Addiction Biology最新文献

Drinking as a coping method in response to pain is a complex behaviour, involving multiple neural, motivational, and psychological factors. Among these factors, pain sensitivity and pain-related drinking motive can significantly promote alcohol use. In contrast, proactive avoidance – a beneficial strategy of initiating overt actions to avoid negative outcomes – reduces harmful consumption. Yet, these factors have not been assessed as potential predictors of future drinking behaviour. Here, in a longitudinal study we collected fMRI data in 50 drinkers who, at baseline, performed a probabilistic learning go/nogo task that involved proactive avoidance of painful electric shocks. Pain-related psychological measures and the neural correlates of proactive avoidance were examined in relation to participants' alcohol use and craving in the following 12 months. We found that deficits in proactive avoidance were associated with future drinking severity. Importantly, diminished activation of the dorsal anterior cingulate cortex (dACC) during proactive avoidance also predicted subsequent percentage of heavy drinking days. Using Bayesian network modelling, we established a potential pathway in which drinkers' heightened pain sensitivity led to greater pain-avoidance drinking motive and alcohol craving. Both craving and weakened dACC activation to proactive avoidance predicted higher levels of drinking during the follow-up period. Taken together, our study identified pain sensitivity, pain-avoidance drinking motive, and impaired proactive avoidance as predictors of future alcohol use severity. These findings highlight the roles of pain response, thus potentially informing interventions for individuals at risk of alcohol use disorders.

The relationship between stress, hair cortisol and alcohol consumption has mostly been investigated among clinical and adult study samples, with inconsistent findings. The present study aimed to examine cross-sectional and longitudinal associations between chronic stress, hair cortisol and average past-year alcohol consumption within a population-based sample of adolescents and young adults. At baseline of the epidemiological cohort study, N = 1180 individuals aged 14–21 from Dresden, Germany, were assessed (11/2015–12/2016). A maximum N = 1055 were analysed in cross-sectional analyses and a maximum N = 722 in longitudinal analyses (1-year follow-up). Multivariate linear regression analyses were conducted to reveal cross-sectional associations between perceived chronic stress, hair cortisol concentration and average past-year alcohol consumption in males and females. Longitudinally, weighted linear regression models examined relationships between (a) perceived chronic stress at baseline and altered hair cortisol concentration over 1 year, (b) perceived chronic stress/hair cortisol concentration at baseline and altered average alcohol consumption over 1 year and (c) average past-year alcohol consumption at baseline and altered stress/hair cortisol concentration over 1 year. Cross-sectionally, no significant relationships were found between stress, hair cortisol and average past-year alcohol consumption at baseline. In females, higher baseline perceived chronic stress was associated with an increase in hair cortisol concentration over 1 year, whereas no relationship was found in the cross-sectional analysis between baseline perceived chronic stress and baseline past-year average alcohol consumption. When using hair cortisol as a biomarker for stress perception, the focus of future research should be on potential time lags between perceived chronic stress and hair cortisol increase.

Oligodendrocytes are a key cell type within the central nervous system (CNS) that generates the myelin sheath covering axons, enabling fast propagation of neuronal signals. Alcohol consumption is known to affect oligodendrocytes and white matter in the CNS. However, most studies have focused on foetal alcohol spectrum disorder and severe alcohol use disorder. Additionally, the impact of alcohol dosage on oligodendrocytes has not been previously investigated. In this study, we evaluated transcriptomic changes in C57BL6/J cultured mature oligodendrocytes following exposure to moderate and high concentrations of alcohol. We found that high concentrations of alcohol elicited gene expression changes across a wide range of biological pathways, including myelination, protein translation, integrin signalling, cell cycle regulation and inflammation. Further, our results demonstrate that transcriptomic changes are indeed dependent on alcohol concentration, with moderate and high concentrations of alcohol provoking distinct gene expression profiles. In conclusion, our study demonstrates that alcohol-induced transcriptomic changes in oligodendrocytes are concentration-dependent and may have critical downstream impacts on myelin production. Targeting alcohol-induced changes in cell cycle regulation, integrin signalling, inflammation or protein translation regulation may uncover mechanisms for modulating myelin production or inhibition. Furthermore, gaining a deeper understanding of alcohol's effects on oligodendrocyte demyelination and remyelination could help uncover therapeutic pathways that can be utilized independently of alcohol to aid in remyelinating drug design.

Alcohol use disorder is a severe mental health condition causing medical consequences and preterm death. Alcohol activates the mesolimbic dopamine system leading to an increase of extracellular dopamine (DA) in the nucleus accumbens, an event that is associated with the reinforcing effects of alcohol. Cholinergic interneurons (CIN) are important modulators of accumbal DA signalling, and depletion of accumbal CIN attenuates the alcohol-induced increase in extracellular DA. The aim of this study was to explore the functional role of accumbal CIN in alcohol-related behaviour. To this end, ablation of CIN was induced by local administration of anticholine acetyltransferase-saporin bilaterally into the nucleus accumbens of male Wistar rats. Alcohol consumption in ablated and sham-treated rats was studied using a two-bottle-choice intermittent alcohol consumption paradigm. Rats with depleted CIN consumed significantly less alcohol than sham-treated controls. No differences in sucrose preference, motor activity, water intake or weight gain were noted between treatment groups, suggesting that the ablation selectively affected alcohol-related behaviour. In conclusion, this study further supports a role for accumbal CIN in regulating alcohol-consummatory behaviour.

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 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.

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 human brain consists of functionally segregated networks, characterized by strong connections among regions belonging to the same network and weak connections between those of different networks. Alcohol use disorder (AUD) is associated with premature brain aging and neurocognitive impairments. Given the link between decreased brain network segregation and age-related cognitive decline, we hypothesized lower brain segregation in patients with AUD than healthy controls (HCs). Thirty AUD patients (9 females, 21 males) and 61 HCs (35 females, 26 males) underwent resting-state functional MRI (rs-fMRI), whose data were processed to assess segregation within the brain sensorimotor and association networks. We found that, compared to HCs, AUD patients had significantly lower segregation in both brain networks as well as poorer performance on a spatial working memory task. In the HC group, brain network segregation correlated negatively with age and positively with spatial working memory. Our findings suggest reduced brain network segregation in individuals with AUD that may contribute to cognitive impairment and is consistent with premature brain aging in this population.

Pain and alcohol use disorder (AUD) frequently co-occur, but the underlying neurobiology is not well-understood. Although many studies have reported disruptions in stress and reward cue-elicited neural reactivity and heightened alcohol craving in individuals with AUD, little is known about these constructs among patients who experience pain. Here, individuals with pain (Pain+, n = 31) and without pain (Pain−, n = 37) completed a well-validated functional magnetic resonance imaging (fMRI) paradigm involving stress (S), alcohol (A) and neutral (N) cue exposure with repeated alcohol craving assessments. Using whole-brain, voxel-based analyses (p < 0.001, whole-brain cluster correction at α < .05), the Pain+ versus Pain− group evidenced greater dorsal anterior cingulate cortex and left amygdala hyperactivation during N, but hypoactivation during the S-N contrast. Additionally, Pain+ exhibited blunted right anterior insular cortex (AIC) during S-N and blunted anteromedial thalamus and left AIC with hyperactive orbitofrontal cortex (OFC) during A-N. Exploratory analyses further revealed that individuals with pain and AUD (n = 17) relative to pain alone (n = 14) showed hyperactive bilateral AIC and hypoactive right dorsal caudate during A-N. Alcohol cue-induced craving, significantly higher in Pain+ (p = 0.03), correlated with blunted right AIC and OFC responses during A-N. In sum, these results provide first evidence of heightened alcohol cue-elicited craving and disrupted stress- and alcohol cue-reactivity within corticostriatal-limbic regions implicated in negative affect and preoccupation/anticipation stages of AUD in those with pain and with comorbid pain and AUD. Future investigations of pain-AUD interaction are needed that include systematic pain assessment and longitudinal designs with larger sample sizes.