Addiction Biology最新文献

Morphine dependence or addiction is a serious global public health and social problem, and traditional treatments are very limited. Deep brain stimulation (DBS) has emerged as a new potential treatment for drug addiction. Repeated use of morphine leads to neuroadaptive and molecular changes in the addiction-related brain regions. We have previously performed isobaric tags for relative and absolute quantitation (iTRAQ) labelling coupled with 2D-LC MS/MS in anterior insular samples from rats treated with saline control, morphine or morphine plus DBS, and the identified expression of eight proteins are altered by morphine and reversed by high-frequency DBS (HF-DBS). In this study, we analysed the proteomic data in more details. A total of 5575 proteins were identified. Relative to the saline group, the morphine group showed 14 down-regulated and three up-regulated proteins. There were 118 proteins increased and 87 proteins decreased between DBS implanted animals and morphine group. Several differentially expressed proteins were verified with parallel reaction monitoring (PRM) assay. Based on Gene Ontology enrichment an KEGG pathway analyses, the majority of these differentially expressed proteins (DEPs) were involved in protein metabolic process, G-protein coupled receptor signalling pathway, calcium-mediated signalling, neurotransmitter transport, dopaminergic synapse and mTOR signalling pathway. These data offer a comprehensive understanding of the proteomic changes associated with morphine addiction and DBS therapy in addicted animal models, which is important for the development of DBS interventions for drug addiction.

The ability of environmental cues to trigger alcohol-seeking behaviours is thought to facilitate problematic alcohol use. Individuals' tendency to attribute incentive salience to cues may increase the risk of addiction. We sought to study the relationship between incentive salience and alcohol addiction using non-preferring rats to model the heterogeneity of human alcohol consumption, investigating both males and females. Adult rats were subjected to the alcohol deprivation effect (ADE) paradigm, where they were given voluntary access to different alcohol solutions with repeated interruptions by deprivation and reintroduction phases over a protracted period (five Alcohol Deprivation Cycles). Before each Alcohol Deprivation Cycle, rats were tested in the Pavlovian Conditioned Approach (PCA) paradigm, which quantifies the individual salience toward a conditional cue and the reward, thus allowing us to trace the process of attributing incentive salience to reward cues. During the final Alcohol Deprivation Cycle (ADE5), animals were tested for compulsive-like behaviour using quinine taste adulteration. We investigated sex differences in drinking behaviour and PCA performance. We observed thatb females drank significantly more alcohol than males and displayed more sign-tracking (ST) behaviour in the PCA, whereas males showed goal-tracking (GT) behaviour. Furthermore, we found that high drinkers exhibited more ST behaviour. The initial PCA phenotype was correlated with later alcohol consumption. Our findings indicate a complex relationship between incentive salience and alcohol addiction and emphasize the importance of considering both sexes in preclinical research.

The ventromedial prefrontal cortex (VMPFC), located along the medial aspect of the frontal area, plays a critical role in regulating arousal/emotions. Its intricate connections with subcortical structures, including the striatum and amygdala, highlight the VMPFC's importance in the neurocircuitry of addiction. Due to these features, the VMPFC is considered a promising target for transcranial magnetic stimulation (TMS) in substance use disorders (SUD). By the end of 2023, all 21 studies targeting VMPFC for SUD used anatomical landmarks (e.g., Fp1/Fp2 in the EEG system) to define coil location with a fixed orientation. Nevertheless, one-size-fits-all TMS over VMPFC has yielded variable outcomes. Here, we suggested a pipeline based on a tailored TMS targeting framework aimed at optimally modulating the VMPFC-amygdala circuit on an individual basis. We collected MRI data from 60 participants with methamphetamine use disorders (MUDs). We examined the variability in TMS target location based on task-based functional connectivity between VMPFC and amygdala using psychophysiological interaction (PPI) analysis. Electric fields (EF) were calculated for fixed vs. optimized location (Fp1/Fp2 vs. individualized maximal PPI), orientation (AF7/AF8 vs. optimized algorithm) and intensity (constant vs. adjusted) to maximize target engagement. In our pipeline, the left medial amygdala, identified as the brain region with the highest (0.31 ± 0.29) fMRI drug cue reactivity, was selected as the subcortical seed region. The voxel with the most positive amygdala-VMPFC PPI connectivity in each participant was considered the individualized TMS target (MNI-coordinates: [12.6, 64.23, -0.8] ± [13.64, 3.50, 11.01]). This individualized VMPFC-amygdala connectivity significantly correlated with VAS craving after cue exposure (R = 0.27, p = 0.03). Coil orientation was optimized to increase EF strength over the targeted circuit (0.99 ± 0.21 V/m vs. the fixed approach: Fp1: 0.56 ± 0.22 and Fp2: 0.78 ± 0.25 V/m) and TMS intensity was harmonized across the population. This study highlights the potential of an individualized VMPFC targeting framework to enhance treatment outcomes for addiction, specifically modulating the personalized VMPFC-amygdala circuit.

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.