Addiction Biology最新文献

Although substance use is associated with a shortened lifespan, impeded health and accelerated biological ageing, the factors contributing to the associations between substance use and ageing are poorly understood. We used summary statistics from genome-wide association studies (GWAS) to investigate whether substance involvement (N from 28K to 2M)—including alcohol, tobacco, cannabis and opioid use and use disorders—is genetically correlated with various ageing metrics (N from 162K to 2.7M) and whether these correlations reflect shared genetic etiologies or putative causal relationships. Using Linkage Disequilibrium Score Regression (LDSC), we found widespread evidence of genetic correlations between substance use/use disorders and indices of physical, cognitive and biological ageing. We then employed a series of Mendelian randomization–based approaches, finding significant causal effects of genetic predispositions to both tobacco use disorder and quantity of tobacco smoked on various markers of ageing. Causal effects of problematic alcohol use and cannabis use disorder were also found, though findings were mixed. Evidence of reverse causality (i.e., ageing causing substance use), meanwhile, was scant. Collectively, these results demonstrate strong triangulation across approaches and highlight the importance of integrating genetic insights into public health strategies for reducing the burden of SUDs across the lifespan.

Alcohol misuse impairs sleep quality and circadian rhythms. Yet, sleep is essential, as a lack of sleep is a predictive factor for addiction and relapse risk in patients with alcohol use disorder (AUD). On the contrary, effective insomnia treatment after withdrawal increases abstinence. Meanwhile, physical activity (PA) has been shown to improve sleep quality and circadian rhythms in nonclinical population. Hence, it would be interesting to assess the impact of PA on sleep in alcohol users with and without dependence. Systematic search was conducted using Prisma guidelines for the screening and ROB-1 for bias analysis of randomized controlled trial (RCT). Out of 4995 studies screened, none assess as main purpose the impact of PA on sleep in alcohol users. Still, 81.8% of the selected studies, in their secondary outcomes, highlight PA's positive association with sleep in alcohol users with or without dependence. Main positive sleep outcomes were insomnia and sleep fragmentation reduction as well as sleep quality and duration improvement. There is a lack of publication regarding the impact of PA on sleep in nonclinical alcohol users and AUD patients. Still, PA appears to enhance sleep in both populations. Further well-designed RCTs are needed to produce robust data. In the first instance, feasibility study should be performed as adhesion can be an issue in the population. Finally, different PA programs (frequency, intensity, time, type and duration) should be compared to determine the optimal dose in different AUD status (intoxication, withdrawal and abstinence).

Evidence from human self-report and rodent models indicate that cocaine can induce a negative affective state marked by panic and anxiety, which may reduce future cocaine use or promote co-use with opiates. Dynorphin-mediated signalling within the striatum is associated with negative affect following cocaine withdrawal and stress-induced cocaine seeking. Here, we used a trace conditioning procedure to first establish the optimum parameters to capture this transient cocaine negative affective state in wild-type mice, and then we investigated striatal opioid peptides as a substrate mediating cocaine conditioned place avoidance (CPA). Previous reports indicate that trace conditioning, where drug administration occurs after removal from the conditioning chamber, results in CPA to ethanol, nicotine and amphetamine. We tested different cocaine doses, conditioning session lengths and apparatus types to determine which combination yields the best cocaine CPA. Cocaine CPA was moderately larger at the highest cocaine dose (25 mg/kg), but this did not generalize across apparatus types and the effect was transient; thus, data were collapsed across all parameters. Cocaine conditioning scores were variable but also became more polarized across conditioning, with approximately equal proportions developing preference and avoidance. We then correlated cocaine CPA with striatal gene expression levels of the opioid peptides enkephalin (Penk) and dynorphin (Pdyn) using qPCR. Cocaine CPA was correlated with low Pdyn levels and a low Pdyn:Penk ratio in the ventral, but not dorsal, striatum. Consistent with this, mice with higher striatal Pdyn relative to Penk were more resistant to developing cocaine CPA compared with littermate controls. This approach revealed a subset of subjects sensitive to the aversive state immediately following cocaine administration. Our findings suggest that striatal dynorphin has opposing roles in mediating the aversion associated with acute cocaine intoxication versus cocaine withdrawal.

4-hydroxyindole-3-acetic acid (4-HIAA) is a metabolite of psilocin. Here, we explored the ability of 4-HIAA to cross the blood–brain barrier and its potential effects on methamphetamine (METH)-induced conditioned place preference (CPP) in mice. Treatment with 1-mg/kg 4-HIAA inhibited CPP formation during the acquisition phase, promoted METH extinction and inhibited METH relapse. Furthermore, the regulatory effect of 4-HIAA on METH was underscored by altered 5-HT expression in the nucleus accumbens. Collectively, our findings provide novel insights into the molecular mechanisms of the 4-HIAA-induced blockade of the acquisition, extinction and reinstatement of METH-induced CPP.

Studies investigating proteomic associations with alcohol consumption and the genetic links of these proteins to alcohol-related traits are scarce. The aims of our study were (1) to identify proteins associated with alcohol consumption and (2) to investigate the molecular pathways and genetics linking the identified proteins to alcohol consumption and related sociomedical conditions. We generated proteomic and genotypic data from blood samples of 387 Finnish twins (age range: 56–70) and calculated polygenic risk scores (PRSs) of eight alcohol-related traits: obesity, alcohol dependence, number of drinks per week, number of cigarettes per day, major depressive disorders (MDDs), schizophrenia, externalising behaviour and educational attainment. We identified 20 (out of 2321) proteins associated with alcohol consumption, expressed as log ethanol grams per month, after Bonferroni correction and adjustment for BMI, sex and age. Within-pair analyses in monozygotic twin pairs showed that some of the identified associations persisted after accounting for genetic confounding. While only the PRS representing genetic risk for the number of alcoholic drinks per week was associated with alcohol consumption, several proteins were associated with PRSs, in particular the PRS of MDD. All identified proteins were significantly replicated in the UK Biobank, and pathway analysis suggested their collective connection to alcohol consumption might be explained by oxidative stress and cell damage. In conclusion, we identified several alcohol-associated plasma proteins whose levels are also linked to genetic risk for mental illness and substance use. Our study suggests the potential of proteins as biomarkers for early detection of alcohol-related disorders.

Opportunistic interventions (OIs) are health events facilitated by healthcare providers through education that can motivate individuals to adopt risk-reducing behaviours. Our aim was to evaluate transient elastography (TE) as an OI in patients with AUD by assessing changes in validated psychometric scores (PS) of alcohol insight and readiness for change. In this prospective, proof-of-concept pilot study, patients with AUD without TE in the past year were enrolled from an inpatient addiction unit. At baseline, three PS assessing insight and readiness to change were administered: Hanil Alcohol Insight Scale (HAIS), revised Readiness Ruler (RR) and Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES-8A). TE was performed, interpreted, and followed by repeat PS testing. The primary outcome was change in PS. Secondary outcomes were prevalence of fibrosis and steatosis on TE, alcohol use and linkage to hepatology care. From 4 January 2022 to 4 January 2023, 23 patients were enrolled: mean age: 51 years (SD ± 12), 74% male, 61% White and all with severe AUD, and mean of 20 (± 9) daily drinks, 286 g (± 127 g) or 35.7 (± 15.9) units of alcohol, for a median of 14 years (IQR 10–21.5). After TE, there were significant increases in revised RR and SOCRATES-8A from 5 to 8.6 (± 2.1, p < 0.01) and 81.5 to 85.0 (± 8.0, p = 0.04), respectively, indicating improved motivation and readiness for change. HAIS did not change: 11.1–11.0 (± 3, p = 0.36). Cirrhosis and steatosis grade ≥ 2 were detected in 4/23 (17%) and 8/23 (35%), respectively. In this pilot study, performing and interpreting results of TE to inpatients with AUD increase readiness for change and efficiently detects advanced fibrosis.

Cigarette smoking is the single most significant cause of preventable death in the world. Tobacco smoking causes exposure to thousands of chemicals and disrupts biological pathways. It impacts several organs, including the brain, where its effects are mediated by nicotinic acetylcholine receptors. Women seem to be more susceptible to the negative health effects of smoking. In this study, we focused on the changes in the metabolic profile of human postmortem frontal cortex and cerebrospinal fluid (CSF) samples associated with high levels of the nicotine metabolite cotinine. We used non-targeted metabolomics to analyse post-mortem frontal cortex and CSF samples from the Tampere Sudden Death Study cohort. We identified 137 cases (24 females) with high cotinine levels, indicating nicotine exposure. For controls, we identified 82 subjects (20 females) with no cotinine in the frontal cortex or CSF samples and no known history of smoking based on medical records and autopsy reports. Cases had significantly higher levels of 1-methylhistamine (Cohen's d = 0.66, p < 0.0001) and N-acetylputrescine (d = 0.84, p < 0.0001), and lower levels of aspartic acid (d = −0.53, p < 0.001), 3-methylhistidine (d = −0.58, p = 0.0004) and taurine (d = −0.47, p = 0.0002) in the frontal cortex compared to controls. Compared to the frontal cortex, differences between cases and controls were smaller in the CSF samples. Most of the observed differences were similar in both sexes, with a few exceptions like low ergothioneine levels, observed especially in female cases. In conclusion, smoking or nicotine exposure is associated with alterations in metabolites linked to increased oxidative stress and neuroinflammation, as well as reduced neurotransmitter levels in the frontal cortex.

Post-retrieval interventions based on memory reconsolidation have shown promise in reducing addiction-related memories. However, research on methamphetamine (MA) use, particularly in humans, remains limited. This study aimed to evaluate the efficacy of a post-retrieval intervention paradigm in managing methamphetamine use disorder (MUD) with 46 individuals from a compulsory drug rehabilitation centre. A single-blind design was employed, with participants randomly assigned to one of three groups: (1) retrieval–no intervention, (2) retrieval–extinction and (3) retrieval–cognitive task. The study involved baseline testing, followed by memory retrieval using MA cues, and one of the three interventions during the memory reconsolidation window. The interventions were as follows: (1) no further intervention after retrieval, (2) extinction training and (3) playing Tetris after memory reactivation. Relapse was assessed through physiological and psychological indicators, with a focus on both spontaneous and cue-induced relapse of MUD memory. The results showed that both retrieval–extinction and retrieval–cognitive task showed benefits in reducing cravings and preventing relapse in MUD compared to retrieval alone. Physiological and psychological indicators of MA memory relapse showed weak correlation and differed across several dimensions. These findings suggest new strategies for MUD intervention and provide valuable insights for clinical treatment. Limitations of the study are also discussed.