Addiction Biology最新文献

Abstinence from drug use is often the result of the associated negative consequences. However, relapse occurs in a large proportion of abstinent users, and the underlying brain mechanisms are not clear. An arguably relevant brain area is the posterior paraventricular nucleus of the thalamus (pPVT), which plays a role in motivational processes and addiction-like behaviours. Using a punishment-imposed abstinence procedure, we assessed the effect of chemogenetic inhibition and excitation of the pPVT on food deprivation-induced relapse to heroin-seeking in male and female rats. Rats were trained to self-administer heroin (0.1 mg/kg/infusion) for 2 weeks under a seeking–taking chain schedule. For punishment-imposed abstinence, a mild footshock (0.2 to 0.6 mA) was delivered on 30% of the completed seek lever links instead of access to the take lever. Relapse to heroin-seeking was tested after 24 h of food deprivation and under sated condition. Animals were injected (i.p.) with either a DREADD ligand or vehicle 15–20 min before the tests. There was no sex difference in heroin self-administration or punishment-imposed abstinence. Under the food deprivation condition, chemogenetic inhibition of the pPVT increased heroin-seeking compared to the control group, only in male rats. Chemogenetic excitation of the pPVT resulted in an increase in heroin-seeking under food deprivation conditions. Our results support an involvement of the pPVT in relapse to heroin-seeking and suggest a sex-dependent effect.

Caffeine is one of the most widely consumed psychoactive substances globally. It acts as a non-selective adenosine receptor antagonist. Despite its extensive use, the effects of caffeine on the central nervous system remain poorly understood. This study aims to investigate the behavioural changes and underlying neural mechanisms associated with caffeine addiction. The results of conditioned place preference (CPP) revealed that caffeine induces a strong preference shift, demonstrating its rewarding properties. 3D Behavioural Profiling and Motion Analysis further demonstrated significant differences in locomotion, rearing and sniffing behaviours between caffeine-treated and saline-treated groups. C-fos and fibre photometry experiments revealed that caffeine activates the medial prefrontal cortex (mPFC) region. Transcriptomic profiling revealed a significant enrichment of pathways associated with transcriptional regulation and calcium signalling in the medial prefrontal cortex (mPFC) of caffeine-treated mice. Together, these findings provide a multidimensional perspective on caffeine's addictive properties, as well as its modulation of mPFC activity and molecular pathways. This contributes to a deeper understanding of caffeine's effects on the central nervous system.

Long-term abuse of methcathinone reduces grey matter volume in the prefrontal cortex and consequently impairs learning and memory abilities. However, the exact mechanism of damage remains unknown. Therefore, this study aimed to analyse the potential mechanisms underlying methcathinone-induced neural damage using transcriptomic analysis. Accordingly, 32 Sprague Dawley rats were randomly divided into four groups: control, low-dose, medium-dose and high-dose. Low, medium and high methcathinone doses (0.25, 5 and 20 mg/kg) were administered to the animals in the three treatment groups once daily via intraperitoneal injection for 2 weeks. Finally, the learning and memory functions of all the animals were tested using the Morris water maze. Electron microscopy and Golgi staining were used to observe changes in synaptic structure, and transcriptome sequencing was performed in the prefrontal cortex of the control and high-dose groups. Key differentially expressed genes were quantified using quantitative real-time reverse transcription polymerase chain reaction. Collectively, methcathinone induced learning and memory decline in rats and destroyed the synaptic structure of the rat prefrontal cortex. In the transcriptomic analysis, 1457 (694 up-regulated and 763 down-regulated) genes were differentially expressed in the prefrontal cortex of rats in the high-concentration group compared to that in the control group. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes analysis revealed that differential genes were enriched in synapses, neurotransmitter systems, homeostasis of Ca²⁺ concentration and membrane potential regulation. This indicates that methcathinone adversely affects neurotransmitter regulation, Ca²⁺ signalling and membrane potential regulation, thereby destroying synapse structure and causing learning and memory dysfunction. Combined with the above molecular mechanisms, seven key genes were identified: nerve growth factor (NGF), dopamine receptor D1 (DRD1), dopamine receptor D2 (DRD2), solute carrier family 1 member 2 (SLC1A2), calcium/calmodulin-dependent protein kinase II alpha (CAMK2A), synaptotagmin 1 (SYT1) and glutamate ionotropic receptor N-methyl-d-aspartate type subunit 2A (GRIN2A). This study demonstrates that methcathinone causes neural damage and provides possible molecular mechanisms and target genes to clarify the mechanism of methcathinone-induced neural damage.

The use of Pavlovian-to-instrumental transfer (PIT) in addiction research is on the rise as a means of assessing an individual's susceptibility to interference between Pavlovian and instrumental control over behaviour. However, the reliability of PIT tasks has been rarely assessed.The present study provides an investigation of the reliability of PIT, both on a behavioural and neural level, examining split-half as well as test–retest reliability. We assessed two different samples: (1) a mixed detoxified alcohol-dependent sample (with controls) comprising 119 behavioural and 69 fMRI datasets assessed twice within 3–4 weeks and (2) a developmental sample with 117 behavioural and 91 fMRI datasets assessed twice after 3 years. We computed two behavioural parameters of PIT (interference and motivational PIT effects) that were used in our previous studies. The interference PIT effect was assessed as the difference in error rates between the congruent and incongruent trials of the PIT task. The motivational PIT effect was assessed as the linear relationship between the number of button presses influenced by Pavlovian-conditioned environmental cues. We further assessed the reliability of four predefined fMRI PIT contrasts.On the behavioural level, our results revealed excellent split-half reliability for both the interference (r = 0.92–0.97) and motivational (r = 0.94–0.98) aspects of PIT in both clinical and developmental samples. In comparison, test–retest reliability after 3 weeks was lower (clinical sample: ICC = 0.53) and again lower yet still significant despite neurodevelopmental brain maturation after 3 years (developmental sample: ICC = 0.26–0.29). In the fMRI analysis, regions of interest showed acceptable ICCs in the incongruent and congruent contrasts (split-half: 0.59–0.80; test–retest: 0.13–0.51). Global overlap assessments using Jaccard coefficients revealed individual-level variability in neural responses (split-half: 47%–51% overlap; test–retest: 29%–35% depending on the sample and contrast). All fMRI reliability coefficients for the motivational PIT effect were below 0.17.Overall, behavioural PIT reliability was good, especially from the split-half perspective. For neuroimaging, the incongruent contrast seems best suited for predicting individual outcomes, while the neural motivational PIT effect seems to represent more changeable current states.

This study systematically investigates the multidimensional rehabilitative effects and neurobiological mechanisms of exercise interventions in individuals with substance use disorders (SUDs). By synthesizing and critically analysing current evidence, the aim is to establish a theoretical framework for exercise-based rehabilitation and provide empirical support for optimizing intervention strategies. A comprehensive literature review was conducted, encompassing 39 core studies on exercise interventions in drug rehabilitation. Evidence-based medicine principles were applied to integrate mechanistic findings and evaluate effect sizes. The review focused on examining the physiological, psychological and neurobiological effects of various exercise modalities in individuals with SUD. Findings consistently demonstrate that exercise interventions are effective in reducing drug craving and withdrawal symptoms, improving overall quality of life and potentially lowering relapse rates. For individuals undergoing rehabilitation, exercise promotes improvements in physical health, psychological well-being and social functioning, while concurrently attenuating relapse vulnerability. As a nonpharmacological, multitarget intervention, exercise therapy exhibits significant potential in promoting neuroplasticity and facilitating psychological recovery in individuals with SUD. Standardized exercise prescriptions should be integrated into existing rehabilitation frameworks. Future research should emphasize comparative effectiveness across exercise modalities, explore the benefits of multimodal interventions, and further elucidate the interplay between biological, clinical and psychosocial mechanisms to enhance long-term rehabilitation outcomes.

Alcohol use disorder is a severe public health problem; however, the specific mechanisms remain unclear. Our previous studies have identified ‘ELANE’ as the Hub gene in alcohol use disorder. However, its role in the clinical practice of alcohol use disorders has not been confirmed. A total of 53 healthy controls and 90 patients with alcohol use disorders were enrolled. Clinical factors were gathered, and a 1-year relapse follow-up was carried out. The group with alcohol use disorder had considerably higher ELANE concentrations than the healthy controls (p < 0.001). Patients were categorized as high ELANE (≥ 2.7651 pg/mL, n = 46) or low ELANE (< 2.7651 pg/mL, n = 44) based on the median ELANE expression level in the alcohol use disorder group. SERPINA3 was statistically significant, according to binary logistic analysis (p = 0.007). After 12 months of follow-up, there was no difference in event-free survival between patients with low and high ELANE levels, according to Kaplan–Meier survival analysis (p = 0.568). ELANE had an area under the curve of 0.8683 (p < 0.0001), according to receiver characteristic curve analysis, and a sensitivity and specificity of 65.6% and 92.5%, respectively. According to Cox regression analysis, marital status was a negative predictor of relapse (β = −0.661; hazard ratio = 0.516; p = 0.038). Plasma ELANE represents a promising neuroinflammatory biomarker for AUD diagnosis, demonstrating excellent specificity albeit moderate sensitivity. The protease–antiprotease imbalance reflected by elevated ELANE and relatively decreased SERPINA3 suggests dysregulated inflammatory homeostasis in AUD. While ELANE lacks prognostic utility for relapse prediction, these findings warrant further investigation of neutrophil elastase inhibitors as potential therapeutic interventions and highlight the critical importance of social support systems in AUD recovery.

Methamphetamine addiction is a chronic brain disorder involving significant neuroadaptive changes, with recent research emphasizing the role of epigenetic mechanisms, particularly DNA methylation. This study aims to evaluate the diagnostic potential of gene methylation by identifying and validating differentially methylated genes in methamphetamine-dependent individuals versus healthy controls. A genome-wide differentially methylated analysis was conducted using methylation microarray technology. Subsequently, pyrosequencing was employed for validation with an expanded sample size, examining 27 CG sites across eight candidate genes: ATP6V1C1, CES1, USP7, GABRB1, KCNQ2, LIAS, CIZ1 and GNG7. ROC curve analyses and correlation assessments with biochemical markers and drug use patterns were also performed. Significant methylation alterations were observed in GABRB1, CES1, KCNQ2 and USP7 between methamphetamine-dependent individuals and controls. Specifically, GABRB1 and KCNQ2 showed decreased methylation, while CES1 exhibited increased methylation. USP7 displayed site-specific changes. ROC curve analysis showed that a specific site in the GABRB1 gene demonstrated excellent diagnostic accuracy (AUC = 0.902). Methylation levels in CG sites in CES1 showed high diagnostic accuracy (AUC = 0.755) for methamphetamine dependence, while the AUC values for KCNQ2 and USP7 were 0.68 and 0.664, respectively, indicating moderate classification. Besides, the study revealed significant positive correlations between diastolic pressure and both the duration of methamphetamine use and KCNQ2 methylation levels. Additionally, USP7 methylation levels showed a positive correlation with the duration of drug use. These findings provide valuable insights for the development of diagnostic biomarkers and targeted therapeutic interventions. Future research will focus on elucidating the functional roles of these genes in the pathophysiology of methamphetamine addiction and their potential applications in treatment strategies.

Protracted abstinence (PA) is the commonly implemented treatment of heroin-dependent individuals (HDIs) in China. However, the effect of abstinence duration on the brain function of HDIs during PA using resting-state functional magnetic resonance imaging (fMRI) remains unclear. Fourteen HDIs who had finished PA for about 6 months (PA6), 16 HDIs who had completed PA for about 11 months (PA11) and 15 demographically matched healthy controls (HC) underwent this fMRI study. We analysed the difference in amplitude of low-frequency fluctuation (ALFF) values among the three groups. Then we analysed the difference in functional connectivity (FC) based on the differential regions of ALFF. Additionally, we examined the relationship between FC of differential brain regions and abstinence duration. The differences in ALFF among the three groups were found to be significant in the bilateral putamen and left inferior parietal lobule (single voxel p < 0.001, cluster level p < 0.05 and GRF-corrected). Compared with the PA6 group, the PA11 group showed lower ALFF values of the differential regions with a tendency toward the HC group. Meanwhile, the PA11 group showed lower FC between the left putamen and left insula, between the right putamen and left insula and between the left inferior parietal lobule and bilateral inferior frontal gyrus (IFG), but higher FC between the left putamen and left inferior temporal gyrus. The above FC of HDIs negatively correlated with the abstinence duration, except for the left putamen–inferior temporal gyrus FC. The prolonged abstinence duration may be useful to restore the impaired brain function of HDIs to some extent, although more data are needed to validate this in future studies.

Identifying shared neural mechanisms influenced by diverse classes of drugs of abuse is essential for understanding addiction and for developing broad-spectrum treatments for substance use disorders. Previous studies indicate that many drugs of abuse increase dopamine output from the ventral tegmental area (VTA) by altering the balance of excitatory and inhibitory inputs onto dopamine neurons, thereby promoting maladaptive plasticity within reward circuits. Here, we demonstrate in rats that acute injections of morphine and cocaine, but not saline, disrupt chloride homeostasis in VTA GABA neurons. This disruption is characterised by a depolarised GABA_A reversal potential, impaired chloride extrusion, and posttranslational downregulation of the potassium chloride cotransporter KCC2. Although previous studies linked drug-induced posttranslational downregulation of KCC2 in the VTA to glucocorticoid receptor activation, we found that a glucocorticoid receptor antagonist did not prevent cocaine- and morphine-induced disruption of chloride homeostasis. Instead, our data show that dopamine D1/D5 receptor activation is both necessary and sufficient for these alterations. Notably, chloride homeostasis remains impaired for several weeks after volitional morphine self-administration, indicating long-lasting plasticity. These findings complement previous work on nicotine and alcohol, suggesting a shared mechanism of inhibitory plasticity in the VTA following drug exposure. Given that chloride dysregulation in VTA GABA neurons influences downstream circuit function and promotes maladaptive behaviours associated with drug use, we propose KCC2 as a promising therapeutic target for substance use disorders.

Cannabis use disorder (CUD) affects ~22-million people globally and is characterised by difficulties in cutting down and quitting use, but the underlying neurobiology remains unclear. We examined resting-state functional connectivity (rsFC) between regions of interest (ROIs) of the addiction neurocircuitry and the rest of the brain in 65 individuals with moderate-to-severe CUD who reported attempts to cut down or quit, compared to 42 controls, and explored the association between rsFC and cannabis exposure and related problems, to elucidate potential drivers of rsFC alterations. The CUD group showed greater rsFC than controls between ROIs implicated in reward processing and habitual substance use (i.e., nucleus accumbens, putamen and pallidum) and occipito/parietal areas implicated in salience processing and disinhibition. Putamen-occipital rsFC correlated with levels of problematic cannabis use and depression symptoms. CUD appears to show neuroadaptations of the addiction neurocircuitry, previously demonstrated in other substance use disorders.