Addiction Biology最新文献

Cigarette smoking is a prevalent and critical global health issue, with inconsistent findings for its effects on endogenous progesterone concentrations. This large multicentre study investigated the associations between various markers of smoking behaviour and plasma progesterone concentrations using a sex-segregating approach. We studied 747 males aged 18-65 years and 158 peri-/postmenopausal females aged 50-65 years and assessed differences in plasma progesterone concentrations between smokers and never-smokers and associations of plasma progesterone concentrations with the Fagerström Test for Nicotine Dependence (FTND) score, cigarette pack years, age at onset of regular smoking, number of cigarettes smoked daily, exhaled carbon monoxide (CO), plasma cotinine and the Questionnaire of Smoking Urges (QSU) score. In models adjusted for age, body mass index (BMI), years of education, Alcohol Use Disorder Identification Test (AUDIT) scores, intake of any medication and study centre, and after correction for multiple hypothesis testing, there were no significant differences in plasma progesterone concentrations between smokers and never-smokers, and no significant associations between any of the mentioned markers of smoking behaviour and plasma progesterone concentrations in either males or females. The results suggest that smoking behaviour has no substantial effect on plasma progesterone concentrations and is not an important confounder in studies investigating progesterone.

While alcohol use disorder can be treated with pharmacological interventions, ketosis is a recently proposed treatment option. Ketosis, defined by elevated concentrations of ketone bodies such as β-hydroxybutyrate (BHB), can be induced by a ketogenic diet or by supplements. As a supplement, both the salt and ester formulation of BHB rapidly increase blood ketone levels. Although preclinical studies have revealed that a ketogenic diet or a mix of ketone supplements reduces alcohol intake and alleviates withdrawal symptoms, the impact of BHB supplements on alcohol-related responses remains to be defined. We first assessed the efficacy of BHB in ester versus salt formulation on general locomotor activity, exogenous ketosis and alcohol-induced locomotor stimulation in male mice. We then investigated the impact of the BHB salt on alcohol intake in male and female rats. In attempts to define mechanisms influenced by the BHB salt, monoamines and their metabolites were measured in the nucleus accumbens (NAc), a brain region associated with alcohol reward. Initial results indicate that the BHB salt had a greater impact on ketone levels, glucose-ketone index and inhibition of alcohol-induced locomotor stimulation compared to the BHB ester, without altering the general locomotor activity. We further found that BHB salt dose-dependently lowered alcohol intake in rats of both sexes and that females responded to lower doses than males. Moreover, BHB salt elevated dopamine and noradrenaline and their metabolites in the NAc of male mice. Overall, this study provides insight into the role of BHB salt in modulating rodent alcohol-related behaviours.

Methamphetamine (Meth) is a psychoactive and neurotoxic chemical. Selective antibodies against Meth molecules have been examined for the treatment of Meth abuse through immunization. Antibodies with high affinity for Meth can capture Meth molecules and reduce Meth response. We previously reported that intraperitoneal administration of adeno-associated virus serotype vector serotype 8 carrying Meth-specific monoclonal antibody transgene (AAV8-MethAb, 2.5 × 10¹⁰ VGC per mouse) induced long-term and stable expression of Meth-antibody in the peripheral. Mice receiving AAV8-MethAb had a lower Meth level in the blood and brain and attenuated Meth-induced locomotor activity after an acute dose of Meth. The effect of AAV-MethAb in animals receiving repeated Meth administration was still not known. In this study, we first investigated the tropism of AAV serotypes in rat primary dopaminergic (DA) neuronal culture. We found that AAV6 is an optimal gene carrier for MethAb. AAV6-MethAb or AAV6-mCherry was used in cellular and animal models of chronic Meth use. In primary DA neuronal culture, repeated Meth administration increased the dendritic branching of DA neurons, which was antagonized by AAV6-MethAb. AAV6-MethAb or AAV6-mCherry was stereotaxically administered to the nucleus accumbens (NAc) of adult CD1 mice. Two weeks after the viral injection, animals were stimulated with a daily dose of Meth for 7 days. Repeat Meth administrations led to a progressive increase in locomotor activity or behaviour sensitization. This response was significantly attenuated in mice receiving AAV6-MethAb. Using qRTPCR and Western analysis, we demonstrated that MethAb mRNA and protein were expressed in the NAc. Previous reports indicated that Meth sensitization was associated with upregulation of tyrosine hydroxylase (TH) in the NAc. Using Western blot analysis, we found that AAV6-MethAb significantly reduced TH protein levels in Meth-sensitized mice. Taken together, our data support that intracerebral administration of AAV6-MethAb reduced Meth sensitization. Our data support a novel antibody gene therapy for Meth abuse.

The pronounced heterogeneity in smoking trajectories-ranging from occasional or heavy use to successful quitting -highlights substantial interindividual variation within the smoking population. Machine learning is particularly well suited to capture these complex patterns that may be challenging for traditional inferential statistics to uncover. In this study, we applied machine learning to data from a population-based cohort to identify multimodal markers that distinguish smokers from never smokers at baseline and predict long-term cessation success at a 10-year follow-up. We employed 10 times repeated nested cross-validation (10 outer folds, 5 inner folds) to analyse baseline data (T1) from 707 smokers-including 222 heavy smokers (FTND ≥ 4)-and 864 never smokers for smoking status classification. At the 10-year follow-up (T2), we further classified 60 successful quitters (≥ 1 year abstinent) versus 81 non-quitters. Feature importance was assessed using averaged SHAP values derived from test set predictions. Classification models achieved the following performance, expressed by the area under the receiver operating characteristic curve (AUROC; mean ± SD): smokers versus never smokers, 0.85 ± 0.03; heavy smokers versus never smokers, 0.92 ± 0.03; and quitters versus non-quitters, 0.68 ± 0.13. SHAP analysis identified markers of frontal functioning, cognitive control and smoking behaviour within the social environment among the most influential predictors of both smoking status and cessation success. In conclusion, our machine learning analyses support a multifactorial model of smoking behaviour and cessation success, which may inform nuanced risk stratification to advance the development of personalized cessation strategies.

Cue-induced craving-the desire to use a drug triggered by exposure to cues associated with prior use-is a central mechanism in the development and maintenance of problematic substance use behaviours. Drug cues have the power to induce craving even in long-term abstinent individuals, which has led clinicians to advise patients to avoid the people, places and objects that are associated with their use. This preliminary study builds on prior behavioural research that demonstrates that exposure to multimodal drug cues can increase craving even after the drug cues are removed from the environment. We used a novel fMRI paradigm that combined multimodal cannabis cue-exposure with resting-state functional connectivity to examine positive and negative functional connectivity (i.e., correlations and anticorrelations) between the ventral tegmental area (VTA) and the striatum, a circuit critically involved in reward processing and addiction. Intrinsic VTA-striatal connectivity was measured in 28 individuals who use cannabis regularly (CU group) and 26 age- and sex-matched controls who had never used cannabis before and after multimodal (visual and olfactory) cannabis cue exposure. Craving was assessed at baseline using the Marijuana Craving Questionnaire-Short Form to test whether VTA-striatal connectivity was correlated with self-reported craving measured prior to the fMRI scan. There were no significant group differences in VTA-striatal connectivity during the baseline resting-state scan. However, following cue exposure, CU participants showed significantly greater VTA-caudate connectivity compared to controls. Further, within the CU group, baseline craving was positively correlated with VTA-striatal connectivity at both time points. Our preliminary findings support prior investigations demonstrating that alterations of mesostriatal connectivity are associated with cannabis use and craving in individuals with problematic cannabis use. In addition, the observation of altered connectivity during the post-cue resting-state scan-after multimodal cannabis cues were removed-suggests a potential neural mechanism by which cue exposure may contribute to relapse vulnerability in individuals with problematic cannabis use.

Methamphetamine (METH) abuse can inflict profound and enduring neurotoxic effects on the brain, culminating in cognitive dysfunction and impairment of learning and memory. Physical exercise can stimulate both structural and functional adaptations in the central nervous system. The primary objective of this study was to elucidate the safeguarding effect and underlying mechanisms of treadmill exercise intervention in the brains of METH-addicted mice. Two-month-old adult mice were randomly assigned into three distinct groups: the control group (Group C), receiving intraperitoneal injections of saline; the METH treatment group (Group Ma), exposed to intraperitoneal METH administration; and the exercise group (Group Ea), which underwent a two-week regimen of treadmill exercise intervention following intraperitoneal METH exposure. The conditioned place preference experiment was executed to evaluate METH addiction. The results showed that both Groups Ma and Ea mice became addicted to METH after METH administration (p < 0.05, n = 6). In the Y-maze experiment, the exploration time of mice in Group Ea in the novel arm was significantly higher than that in Group Ma (p < 0.05, n = 6), indicating that exercise intervention improved the learning and memory capabilities of mice. Subsequently, the mouse brain specimens were harvested for transcriptome sequencing and real-time fluorescence quantitative PCR analysis (n = 3). Transcriptome sequencing analysis identified 316 differentially expressed genes (DEGs) in Group Ma compared to Group C, while 156 DEGs were detected in Group Ea compared to Group Ma. Kyoto Encyclopedia of Genes and Genomes analysis outcomes underscored the substantial association of DEGs, discerned in exercise-intervention mice compared to METH-treated mice, with key signalling pathways, notably the PI3K-Akt, mTOR and Wnt signalling pathways, among others. Cross-analysis revealed 43 DEGs in exercise-treated mice, such as NFKBIA, CXCL12 and Vav3. Our results revealed changes in the expression profile of the brain transcriptome of METH-addicted mice and indicated that treadmill exercise intervention affects the expression changes of the brain transcriptome of METH-addicted mice. The above research results provide unique insights into the further study of the mechanism of treadmill exercise intervention in improving the learning and memory abilities of METH-induced mice.

N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with SUD and (2) explore subgroup differences, risk of bias and publication bias across trials. Database searches of PubMed, Cochrane Library and ClinicalTrials.gov were conducted in June and July of 2023 to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analysed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses and leave-one-out analyses were conducted to examine the treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests and funnel plot tests were conducted to examine the risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015-0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. Overall, our findings are contrary to those of prior meta-analyses, suggesting a limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.

Ethanol has profound acute effects on hepatic metabolism. While many of these effects are mediated via the redox imbalance that accompanies hepatic ethanol oxidation via the alcohol dehydrogenase (ADH) pathway, there is increasing evidence that ethanol also perturbs hepatic metabolism via its modulation of cyclic AMP-mediated signalling pathways. This paper examines the effects of ethanol on glucagon-stimulated protein phosphorylation using SDS-PAGE to analyse the 32P-labelling of cytosolic peptides in isolated rat hepatocytes pre-equilibrated with 32PO4(3-). We show that ethanol has biphasic effects on glucagon-stimulated protein phosphorylation. At a low concentration (50 mM), ethanol decreased the phosphorylation of certain peptides, whereas at higher concentrations (100-200 mM) it increased the 32P-labelling of all of the eleven glucagon-stimulated cytosolic peptides. The non-metabolizable alcohol 2-methylpyrazole-2-ol had no effects on glucagon-stimulated protein phosphorylation. The ADH inhibitor 4-methylpyrazole at 150 mM ethanol concentration abolished the potentiating effect of ethanol on the glucagon-stimulated phosphorylation of most peptides. In conclusion, the results indicate that ethanol alters glucagon-receptor-dependent protein phosphorylation in isolated hepatocytes via a complex mechanism that is partially dependent on ethanol oxidation via ADH.