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International Journal of Molecular... Jun 2024Alcohol use disorder (AUD) is a chronic neurobehavioral condition characterized by a cycle of tolerance development, increased consumption, and reinstated craving and...
Alcohol use disorder (AUD) is a chronic neurobehavioral condition characterized by a cycle of tolerance development, increased consumption, and reinstated craving and seeking behaviors during withdrawal. Understanding the intricate mechanisms of AUD necessitates reliable animal models reflecting its key features. (), with its conserved nervous system and genetic tractability, has emerged as a valuable model organism to study AUD. Here, we employ an ethanol vapor exposure model in , recapitulating AUD features while maintaining high-throughput scalability. We demonstrate that ethanol vapor exposure induces intoxication-like behaviors, acute tolerance, and ethanol preference, akin to mammalian AUD traits. Leveraging this model, we elucidate the conserved role of c-jun N-terminal kinase (JNK) signaling in mediating acute ethanol tolerance. Mutants lacking JNK signaling components exhibit impaired tolerance development, highlighting JNK's positive regulation. Furthermore, we detect ethanol-induced JNK activation in . Our findings underscore the utility of with ethanol vapor exposure for studying AUD and offer novel insights into the molecular mechanisms underlying acute ethanol tolerance through JNK signaling.
Topics: Animals; Caenorhabditis elegans; Ethanol; Drug Tolerance; Caenorhabditis elegans Proteins; MAP Kinase Signaling System; JNK Mitogen-Activated Protein Kinases; Alcoholism; Disease Models, Animal
PubMed: 38928105
DOI: 10.3390/ijms25126398 -
Biomedicines May 2024The escalating rates of morbidity and mortality associated with opioid use disorder (OUD) have spurred a critical need for improved treatment outcomes. This study aimed...
The escalating rates of morbidity and mortality associated with opioid use disorder (OUD) have spurred a critical need for improved treatment outcomes. This study aimed to investigate the impact of prolonged exposure to Fentanyl, a potent opioid, on behavior, biochemical markers, oxidative stress, and the composition of the gut microbiome. Additionally, we sought to explore the therapeutic potential of in mitigating the adverse effects of Fentanyl withdrawal. The study unveiled that chronic Fentanyl administration induced a withdrawal syndrome characterized by elevated cortisol levels (12.09 mg/mL, compared to 6.3 mg/mL for the control group). This was accompanied by heightened anxiety, indicated by a reduction in time spent and entries made into the open arm in the Elevated Plus Maze Test, as well as depressive-like behaviors, manifested through increased immobility time in the Forced Swim Test. Additionally, Fentanyl exposure correlated with decreased gut microbiome density and diversity, coupled with heightened oxidative stress levels, evidenced by elevated malondialdehyde (MDA) and reduced levels of catalase (CAT) and superoxide dismutase (SOD). However, both post- and co-administration of exhibited substantial improvements in these adverse effects, effectively alleviating symptoms associated with OUD withdrawal syndrome and eliciting positive influences on gut microbiota. In conclusion, this research underscores the therapeutic potential of in managing Fentanyl withdrawal symptoms. The findings indicate promising effects in alleviating behavioral impairments, reducing stress, restoring gut microbiota, and mitigating oxidative stress, offering valuable insights for addressing the challenges of OUD treatment.
PubMed: 38927359
DOI: 10.3390/biomedicines12061152 -
Biology Jun 2024Eales' Disease is an idiopathic peripheral retinal vasculopathy first described by British ophthalmologist Henry Eales in 1880. Most prevalent in healthy young males,... (Review)
Review
Eales' Disease is an idiopathic peripheral retinal vasculopathy first described by British ophthalmologist Henry Eales in 1880. Most prevalent in healthy young males, Eales' Disease often presents with symptoms of sudden blurry or decreased vision and floaters. Although no clear, standardized stage of the disease exists, it progresses through three overlapping phases-peripheral periphlebitis, ischemic capillary ischemia, and retinal neovascularization. The etiology of Eales' Disease is unknown and appears to be multifactorial, but post-TB hypersensitivity to tuberculoprotein and DNA is the most potential cause in the etiology of Eales' Disease. With a thorough examination of the clinical presentation and diagnosis of Eales' Disease-incorporating the latest clinical findings related to the condition-the investigation for Eales' Disease extends to explore recent potential connections with other ocular conditions or possible cofactors, such as glaucoma, uncontrolled diabetes, drug abuse, or inherited medical conditions. Moreover, focusing on critical insights into the treatment of Eales' Disease across its various stages of progression, the overarching goal of the paper is to refine and suggest possible future diagnostic and therapeutic strategies. Widening our understanding of pathophysiology and utilizing various treatment options for individual patients holds immense potential for advancing ocular medicine and optimizing patient care for people with this disease with unknown pathophysiology.
PubMed: 38927340
DOI: 10.3390/biology13060460 -
Biomolecules Jun 2024Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead...
Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT.
Topics: Modafinil; Dopamine Plasma Membrane Transport Proteins; Humans; Molecular Dynamics Simulation; Binding Sites; Dopamine Uptake Inhibitors; Structure-Activity Relationship; Protein Binding
PubMed: 38927116
DOI: 10.3390/biom14060713 -
BMC Nursing Jun 2024By evaluating nurses' attitudes and behaviors regarding narcotic drug safety and addiction, effective strategies need to be developed for combating addiction in...
BACKGROUND
By evaluating nurses' attitudes and behaviors regarding narcotic drug safety and addiction, effective strategies need to be developed for combating addiction in healthcare institutions. This study, aimed at providing an insight into patient and staff safety issues through the formulation of health policies, aimed to evaluate nurses' attitudes and behaviors regarding narcotic drug safety and addiction.
METHODS
The study was conducted in a descriptive cross-sectional design. It was carried out with 191 nurses in a public hospital between March 2023 and August 2023. Data were collected through face-to-face interviews, gathering socio-demographic information and utilizing the Addictive Substance Attitude Scale. The data were analyzed using independent sample t-tests, one-way ANOVA tests, and regression analysis (P < .001 and p < .05).
RESULTS
The average age of the participants was determined to be 36.58 ± 8.40. It was reported by 85.3% of nurses that narcotic drug follow-ups in their units were conducted according to procedures. In the study, it was found that 63.9% of nurses did not know the procedure to be followed towards a healthcare professional identified as a narcotic substance addict. The total mean score of the Addictive Substance Attitude Scale of nurses participating in the study was 74.27 ± 14.70. A significant difference was found between the total scores of the scale and the level of education of nurses, the follow-up status of the drugs in the unit where they work, their status of receiving narcotic drug addiction training, and their routine use of the half-dose drug disposal form (p < .05).
CONCLUSIONS
The findings of this study underscore the importance of evaluating nurses' attitudes and behaviors regarding narcotic drug safety and addiction. These results indicate the need for nursing administrators, particularly in terms of patient and staff safety, to adopt more effective policies and strategies.
PubMed: 38926826
DOI: 10.1186/s12912-024-02109-2 -
BMC Public Health Jun 2024Illicit drug and high-risk alcohol use among adolescents leads to poor health outcomes. We enrolled adolescents from urban slums in Kampala, Uganda, to assess baseline...
BACKGROUND
Illicit drug and high-risk alcohol use among adolescents leads to poor health outcomes. We enrolled adolescents from urban slums in Kampala, Uganda, to assess baseline prevalence and factors associated with illicit drug and high-risk alcohol consumption.
METHODS
We conducted a cross-sectional study using data collected in a cohort that enrolled 14-19-year-old male and female participants from 25 March 2019 to 30 March 2020. Data was collected on social demographics, sexual behavior, and reproductive health using interviewer-administered questionnaires. The main outcomes were illicit drug use and high-risk alcohol use. Data on alcohol use was collected using the Alcohol Use Disorder Identification Test (AUDIT); results were dichotomized. Factors associated with each outcome were analyzed using multivariable logistic regression.
RESULTS
We enrolled 490 participants (60.6% female) with a median age of 18 (IQR 17-18) years, 84.9% had less than secondary education, 48.4% had their sexual debut before 15 years, 47.1% reported paid sex in the past 3 months and 22.8% had a sexually transmitted infection (chlamydia, gonorrhea, and active syphilis) baseline characteristics associated with illicit drug use in the past 3 months were male gender (aOR 12.45; 95% CI 7.21-21.50) being married (aOR 2.26; 95%CI 1.03-4.94) 10 or more paying sexual partners (aOR 2.45; 95%CI 1.05-5.69) and high-risk alcohol use (aOR 3.94; 95%CI 2.10-7.40), baseline characteristics associated with high-risk alcohol use were male gender (aOR 0.29; 95% CI 0.13-0.63) emotional violence from sexual partners (aOR 2.35; 95%CI 1.32-418) illicit drug users com (aOR 3.94; 95% CI 2.10-7.40).
CONCLUSION
Illicit drug and high-risk alcohol use are prevalent among male adolescents and adolescents involved in high-risk sexual behavior living in the urban slums of Kampala.
Topics: Humans; Adolescent; Male; Uganda; Female; Cross-Sectional Studies; Poverty Areas; Prevalence; Substance-Related Disorders; Illicit Drugs; Young Adult; Risk Factors; Sexual Behavior; Urban Population; Alcohol Drinking
PubMed: 38926824
DOI: 10.1186/s12889-024-19250-x -
Research Involvement and Engagement Jun 2024Clustering and co-occurring of family adversities, including mental health problems, substance use, domestic violence and abuse, as well as poverty can increase health...
Co-design workshops with families experiencing multiple and interacting adversities including parental mental health, substance use, domestic violence, and poverty: intervention principles and insights from mothers, fathers, and young people.
BACKGROUND
Clustering and co-occurring of family adversities, including mental health problems, substance use, domestic violence and abuse, as well as poverty can increase health and behavioural risks for children, which persist throughout the life course. Yet, interventions that acknowledge and account for the complex interactive nature of such risks are limited. This study aimed to develop intervention principles based on reflections from mothers, fathers, and young people who experience multiple and interacting adversities. These principles will show how family members perceive an intervention may bring about positive change and highlight key insights into design and delivery.
METHODS
A series of six co-design workshops with mothers, fathers, and young people who experienced multiple and interacting adversities (n = 41) were iteratively conducted across two regions in England (London and North-East) by four researchers. Workshop content and co-design activities were informed by advisory groups. Data from facilitator notes and activities were analysed thematically, resulting in a set of intervention principles.
RESULTS
The intervention principles highlighted that: (1) to reduce isolation and loneliness parents and young people wanted to be connected to services, resources, and peer support networks within their local community, particularly by a knowledgeable and friendly community worker; (2) to address feelings of being misunderstood, parents and young people wanted the development of specialised trauma informed training for practitioners and to have the space to build trusting, gradual, and non-stigmatising relationships with practitioners; and (3) to address the needs and strengths of individual family members, mothers, fathers, and young people wanted separate, tailored, and confidential support.
CONCLUSIONS
The current study has important implications for practice in supporting families that experience multiple and interacting adversities. The intervention principles from this study share common characteristics with other intervention models currently on offer in the United Kingdom, including social prescribing, but go beyond these to holistically consider the whole families' needs, environments, and circumstances. There should be particular focus on the child's as well as the mothers' and fathers' needs, independently of the family unit. Further refinement and piloting of the developing intervention are needed.
PubMed: 38926798
DOI: 10.1186/s40900-024-00584-0 -
Harm Reduction Journal Jun 2024People who inject drugs (PWID) are at risk of HIV acquisition. The number of PWID in South African cities is increasing, and in spite of an advanced HIV prevention and...
BACKGROUND
People who inject drugs (PWID) are at risk of HIV acquisition. The number of PWID in South African cities is increasing, and in spite of an advanced HIV prevention and treatment programme, there are PWID who experience challenges accessing sexual and reproductive health (SRH) and HIV related services. Access to and acceptability of SRH and harm reduction services by PWID needs to be further understood and explored.
METHODS
In-depth interviews (IDIs) were conducted with 10 key stakeholders and 11 PWID, in Durban, South Africa. Interviews were transcribed and translated. Data were thematically analysed using Dedoose software.
RESULTS
Participants described stigma/discrimination from healthcare workers and other clients accessing services as barriers to accessing healthcare services. They were concerned about long waiting times at healthcare facilities because of possibilities of withdrawal, as well as lost opportunities to "hustle". Targeted, non-discriminatory services, as well as mobile clinics existed in the city. Non-governmental organisations reportedly worked together with the public sector, facilitating access to HIV and TB prevention and treatment services. There were also needle exchange programmes and a harm reduction clinic in the city. However, there was limited access to contraceptive and STI services. Although there was reportedly good access to HIV and TB and harm reduction services in the city of Durban, uptake was low.
CONCLUSIONS
The integration of services to enable PWID to access different services under one roof is critical. There is also a need to strengthen linkages between public and private healthcare, and ensure services are provided in a non-discriminatory environment. This will facilitate uptake and access to more comprehensive SRH and harm reduction services for PWID in Durban, South Africa.
Topics: Humans; South Africa; Harm Reduction; Health Services Accessibility; Substance Abuse, Intravenous; Female; Adult; Male; HIV Infections; Social Stigma; Patient Acceptance of Health Care; Reproductive Health Services; Middle Aged; Sexual Health; Needle-Exchange Programs; Reproductive Health
PubMed: 38926755
DOI: 10.1186/s12954-024-01042-6 -
Neuropsychopharmacology : Official... Jun 2024Converging evidence indicates that both dopamine and glutamate neurotransmission within the nucleus accumbens (NAc) play a role in psychostimulant self-administration...
Converging evidence indicates that both dopamine and glutamate neurotransmission within the nucleus accumbens (NAc) play a role in psychostimulant self-administration and relapse in rodent models. Increased NAc dopamine release from ventral tegmental area (VTA) inputs is critical to psychostimulant self-administration and NAc glutamate release from prelimbic prefrontal cortex (PFC) inputs synapsing on medium spiny neurons (MSNs) is critical to reinstatement of psychostimulant-seeking after extinction. The regulation of the activity of MSNs by VTA dopamine inputs has been extensively studied, and recent findings have demonstrated that VTA glutamate neurons target the NAc medial shell. Here, we determined whether the mesoaccumbal glutamatergic pathway plays a role in psychostimulant conditioned place preference and self-administration in mice. We used optogenetics to induce NAc release of glutamate from VTA inputs during the acquisition, expression, and reinstatement phases of cocaine- or methamphetamine-induced conditioned place preference (CPP), and during priming-induced reinstatement of cocaine-seeking behavior. We found that NAc medial shell release of glutamate resulting from the activation of VTA glutamatergic fibers did not affect the acquisition of cocaine-induced CPP, but it blocked the expression, stress- and priming-induced reinstatement of cocaine- and methamphetamine CPP, as well as it blocked the priming-induced reinstatement of cocaine-seeking behavior after extinction. These findings indicate that in contrast to the well-recognized mesoaccumbal dopamine system that is critical to psychostimulant reward and relapse, there is a parallel mesoaccumbal glutamatergic system that suppresses reward and psychostimulant-seeking behavior.
PubMed: 38926603
DOI: 10.1038/s41386-024-01905-3 -
Scientific Data Jun 2024Major depressive disorder (MDD) and substance-use disorders (SUDs) often lead to premature aging, increasing vulnerability to cognitive decline and other forms of...
Major depressive disorder (MDD) and substance-use disorders (SUDs) often lead to premature aging, increasing vulnerability to cognitive decline and other forms of dementia. This study utilized advanced systems bioinformatics to identify aging "signatures" in MDD and SUDs and evaluated the potential for known lifespan-extending drugs to target and reverse these signatures. The results suggest that inhibiting the transcriptional activation of FOS gene family members holds promise in mitigating premature aging in MDD and SUDs. Conversely, antidepressant drugs activating the PI3K/Akt/mTOR pathway, a common mechanism in rapid-acting antidepressants, may accelerate aging in MDD patients, making them unsuitable for those with comorbid aging-related conditions like dementia and Alzheimer's disease. Additionally, this innovative approach identifies potential anti-aging interventions for MDD patients, such as Deferoxamine, Resveratrol, Estradiol valerate, and natural compounds like zinc acetate, genistein, and ascorbic acid, regardless of comorbid anxiety disorders. These findings illuminate the premature aging effects of MDD and SUDs and offer insights into treatment strategies for patients with comorbid aging-related conditions, including dementia and Alzheimer's disease.
Topics: Humans; Depressive Disorder, Major; Substance-Related Disorders; Aging, Premature; Antidepressive Agents
PubMed: 38926475
DOI: 10.1038/s41597-024-03538-z