Valproate may hold promise as a treatment for addiction. However, there are limited studies examining the effects of magnesium valproate (VPA-Mg) on methamphetamine (MA) addiction, and the relevant mechanisms have not been thoroughly discussed. This study aims to explore the potential therapeutic effects of VPA-Mg on MA addiction and to investigate its possible mechanisms. The effects of VPA-Mg on MA addiction were investigated using conditioned place preference (CPP) and behavioural sensitisation models in rats. VPA-Mg was administered during CPP formation and extinction phases to evaluate its effects on MA-induced CPP formation and reinstatement. Behavioural sensitisation assessed the impact of VPA-Mg during sensitisation induction and expression phases, with spontaneous activity and MA dosing optimised beforehand. Furthermore, western blotting was performed on brain regions including the prefrontal cortex (PFC), hippocampus (Hip), nucleus accumbens (NAc) and ventral tegmental area (VTA) to measure glycogen synthase kinase 3 beta (GSK-3β) and dopamine transporter (DAT) protein levels. VPA-Mg did not exhibit a significant impact on MA-induced CPP formation. VPA-Mg significantly reduced the establishment and expression of MA-induced behavioural sensitisation (p < 0.01). Pre-treatment with VPA-Mg for 3 days before the expression period also inhibited sensitisation (p < 0.05). In addition, the ratio of p-GSK-3β to t-GSK-3β in the PFC, Hip and VTA of rats with behavioural sensitisation significantly decreased, and the expression of DAT decreased significantly (p < 0.01). VPA-Mg can reverse the increase in GSK-3β activity in the Hip and the decrease in DAT in the PFC and Hip caused by repeated MA use (p < 0.05). VPA-Mg exhibits anti-addictive effects on MA dependence and relapse prevention. GSK-3β activation and DAT downregulation in addiction-related brain regions (PFC, Hip, VTA) are closely linked to MA addiction, suggesting potential therapeutic targets. VPA-Mg may exert its effects by modulating these pathways, particularly in the PFC and Hip.
Unique populations of basolateral amygdala (BLA) neurons regulate anxiety and reward through projections targeting downstream regions like the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAC). We showed previously that withdrawal from chronic ethanol exposure (CIE/WD) produced population- and sex-specific alterations to distinct glutamatergic inputs. The current study examined GABAergic function in these distinct populations (BLANAC and BLABNST neurons). We found that CIE/WD diminished feed-forward GABA release from lateral paracapsular cells (LPCs) specifically onto male BLANAC neurons. Pharmacological manipulations showed this dysregulation was caused by the enhanced activity of μ-opioid receptors. CIE/WD did not alter evoked GABA release from local interneurons onto either population. However, females expressed greater GABA release from these local interneurons compared to males. Immunostaining and confocal microscopy revealed lower colocalization between the GABA vesicular transporter, vGAT and parvalbumin in females, indicating that greater GABA releases from local interneurons in this sex may be a compensatory response to lower levels of perisomatic innervation by PV+ interneurons. Consistent with this, there were no sex differences related to spontaneous GABAergic synaptic events although CIE/WD decreased their frequency specifically in BLABNST neurons from both sexes. Altogether, these findings demonstrate that CIE/WD dynamically alters GABAergic function in an input-, sex- and population-specific fashion. Moreover, there are basal sex differences in both the anatomy of BLA GABAergic synapses and their function.
Alcohol use disorder (AUD) is associated with chronic inflammation and immune dysregulation, yet no validated immune-based markers exist to support assessment or monitoring. This study identifies interleukin-1 beta (IL-1β) in whole blood as a promising candidate biomarker of AUD risk, based on Alcohol Use Disorders Identification Test (AUDIT) scores. Twenty-eight non–treatment-seeking adults, with AUDIT scores between 2 and 22, provided whole blood samples. We aimed to identify biomarkers that signal immune changes associated with early AUDIT score risk, where interventions may be most effective. Luminex multiplex immunoassays quantified 14 immune-related mediators in combined cell lysates and supernatants. IL-1β, IL-18, IL-7 and CCL11 were significantly elevated in individuals with higher AUDIT scores. IL-1β showed the largest effect size (Cohen's d) and was the most consistent predictor of both AUDIT and AUDIT-Consumption (AUDIT-C) scores across random forest and linear regression analyses. Moderated multiple regression (MMR) confirmed that IL-1β predicted both scores independent of other immune mediators. Receiver operating characteristic (ROC) analyses demonstrated discriminative potential, with IL-1β achieving an AUC of 0.81 (good discrimination) for AUDIT ≥ 6 (true positive rate [TPR] = 0.71; false positive rate [FPR] = 0.14) and an AUC of 0.94 (excellent discrimination) for AUDIT-C thresholds (TPR = 0.80; FPR = 0.00). Principal component analysis (PCA) revealed greater immune variability in the high-risk group, particularly among proinflammatory mediators, suggesting immune dysregulation. This study demonstrates the utility of integrating whole blood immune profiling with high-sensitivity multiplex immunoassays, and applying both traditional statistical methods and machine learning to explore potential biomarkers for AUD risk. IL-1β is a statistically robust and clinically relevant candidate biomarker of AUD risk assessed by AUDIT scores. These findings require replication in larger, independent samples to determine their translational potential in addiction medicine.
This study aimed to investigate the role of LVV-hemorphin-7 (LVV-H7) in alcohol dependence. LVV-H7 is a short peptide derived from the cleavage of haemoglobin chains that binds to opioid receptors and plays diverse roles in various physiological and pathological processes. Additionally, LVV-H7 is cleaved at higher concentrations in the presence of alcohol. We conducted behavioural experiments in animal models and performed proteomic analyses of CNS tissues from alcohol-addicted rats to identify LVV-H7 binding partners. Using fluorescent microscopy, we confirmed the blood–brain barrier (BBB) permeability of synthesized LVV-H7 and its releasing enzyme inhibitor, pepstatin. Our results revealed a dose-dependent correlation between LVV-H7 quantities and alcohol levels. Mass spectrometry-based analyses identified LVV-H7's protein-binding targets in CNS tissues of addicted rats and the enzymes responsible for their degradation. These findings highlight the significant role of LVV-H7 in the mechanisms underlying alcohol dependence and indicate the potential role of hemorphin as a therapeutic target.
This study employed network meta-analysis to evaluate the impact of several exercise interventions on mobile phone addiction. The aim is to determine the most effective exercise intervention measures and establish a reference for future intervention measures to improve mobile phone addiction. We systematically searched the relevant literature on the Web of Science, PubMed, Embase, Cochrane Library, China Knowledge, Wanfang and other domestic and foreign databases. We assessed the risk of bias according to the revised Cochrane Randomised Trial Bias Risk tool and performed traditional and Web-based meta-analyses using Review Manager 5.3 and Stata 14.0. The traditional meta-results showed that exercise intervention was superior to the control group in improving mobile phone addiction (SMD = −1.05, 95%CI −1.62, −0.48). Network meta-analysis results show that aerobic exercise (AE) is superior to other sports in reducing the total score of mobile phone addiction among teenagers, and the probability of aerobics becoming the best intervention for mobile phone addiction among teenagers is the highest (SUCRA = 95.6%). Exercise intervention can reduce the score of mobile phone addiction, while AE has more advantages in improving mobile phone addiction. However, due to the influence of sample size and the quality of the included literature, it is recommended that the results be further verified in the future.
Chronic nicotine administration leads to neuroadaptations, an important process in nicotine and tobacco dependence for which treatments are limited. The cysteine pro-drug, N-acetyl-cysteine (NAC), is a promising glutamatergic agent that has shown some clinical efficacy in reducing nicotine use in humans. The purpose of this study was to examine NAC in two rodent models of nicotine dependence. NAC (0, 5, 20, 50 and 100 mg/kg) was examined on locomotor activity in groups of rats previously exposed to nicotine or saline. In the second experiment, NAC (0, 50 and 100 mg/kg i.p.) was evaluated against the discriminative stimulus effects of nicotine (0.2 mg/kg) using a two-lever procedure under a tandem schedule (VI10”-FR10) of food reinforcement. Pre-treatment with NAC in doses greater than 20 mg/kg attenuated the expression of conditioned hyperactivity when rats were placed in locomotor boxes previously paired with chronic nicotine administration. The same doses of NAC had modest effects in attenuating nicotine-stimulated hyperactivity in nicotine-treated or saline-treated rats tested in the same locomotor boxes. In the discrimination task, NAC did not generalise to the nicotine stimulus and nor did it modify the dose–response curve to nicotine, suggesting that NAC may not modify the subjective effects of nicotine. These results suggest NAC selectively attenuates conditioned responses to nicotine-paired stimuli without modifying nicotine-induced hyperactivity or the discriminative stimulus effects of nicotine. Thus, the study proposes that if NAC was to act in a similar selective manner in humans, the specific action of NAC to attenuate conditioned responses may limit its potential as a treatment to manage nicotine dependence.
The rise of gaming-related content on social media has increased exposure to game-related stimuli, particularly among young people, which may reinforce gaming urges and create difficulties in controlling gaming behaviour. Therefore, understanding the management of gaming desire triggered by such content is critical. Identifying the neural mechanisms underlying resistance to these urges will be crucial for effective prevention and intervention. However, this issue has yet to be directly explored. The present study investigated the neural correlates of resisting gaming desire elicited by gaming-related social media videos using functional magnetic resonance imaging (fMRI). Young habitual online gamers participated in an fMRI study in which they viewed video stimuli under three conditions: (1) gaming cue condition: passive viewing of gaming-related videos; (2) gaming cue resist condition: viewing of gaming-related videos while actively resisting gaming desire; and (3) neutral cue condition. Gaming cues elicited significantly greater activation than neutral cues in the diverse brain areas including bilateral medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, posterior cingulate cortex (PCC), superior temporal gyrus (STG) and precuneus. Compared to the gaming cue condition, the gaming cue resist condition elicited increased activation in the left PCC and bilateral precuneus. Conversely, significant deactivation was observed in the right STG. These findings offer insights into the neural basis of craving resistance in response to social media-based gaming cues and may guide the development of targeted interventions for problematic gaming behaviour.
Adaptive stress coping is often impaired in individuals with alcohol use disorder (AUD). This process relies on neurocircuitry involved in emotional and behavioural regulation, particularly the ventromedial PFC (vmPFC) and orbitofrontal cortex (OFC), along with limbic and ventral striatal regions (e.g., amygdala, hippocampus and nucleus accumbens). These systems are highly sensitive to the neurotoxic effects of alcohol, which may disrupt their ability to flexibly adapt in response to acute stress. This study investigated state-dependent changes (termed ‘flexibility’) in vmPFC-limbic/striatal and OFC-limbic/striatal functional connectivity from rest to acute stress in individuals with AUD versus matched controls and examined associations with coping strategies. Twenty-four adults with AUD (agemean = 33, 11F) and 23 matched controls (agemean = 32, 11F) underwent fMRI during resting-state followed by the Montreal Imaging Stress Task (MIST) and completed the COPE Inventory. Functional connectivity between vmPFC-limbic/striatal and OFC-limbic/striatal regions was assessed during rest and stress (MIST) conditions. Group differences in state-dependent changes in functional connectivity were analysed using repeated-measures ANCOVA. Functional connectivity between the right OFC–right amygdala and right OFC–right hippocampus increased from resting-state to the MIST in the control group, but this shift was not present in the AUD group (group x condition, pFDR < 0.05). Although connectivity did not differ between groups during the MIST (p's > 0.2), the AUD group exhibited elevated connectivity between these regions at rest (p's < 0.05). Moreover, among controls, increased right OFC–right hippocampus connectivity from rest to MIST was associated with more adaptive versus maladaptive coping (p < 0.05). Compared to controls, individuals with AUD exhibited a pattern of inflexible OFC-amygdala and OFC-hippocampus functional connectivity under changing stress conditions. Diminished stress-related connectivity changes in AUD appeared to be driven by elevated functional connectivity at rest. Future studies should test whether this resting-state connectivity pattern reflects an allostatic state that constrains the system's capacity to flexibly respond to acute stress.
Etiological theories of addictive behaviour postulate a key role for decision-making mechanisms. However, current research is lacking compelling computational models for decision-making in multistep forward planning scenarios to identify underlying mechanisms and make derived hypotheses testable.
We used a recently developed planning task and computational model to investigate performance, planning time and inferred forward planning parameters like planning depth and decision noise in 30 individuals diagnosed with mostly mild-to-moderate alcohol use disorder (AUD) relative to 32 healthy control participants, both sampled from the general population.
Contrary to our hypothesis, we did not observe reduced planning depth in participants with AUD but found that participants with AUD showed a higher performance in the planning task. Group differences could be explained by planning time and general cognitive performance. Importantly, participants with AUD invested more time for planning, showed a higher correlation of planning depth with incentive value and showed lower response noise, potentially indicative of higher choice consistency.
The significant differences in planning time, moderation of planning depth by incentive value and choice consistency may reflect higher motivation and willingness to exert effort among participants with AUD compared to healthy controls. Overall, our findings do not support the notion that mild-to-moderate alcohol use disorder is associated with impairments in forward planning across multiple steps.
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