , Animais , Masculino , Cocaína/farmacologia , Isolamento Social , Comportamento Animal/fisiologia , Abrigo para Animais
18.
J Child Sex Abus ; 33(2): 229-242, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38351595

RESUMO

Sexual abuse is a public health problem due to its negative impact on physical and mental health. This study aimed to determine the association between sexual abuse and the use of psychoactive substances among high-school adolescents in Colombia. A cross-sectional analytical study was designed in which tenth and eleventh-grade students were included. Overall, a history of sexual abuse was explored with the Trauma Symptom Checklist, and lifetime substance use was assessed with the United States Centers for Disease Control Youth Risk Behavior Questionnaire. The prevalence of sexual abuse was 17.4%, lifetime alcohol use was 77.4%, cigarette 22.4%, cannabis 11.6%, cocaine 2.7%, and other substances 5.1%. History of sexual abuse was associated with alcohol use (OR = 1.59, 95% CI 1.10-2.30), cigarette (OR = 2.08, 95% CI 1.51-2.85), cannabis (OR = 2.43, 95% CI 1.66-3.56), cocaine (OR = 2.51, 95% CI 1.25-5.04) and use of other substances (OR = 2.33, 95% CI 1.31-4.13). The history of sexual abuse is related to the use of substances in high school adolescents in the Caribbean Region of Colombia. More studies are needed to identify the impact of sexual abuse on short-term and lifelong mental health.


Assuntos
Abuso Sexual na Infância , Cocaína , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Criança , Humanos , Colômbia/epidemiologia , Estudos Transversais , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Estudantes/psicologia , Inquéritos e Questionários , Região do Caribe , Prevalência
19.
Cancer Med ; 13(3): e7019, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38400665

RESUMO

BACKGROUND: Cocaine is an illegal recreational drug used worldwide, yet little is known about whether cocaine inhalation (smoking/snorting) increases the risk of head and neck cancer (HNC). METHODS: The analyses were conducted by pooling data from three case-control studies with 1639 cases and 2506 controls from the International Head and Neck Cancer Epidemiology Consortium. Epidemiologic data, including cocaine use histories, were obtained in face-to-face interviews. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using hierarchical logistic regression models. RESULTS: Controlling for cumulative tobacco and alcohol use, we observed a weak positive association between cocaine use and HNC (ORever vs. never = 1.35, 95% CI: 0.96, 1.90). In stratified analysis, while we did not detect associations among never tobacco or alcohol users due to the limited sample size, the association with cocaine use was observed among tobacco users and alcohol drinkers. ORs for ever and high cumulative use (>18 times) versus never use were 1.40 (95% CI: 0.98, 2.00) and 1.66 (95% CI: 1.03, 2.69) among tobacco users, and 1.34 (95% CI: 0.93, 1.92) and 1.59 (95% CI: 1.00, 2.51) among alcohol drinkers, respectively. CONCLUSION: In this pooled analysis, we observed a weak positive association between cocaine inhalation and HNC risk. Our findings provide preliminary evidence of the potential carcinogenic effect of cocaine on HNC. Because of study limitations, including limited number of cocaine users, confounding, and heterogeneity across studies, future investigations will require larger studies with more detailed information on cocaine use history.


Assuntos
Cocaína , Neoplasias de Cabeça e Pescoço , Humanos , Fatores de Risco , Fumar/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/etiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Estudos de Casos e Controles
20.
Transl Psychiatry ; 14(1): 107, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388464

RESUMO

Epidemiological investigations indicate that parental drug abuse experiences significantly influenced the addiction vulnerability of offspring. Studies using animal models have shown that paternal cocaine use and highly motivated drug-seeking behavior are important determinants of offspring addiction susceptibility. However, the key molecules contributing to offspring addiction susceptibility are currently unclear. The motivation for cocaine-seeking behavior in offspring of male rats was compared between those whose fathers self-administered cocaine (SA) and those who were yoked with them and received non-contingent cocaine administrations (Yoke). We found that paternal experience with cocaine-seeking behavior, but not direct cocaine exposure, could lead to increased lever-pressing behavior in male F1 offspring. This effect was observed without significant changes to the dose-response relationship. The transcriptomes of ventral tegmental area (VTA) in offspring were analyzed under both naive state and after self-administration training. Specific transcriptomic changes in response to paternal cocaine-seeking experiences were found, which mainly affected biological processes such as synaptic connections and receptor signaling pathways. Through joint analysis of these candidate genes and parental drug-seeking motivation scores, we found that gamma-aminobutyric acid receptor subunit gamma-3 (Gabrg3) was in the hub position of the drug-seeking motivation-related module network and highly correlated with parental drug-seeking motivation scores. The downregulation of Gabrg3 expression, caused by paternal motivational cocaine-seeking, mainly occurred in GABAergic neurons in the VTA. Furthermore, down-regulating GABAergic Gabrg3 in VTA resulted in an increase in cocaine-seeking behavior in the Yoke F1 group. This down-regulation also reduced transcriptome differences between the Yoke and SA groups, affecting processes related to synaptic formation and neurotransmitter transmission. Taken together, we propose that paternal cocaine-seeking behavior, rather than direct drug exposure, significantly influences offspring addiction susceptibility through the downregulation of Gabrg3 in GABAergic neurons of the VTA, highlighting the importance of understanding specific molecular pathways in the intergenerational inheritance of addiction vulnerability.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Cocaína , Ratos , Masculino , Animais , Humanos , Área Tegmentar Ventral , Motivação , Cocaína/efeitos adversos , Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Pai , Autoadministração/métodos , Comportamento de Procura de Droga/fisiologia , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo
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