Repetitive drug use results in enduring structural and functional changes in the brain. Addiction research has consistently revealed significant modifications in key brain networks related to reward, habit, salience, executive function, memory and self-regulation. Techniques like Voxel-based Morphometry have highlighted large-scale structural differences in grey matter across distinct groups. Source-based Morphometry (SBM) takes this a step further by incorporating the Independent Component Analysis to detect shared patterns of grey matter variation, all without requiring prior selection of regions of interest. However, SBM has yet to be employed in the study of structural alteration patterns related to cocaine addiction. Therefore, we performed this analysis to explore alterations in structural covariance specific to cocaine addiction. Our study involved 40 individuals diagnosed with Cocaine Use Disorder (CUD) and 40 matched healthy controls. Participants with CUD completed clinical questionnaires assessing the severity of their dependence and other relevant clinical variables. Following the adjustment for age-related effects, we observed notable disparities between groups in two structural independent components, which we identified as the structural cerebellar network and the structural lateral frontoparietal network, which display opposing trends. Specifically, the individuals with CUD exhibited a heightened contribution to the cerebellar network but simultaneously demonstrated a reduced contribution to the lateral frontoparietal network compared to the healthy controls. These findings unveil distinctive covariance patterns of neuroregulation linked with cocaine addiction, which indicates an interruption in the typical structural development in an affected lateral frontoparietal network, while suggesting an extended pattern of neuroregulation within the cerebellar network in individuals with CUD.

Ketamine abuse damages brain function and structure, increasing reactive oxygen species and apoptosis in the cerebral cortex, but moderate-intensity continuous training (MICT) can enhance antioxidant defences and reduce apoptosis. Therefore, we aimed to answer whether MICT can reduce the side effects of chronic ketamine abuse. 24 Wistar rats were split into control (CON), ketamine abuse (KET), exercise after ketamine withdrawal (KET + EX), and non-intervention ketamine withdrawal (KET + WD) groups. Ketamine intervention groups received 50 mg/kg/day ketamine for 8 weeks; KET + EX underwent 5 MICT sessions/week at 60-75% VO2max for 8 weeks post-withdrawal. Post-sampling of cerebral cortex, we evaluated histological changes, apoptotic cell numbers, Bax, Bcl-2, Caspase-3 mRNA/protein, 8-oxo-2'-deoxyguanosine (OXO) expression, glutathione peroxidase (GPX) and glutathione reductase (GR) mRNA and other oxidative stress and antioxidant markers levels. Effect sizes (ES) were used to assess group differences. MICT significantly reduced apoptotic cells (ES = 14.24, p < 0.0001), decreased Bax and caspase-3 protein expression, and increased Bcl-2 compared to the KET group (Bax: ES = 2.77, p = 0.005; caspase-3: ES = 7.73, p < 0.0001; Bcl-2: ES = 12.11, p < 0.001). It also lowered Bax and caspase-3 mRNA (Bax: ES = 4, p = 0.014; caspase-3: ES = 2.29, p = 0.024). MICT reduced OXO and increased GR and GPX mRNA and nitric oxide (NO) level (GR: ES = 2.02, p = 0.016; GPX: ES = 1.98, p = 0.035; OXO: ES = 11.39, p < 0.0001; NO: ES = 3.52, p = 0.003). Levels of malondialdehyde, myeloperoxidase, glutathione, superoxide dismutase, and catalase remained unchanged between groups. MICT seems effective in reducing apoptosis and oxidative damage in the cerebral cortex of rats with long-term ketamine abuse.

ABSTRACTNonneuronal cells mediate neurotransmission and drug addiction. However, the role of oligodendrocytes in stress‐induced cocaine relapses remains unclear. In the present study, we investigated the role of the oligodendrocyte‐abundant molecule crystallin alpha B (CRYAB) in cocaine‐induced conditioned place preference (CPP) relapsed by restraint stress. RNA sequencing (RNA‐seq) was performed to identify oligodendrocytes and stress‐associated molecules in the nucleus accumbens (NAcc) of both drug users and cocaine‐treated animals. Further, we studied which cell subtypes in the brain express CRYAB. The effects of stress hormones and cocaine on CRYAB expression were evaluated in vitro in human oligodendrocytes. CRYAB is upregulated in the NAcc of both cocaine‐treated animals and drug users. CRYAB levels in the NAcc of mice increased during CPP development but decreased following stress‐induced relapse. Interestingly, CRYAB is expressed in oligodendrocytes in the NAcc of mice. Extracellular CRYAB levels are regulated by cocaine and stress hormone treatments in oligodendrocyte cultures. Dopamine levels in the NAcc and CPP development of CPP are significantly increased by cocaine in CRYAB knockout (KO) mice. Further, we demonstrated that CRYAB binds to the excitatory amino acid transporter 2 (EAAT2) in the NAcc of mice treated with cocaine. We suggest that oligodendrocyte‐derived CRYAB regulates dopamine neurotransmission and stress‐evoked cocaine reward behaviour via the modulation of EAAT2 in the NAcc.

One of the many human capabilities acquired during adolescence is the adaptivity in changing environments. In this longitudinal study, we investigated this adaptivity, as measured by probabilistic reversal learning (PReL) tasks, in N = 143 adolescents at ages 14, 16 and 18. Computational modelling and functional magnetic resonance imaging were applied to identify the neurocognitive processes underlying reversal learning and its development. Previous studies have demonstrated a correlation between heavy alcohol use and impaired reversal learning. Our hypothesis was that PReL is negatively associated with current and future alcohol use and that alcohol use impairs PReL by altering neurocognitive processes. Behaviourally, PReL performance improved, which was associated with a lower probability of switching choices and was considered an adaptive process. Computationally, this was accounted for by higher learning rates, enhanced sensitivity to wins and reduced sensitivity to losses in older adolescents. Alcohol consumption increased but remained at a low level for most participants. More risky drinking was associated with less medial frontal activity elicited by reward prediction errors. These findings suggest that reversal learning may be more relevant for the maintenance or escalation of risky than for low-level drinking. Challenges and potential solutions for longitudinal studies such as reliability are discussed.

Addictive behaviour is shaped by the dynamic interaction of implicit, bottom-up and explicit, top-down cognitive processes. In alcohol use disorder (AUD), implicit alcohol-related associations have been shown to predict increased subsequent alcohol consumption and are linked to the risk of relapse. Explicit cognitive processes, exerting prefrontal top-down control, are particularly significant during the critical period following the decision to abstain. This study aims to map implicit and explicit cognitive processes in recently abstinent individuals with AUD and to explore the effect of cathodal transcranial direct current stimulation (tDCS) on implicit associations by modulating top-down control. In this preregistered, double-blind, sham-controlled clinical trial, 30 abstinent individuals with AUD participated in two experimental sessions. They received either 2 mA cathodal tDCS to the left dorsolateral prefrontal cortex (dlPFC) or sham tDCS in a crossover design. During tDCS, participants completed the alcohol approach implicit association test (IAT) and the drinking identity IAT, along with two control tasks. Additionally, we collected explicit ratings of the IAT stimuli and assessed craving before and after each experimental session. Preregistered ANOVAs revealed significant implicit alcohol-avoidance and non-drinking identity biases. Cathodal tDCS did not modulate IAT scores. Explicit ratings showed a preference for non-alcoholic drinks and non-drinking identity, correlating moderately with IAT scores. Exploratory analyses indicated that cathodal tDCS mitigated the increase in nicotine craving during the experimental session. This preregistered clinical trial provides robust evidence that single-session cathodal tDCS to the left dorsolateral prefrontal cortex does not modulate implicit associations in AUD, with Bayesian analyses corroborating the absence of tDCS effects. Our results emphasize the impact of contextual factors on the interplay between explicit and implicit cognitive processes and underscore the importance of investigating multisession stimulation paradigms in future research.

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.

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.

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.