Addiction Biology最新文献

Alcohol use disorder (AUD) is a chronic, relapsing condition that causes extensive systemic damage, yet clinically actionable biomarkers remain lacking. Exosome-derived microRNAs (exo-miRNAs) have emerged as highly stable extracellular indicators of disease state and active regulators of alcohol-induced pathological processes. Unlike proteins or lipids, miRNAs are selectively packaged, cell-type specific and mechanistically linked to inflammation, hepatocellular injury, synaptic dysfunction and neuroimmune signalling. Here, we provide an integrated and updated review of how chronic alcohol exposure reshapes exo-miRNA cargo across organs—particularly the liver, immune system and central nervous system. We summarize the biogenesis and selective sorting of exo-miRNAs, highlight key candidate miRNAs such as miR-122, miR-155, miR-192, miR-29a, miR-30a and miR-124 and analyse their representative gene targets and downstream effects. Furthermore, we distinguish exo-miRNAs with diagnostic potential from those representing promising therapeutic targets and discuss major limitations, including specificity relative to other drugs of abuse. By integrating mechanistic and translational evidence, this review aims to clarify the biological and clinical value of exo-miRNAs and to provide guidance for future precision-medicine strategies in AUD.

Preliminary animal and human studies have shown that blood dihydrotestosterone concentrations are increased in males with alcohol use disorder, and 5α-reductase inhibitors, which decrease dihydrotestosterone concentrations, reduce alcohol consumption. To gain mechanistic insight, we studied the effects of reduced dihydrotestosterone concentrations following pharmacological 5α-reductase inhibition on alcohol cue-elicited brain activity and alcohol craving in males with problematic alcohol use. To this end, this randomized, placebo-controlled, crossover challenge experiment investigated associations between dihydrotestosterone concentrations and brain functional magnetic resonance imaging (fMRI) activity during exposure to visual alcohol cues and alcohol craving following a single dose of 5 mg finasteride versus placebo in 50 males with heavy episodic drinking. We used finasteride because it specifically inhibits 5α-reductase II activity, which is the main enzyme converting testosterone to dihydrotestosterone. Dihydrotestosterone concentrations were lower in the finasteride condition in comparison to the placebo condition, but not significantly associated with brain activation patterns or craving. In the exploratory analyses, we found higher brain activity during exposure to visual stimuli in the right and left caudate nuclei, the right superior frontal gyrus and the left insula in the finasteride condition versus the placebo condition. Moreover, finasteride versus placebo was associated with a higher wish to not drink alcohol. The results of this experimental study do not support the à priori hypothesis that dihydrotestosterone concentrations play a role in brain activation during exposure to visual alcohol cues, but indicate that finasteride effects may be mediated by other pathways. Future studies are requested to investigate the effects of reduced dihydrotestosterone concentrations over a longer time and to shed light on the molecular mechanisms underlying the here observed effects of finasteride.

Trial Registration: DRKS00020569

Cues associated with alcohol consumption can trigger cravings, seeking behaviour and relapse after abstinence in individuals with alcohol use disorder (AUD). These conditioned responses can be attenuated through extinction learning, a core component of cue exposure therapy (CET). CET is effective in some individuals with AUD but not all, so it is necessary to develop strategies to identify and intervene with individuals unlikely to benefit from CET. Another method for attenuating conditioned responding is retrieval-extinction, which renders the original associative memory labile via distinct neural mechanisms. We recently demonstrated that CO₂ reactivity predicts extinction memory for both fear and food cues, and fear memory after retrieval-extinction, and CO₂-induced orexin/c-Fos colocalization predicts fear extinction memory. The purpose of the current study was to examine whether the predictive power of CO₂ reactivity might extend to alcohol-seeking behaviour after extinction or retrieval-extinction in male and female rats. We also examined the relationship between CO₂ reactivity, return of alcohol-seeking behaviour and CO₂-induced orexin/c-Fos colocalization. Male and female rats first underwent alcohol drinking induction in the homecage followed by dependence via exposure to chronic intermittent ethanol vapour or control air and homecage drinking. All rats then underwent Pavlovian alcohol conditioning followed by either standard extinction or retrieval-extinction. They then received a long-term memory (LTM) test and CO₂ challenge followed by euthanasia for brain harvesting. CO₂ reactivity differentially predicted LTM after extinction and retrieval-extinction. There were no relationships between orexin/c-Fos colocalization and CO₂ reactivity or LTM. The predictive power of CO₂ reactivity extends to alcohol-seeking behaviour after extinction and retrieval-extinction in alcohol dependent and nondependent male and female rats, while its relationship with orexin/c-Fos colocalization does not. CO₂ reactivity could be used as a screening tool to determine whether an individual may be a good candidate for CET or a retrieval-extinction–based approach.

Heroin use and major depression are each leading contributors to global disability and premature mortality, yet evidence for a specific association between the two remains fragmented and is often derived from small, treatment-seeking samples. We conducted a cross-sectional analysis of nationally representative data from the 2005–2018 National Health and Nutrition Examination Survey, including 19 022 US adults aged ≥ 20 years with complete information on heroin use, depression status, and relevant covariates. Clinically significant depression was defined as a PHQ-9 score ≥ 10. After multivariable adjustment for sociodemographic, behavioural, and clinical factors, including polysubstance use and chronic medical conditions, lifetime heroin use was independently associated with depression (adjusted OR = 1.85, 95% CI 1.43–2.40; p < 0.001). Subgroup analyses demonstrated that this association was robust and modified by age and smoking status, with significant interaction effects observed (p for interaction < 0.05). Restricted cubic spline analysis among participants with a history of heroin use (n = 439) revealed a non-linear relationship between age at first heroin use and depression risk (p for non-linearity = 0.032), with the highest predicted probability of depression among individuals who initiated use at or before 20.4 years of age. These findings indicate that lifetime heroin use is associated with a substantially increased risk of clinically significant depression in the general US population, particularly among younger adults and current smokers, underscoring the need for integrated screening and concurrent treatment of substance-use and mood disorders.

Amidst the opioid crisis, understanding the genetic basis of opioid use disorder (OUD) is crucial for identifying biological mechanisms and intervention points. However, genome-wide association studies (GWASs) have been hampered by inadequate sample sizes and often the use of control populations not assessed for prior opioid exposure. Because opioid exposure is a prerequisite for the development of OUD, consideration of exposure history in controls is important. Electronic health record data (EHR) paired with genomic information allow a broader sampling of patients with OUD and exposed controls. We leveraged data across two healthcare systems to evaluate the impact of using controls not screened for opioid exposure (‘generic’) versus minimally opioid-exposed control (‘exposed’). First, at the phenotypic level, we conducted phenome-wide association studies (PheWAS) to compare the medical comorbidity profiles of OUD cases when using generic versus exposed controls. While PheWAS results for OUD-related comorbidities were more pronounced when using the generic group, 83% of the disease associations were overlapping and of similar effect sizes. Second, at the genetic level, we conducted GWAS (cases vs. generic; cases vs. exposed) and assessed differences in genetic correlations and degrees of phenotypic misclassification. Genetic results were concordant across control groups based on heritability (generic: 0.16 ± 0.07 vs. 0.10 ± 0.07), associations with the coding OPRM1 variant rs1799971 (p_generic = 8.83E-03 vs. p_exposed = 1.83E-02) and genetic correlations with prior OUD GWAS (r_g-generic = 0.83 ± 0.26 vs. r_g-exposed = 0.78 ± 0.27). Although GWASs were limited by sample size (N_generic = 6269, N_exposed = 6365), compared to an independent OUD GWAS (N = 425 944), the dilution value for the two GWAS was not different from 1, suggesting no major impact of phenotypic misclassification. This study represents the first effort to enhance OUD genetic research through optimization of control definitions using EHR data. Generic controls ascertained within the US health systems, where exposure to prescription opioids is high, offer a practical alternative for genetic studies of OUD.

The insular cortex (IC) is known to underlie drug seeking and relapse for multiple drug classes, yet the precise role the IC plays in opioid use disorder (OUD) remains unclear. In preclinical models of OUD, inhibition of the IC has produced conflicting results, such that in some cases the IC seems to promote opioid seeking whereas in others the IC seems to blunt opioid seeking. These results may be related to the heterogeneity of cortical output circuits, which can have opposing functions despite their relative proximity. Thus, here we examined the role of a specific IC output circuit, from the anterior IC (aIC) to the nucleus accumbens core (NAcc), for opioid seeking. We find in mice that following 14 days of heroin self-administration and 3 days of forced abstinence, optogenetic inhibition of aIC➔NAcc terminals suppresses context-associated opioid seeking. Furthermore, the same manipulation attenuates cued opioid seeking following extinction training. Importantly, we observed no effect of aIC➔NAcc terminal inhibition on sucrose seeking. Together, our results reveal that the IC selectively controls opioid seeking through a discrete population of NAcc projecting neurons, providing the first evidence for a projection-specific role of IC circuitry in opioid seeking and relapse.

Alcohol use disorder (AUD) is characterized by high relapse rates, and relapse is often driven by cue-induced cravings linked to prefrontal–subcortical network dysregulation. This study investigated the neurobiological effects of inhibitory continuous theta-burst stimulation (cTBS) targeting the right dorsolateral prefrontal cortex (rDLPFC) in patients with AUD. In a randomized, double-blind, sham-controlled trial, 28 patients (16 in the active cTBS group and 12 patients in the sham group) underwent 10 sessions of rDLPFC-cTBS. fMRI was performed before and after intervention to assess neural responses to alcohol cues, and relapse was monitored for 1 year. The active cTBS group exhibited a significantly lower relapse risk over the 12-month follow-up compared to the sham group (HR = 0.210, 95% CI [0.070, 0.633]). A significant group-by-intervention interaction was found in the right superior frontal gyrus (p = 0.047); active cTBS prevented the cue-induced hyperactivity that was observed in the sham group, suggesting a network stabilization effect. Furthermore, a machine learning model that was trained on intervention-induced changes in brain-wide neural activity accurately predicted long-term relapse (accuracy: 78.7%; AUC: 0.903). Increased postintervention reactivity to cues in the left medial prefrontal cortex was the strongest predictor of relapse. These findings demonstrate that rDLPFC-cTBS modulates craving-related circuits and that the dynamic neural response to treatment is a powerful biomarker for predicting relapse; the findings pave the way for the development of personalized addiction medicine.

Bromodomain and extra terminal domain (BET) epigenetic ‘reader’ proteins are key regulators of both behavioural and molecular responses to cocaine. In substance use disorder (SUD) models, BET function has primarily been investigated using small molecule inhibitors that prevent both bromodomains of BET proteins from interacting with acetylated histones. Although these inhibitors have been shown to be effective in SUD models, the potential adverse effects of pan-BET inhibition may restrict translational applications. Recently, RVX-208, a clinically tested and domain-selective BET inhibitor, was found to reduce cocaine conditioned responses and cocaine-induced gene expression in the nucleus accumbens (NAc), while avoiding the learning and memory impairments associated with pan-BET inhibitors. However, the effectiveness of RVX-208 in cocaine self-administration procedures remains unclear. Here, we investigated whether repeated RVX-208 treatment during abstinence altered cocaine-seeking behaviour in rats trained to self-administer cocaine. Male and female Sprague Dawley rats underwent 17 days of cocaine or sucrose self-administration, followed by daily treatment with vehicle or RVX-208 (25 mg/kg, ip) during a 14-day abstinence period. Rats in the RVX-208-treated group showed reduced lever pressing compared to vehicle controls. Sucrose-seeking and open field behaviour (distance travelled and time in the centre zone) were not significantly affected by RVX-208 treatment. Proteomic analysis of the NAc revealed that RVX-208 modulated several proteins, including those associated with dopamine activity (DRD1 and SLC6A3), transcriptional regulation (NFKB1), glutamate transport (SLC1A2) and ion channel activity (KCNJ10), and many changes were sex-dependent. Collectively, these findings indicate that domain-selective BET inhibition is effective at reducing cocaine-seeking behaviour and point to novel mechanisms that may contribute to its therapeutic effect.