Addiction Biology最新文献

The cannabinoid receptor 1 (CB1R) in the hippocampus has been involved in impulsivity and alcohol consumption in adolescent rats. However, the role of CB1R in the cerebellum, despite that structure's exceptionally high CB1R density, remains unexplored. We therefore tested the hypothesis that cerebellar CB1R contributes to regulating impulsive behaviour, alcohol consumption and seeking. Male Wistar rats, adolescent (PND25), adult (PND90) and aged (PND365), were assessed on the delay discounting task (DDT) and for voluntary alcohol intake-conditioned place preference (ACPP). CB1R levels were quantified via immunofluorescence in the CRUS II and interposed nucleus. Separate cohorts were used for voluntary alcohol consumption and alcohol-conditioned place preference (ACPP). Results showed that adolescent rats displayed significantly greater impulsivity and alcohol consumption than adults and aged rats, and only adolescents developed ACPP. CB1R expression peaked in adolescents across both cerebellar regions, but only Crus II levels correlated positively with impulsivity (k value), indicating a region- and age-specific contribution. These data reveal, for the first time, that CB1R in cerebellar Crus II selectively underpins adolescent impulsive choice and alcohol consumption and seeking, highlighting both a novel brain locus and a critical developmental window for endocannabinoid modulation.

Alcohol urge regulation, drug urge regulation, motivational attitudes and alcohol expectancies have been linked to substance use, but their combined influence on reward sensitivity and behaviour remains underexplored. This is particularly critical during adolescence and young adulthood, a period of heightened susceptibility to alcohol use and risky behaviours. Using data from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), an accelerated longitudinal design that includes all age groups at each time point, this study examined how these factors interact to shape substance use behaviours, including the onset of regular drinking, binge drinking, drug use and sexual intercourse. Exploratory and confirmatory factor analyses (EFA/CFA) utilized data from Years 7 to 9, comprising 430 participants across all age groups, to identify latent incentive-salience constructs related to urge regulation, motivational attitudes and alcohol expectancies, with a split-sample approach used to validate the factor structure in a mature cohort. Structural equation modelling (SEM) employed longitudinal data from Year 5 predictors and demographic controls to examine outcomes assessed in Year 6, leveraging the developmental focus of this age range. Covariates included age, sex and socio-economic status. EFA/CFA confirmed a robust latent structure, and SEM revealed that alcohol urge regulation significantly predicted past-year binge drinking, while drug urge regulation was negatively associated with total drug use but had no significant effect on alcohol-related behaviours. Alcohol expectancies and demographic factors, such as older age and male sex, were significantly associated with increased substance use, while socio-economic status further influenced these outcomes. Findings highlight the critical role of incentive salience in youth substance use and suggest that prevention strategies should target individual risk factors and demographic influences. Early education and supportive policies may reduce early substance use and its associated harms.

This study aimed to investigate whether structural brain alterations in smokers are accompanied by synchronized changes in functional connectivity, with a focus on understanding the neural mechanisms underlying smoking addiction. We conducted a meta-analysis of voxel-based morphometry (VBM) studies using the Seed Mapping software package to identify consistent grey matter changes in smokers' brains, which were subsequently defined as regions of interest (ROIs). Resting-state functional connectivity between these ROIs and whole-brain voxels was analysed in 53 male smokers and 38 non-smokers. Additional correlation analyses were performed to assess relationships with clinical features. Smokers exhibited reduced functional connectivity between the right lingual gyrus (which showed increased grey matter volume) and the left calcarine sulcus. The right superior frontal gyrus (with decreased grey matter volume) suggested diminished functional connectivity with multiple regions, including the bilateral precentral and postcentral gyrus, left rolandic operculum, left inferior frontal gyrus (opercular part), left midcingulate cortex, bilateral supplementary motor area, left paracentral lobule, right inferior frontal gyrus (triangular part) and right middle frontal gyrus (GRF corrected, voxel-level p < 0.001, cluster-level p < 0.05). Notably, reduced connectivity of some brain regions to the right superior frontal gyrus was negatively correlated with the Fagerström Test for Nicotine Dependence (FTND). Our findings demonstrate that structural brain alterations in smokers are associated with specific disruptions in functional connectivity, particularly within visual attention, executive control and sensorimotor networks. These results provide additional evidence of the neuropathophysiological mechanisms underlying smoking addiction.

Both epidemiological and Mendelian randomization (MR) studies have confirmed the association between smoking and psychiatric disorders, yet the underlying mechanism remains poorly understood. To address this gap, this study aimed to evaluate causal relationships between smoking, brain structural alterations, and psychiatric disorders and to identify genetic and neuroimaging mediators. We analysed summary data from the genome-wide association study (GWAS) and multimodal neuroimaging data, using linkage disequilibrium score regression (LDSC) to quantify genetic correlations and two-sample bidirectional MR to assess causality between smoking and three psychiatric disorders: schizophrenia (SCZ), major depressive disorder (MDD) and bipolar disorder (BD). Additionally, we conducted mediation analysis to identify brain structural mediators and colocalization and pathway analyses to elucidate shared genetic architecture. LDSC analysis revealed significant genetic correlations between smoking and MDD (r_g = 0.41), SCZ (r_g = 0.16) and BD (r_g = 0.15). Consistently, bidirectional MR confirmed a bidirectional causal relationship between smoking and SCZ/MDD and a unidirectional causal effect of smoking on BD. Mediation analysis further revealed that microstructural disorganization in the left uncinate fasciculus mediated 19.6% (95% CI: 3.36%-35.8%) of the effect of smoking on MDD risk. Moreover, colocalization analysis implicated SH2B2 as a pleiotropic locus linking UF orientation dispersion (OD) to prefrontal–amygdala gene expression, suggesting that smoking may exacerbate corticolimbic dysfunction by inducing SH2B2 hypermethylation. Taken together, our findings establish smoking as a causal risk factor for SCZ, MDD and BD, with corticolimbic white matter degeneration serving as a key mediator, and they highlight the SH2B2-TrkB axis as a mechanistic conduit for genetic and environmental risk, pointing to therapeutic targets to disrupt smoking related psychiatric disorders.

Dopamine D2 receptor (D2R)-mediated signalling is involved in reward, motivation and alcohol use disorder. Perturbation of the D2R system may influence an individual's response to alcohol. Alternative splicing of the D2R gene generates two isoforms: D2 long form (D2L) and D2 short form (D2S). It is unclear whether differences in the expression of D2L and D2S influence alcohol's effects. Here we examined if altered expression levels of either D2R isoform would influence alcohol effects on reward-related behaviour and relevant signalling pathways using knockout (KO) mice expressing either D2R isoform. We found that D2L KO mice (expressing only D2S) displayed a strong alcohol conditioned place preference (CPP) compared to WT mice and D2S KO mice (expressing only D2L). Alcohol exposure caused a downregulation of cannabinoid 1 receptors (CB1R) expression but an upregulation of cannabinoid 2 receptors (CB2R) expression in the striatum of D2L KO mice but not in WT and D2S KO mice. In addition, alcohol exposure resulted in decreased Akt phosphorylation selectively in D2L KO mice. Furthermore, the gene expressions of tyrosine hydroxylase (TH), Arc and RETN were also selectively downregulated in D2L KO mice following chronic alcohol exposure. Our results indicated that an alteration in the expression of D2S vs. D2L had significant impacts on alcohol-induced reward and gene expression changes in the striatum. These findings suggest that the increased expression level of D2S to D2L may be a pathophysiological mechanism for developing alcoholism, possibly through triggering a cascade of changes in the cannabinoid-Akt signalling pathway and relevant signalling network.

Alcohol misuse remains a leading cause of preventable death worldwide, prompting research into novel pharmacotherapies for alcohol use disorder (AUD). This study investigated the therapeutic potential of full agonism or positive allosteric modulation of the serotonin 2C receptor (5-HT_2CR) in addressing alcohol binge drinking and seeking behaviours in mice. Using a drinking-in-the-dark paradigm and a context-induced reinstatement model following punishment-imposed abstinence, we assessed the acute effects of 5-HT_2CR ligands lorcaserin, CYD-1-79, VA012 and CTW0415 on alcohol intake and seeking behaviours in mice. Results showed that while lorcaserin effectively reduced both alcohol consumption and seeking behaviours, the 5-HT_2CR positive allosteric modulators (PAMs) did not significantly alter these behaviours over the range of doses examined. These findings suggest that 5-HT_2CR PAMs, at the tested doses, may lack intrinsic efficacy in modulating alcohol use. However, our lorcaserin data demonstrate that targeting 5-HT_2CR remains a valid approach to reduce behaviours associated with AUD.

Problematic use of short video (PUSV) refers to a psychological dependency on short-video applications, characterized by an intense attachment and inability to control usage, resulting in typical addiction symptoms. Although PUSV shares similarities with substance addiction, its clinical presentation exhibits significant differences. Notably, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the International Classification of Diseases, 11th Revision (ICD-11), have not yet officially classified PUSV as an addiction disorder. However, the profound impact of short-video platforms on individuals' physical, mental and daily lives necessitates attention to PUSV. To enable more in-depth and standardized research on this issue, synthesizing and organizing existing studies on its theoretical foundations and mechanisms is crucial. This paper aims to integrate and evaluate existing research on PUSV from four perspectives: qualitative analysis, underlying mechanisms, negative effects and measurement tools, providing a more systematic understanding and approach to this emerging issue.

This narrative review examines recent advances in understanding the epigenetic and transcriptional dynamics of the central–medial amygdala across different stages of ethanol use. It covers the various models and protocols of ethanol administration, emphasizing their strengths and limitations in helping understand ethanol-induced changes in brain and behaviour. The findings from protocols utilizing acute, chronic-intermittent ethanol (CIE) and chronic-continuous ethanol (CCE) exposure are summarized into a proposed mechanism of epigenetic dysregulation and neuroadaptation, spanning from initial ethanol exposure to withdrawal and its influence on gene expression and neuronal activity. This review also explores potential epigenetic targets for therapeutic intervention. Understanding the mechanisms that underlie histone remodelling during initial ethanol exposure, chronic exposure, and withdrawal has the potential to elucidate novel cessation strategies tailored to specific stages of alcohol use disorder (AUD).