Addiction Biology最新文献

Opioid abuse is a severe global health challenge, leading to rising morbidity, mortality, and increasing societal costs. The aim of this study was to investigate neuroinflammation, neuronal damage and potential changes in the orexin system or beta-amyloid metabolism in the cerebrospinal fluid (CSF) of individuals undergoing opioid substitution therapy (OST). This cross-sectional study investigates CSF biomarkers in individuals undergoing OST, compared to control subjects. Participants receiving OST were recruited from the outpatient clinic at the Department of Psychiatry, Sahlgrenska University Hospital, Gothenburg (Sweden). Each participant provided a complete medical history, including details of drug use over the past 6 months, followed by a lumbar puncture to obtain CSF samples. Molecules associated with neuroinflammation, neuronal and glial damage, beta-amyloid metabolism and orexinergic function were analysed in the participants' CSF, alongside electrolyte levels. Specifically, we analysed levels of sTREM-2, YKL-40, IL-1β, IL-6, IL-8, IL-10, TNF-α, AXL, MER, TYRO3, GAS6, NfL, GFAP, total tau (T-tau), phosphorylated tau (P-tau), neurogranin, Aβ40, Aβ42, the Aβ42/Aβ40 ratio, orexin-A, sPDGFR-β and electrolytes. The study included 15 control subjects and 17 in the opioid substitution group. Patients undergoing opioid substitution therapy exhibited elevated levels of sTREM-2, Aβ42/Aβ40 ratio and NfL in their CSF. Conversely, concentrations of Na⁺ and Cl⁻ were lower compared to controls. No significant differences were found between groups for other biomarkers, including orexin-A. However, when normalized to Aβ40 levels, YKL-40, IL-8, TYRO3 and P-Tau were also elevated in individuals with opioid dependence. Elevated biomarkers of neuroimmune activation, neuronal damage and beta-amyloid metabolism in opioid dependence suggest CNS inflammation as a contributor to its pathophysiology. Reduced electrolyte levels imply disrupted CSF water regulation, possibly linked to impaired glial function. These findings highlight both neural and non-neural mechanisms in opioid dependence.

Over 10% of the US population over 12 years old meets criteria for alcohol use disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3-beta (GSK3β) has been implicated in ethanol behaviours and poses as a potential therapeutic target in the treatment of AUD. Here, we investigated the preclinical evidence for tideglusib, a clinically available selective GSK3β inhibitor, in modulating chronic and binge ethanol consumption. Tideglusib decreased ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behaviour (drinking in the dark) without effecting water intake. With drinking in the dark, tideglusib was more potent in males (ED50 = 64.6, CI = 58.9–70.8) than females (ED50 = 79.4, CI = 70.8–93.3). Further, we found tideglusib had no effect on ethanol pharmacokinetics, taste preference or anxiety-like behaviour, although there was a transient increase in total locomotion following treatment. Additionally, tideglusib treatment did not alter liver function as measured by serum activity of alanine aminotransferase and aspartate aminotransferase but did cause a decrease in serum alkaline phosphatase activity. RNA sequencing analysis of tideglusib actions on ethanol consumption revealed alterations in genes involved in synaptic plasticity and transmission, as well as genes downstream of the canonical Wnt signalling pathway, suggesting tideglusib may modulate ethanol consumption via β-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3β in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.

Tobacco use causes more than 8 million deaths globally each year, and the number of younger smokers is growing. It is of great practical importance to explore the underlying neural mechanisms behind the behaviour of young smokers. During cue-induced craving, reward system in the brain generates neural oscillations at specific frequencies. The phase–amplitude coupling (PAC) can capture interactions between these frequencies and may be a more sensitive quantitative indicator for characterizing abnormal neural oscillations in smokers. We monitored the electroencephalography (EEG) data of 30 young smokers during a cue task after 12 h of abstinence, dividing the data into the neutral and smoking-related groups based on different experimental stimuli to analyse the relationship between PAC and craving. In addition, we computed the functional connectivity (FC) under the PAC mechanism. The results showed that the young smokers exposed to smoking-related cues under short-term abstinence conditions had significantly lower PAC values and reduced FC strength in the right prefrontal cortex. In contrast, there was a significant increase in PAC values in the parietal cortex and enhanced FC strength. The correlation analysis showed significant correlations between PAC values and craving. These findings demonstrate for the first time that PAC abnormalities in young smokers exposed to smoking-related cues under short-term abstinence conditions may be related to craving and inhibitory control.

Cannabis is one of the most commonly used illicit drugs worldwide, with its prolonged use potentially leading to various cognitive impairments and brain structural changes. However, current research on the dynamic changes in cortical thickness (CT) related to cannabis use remains limited, especially regarding the relationship between the severity of cannabis use and CT changes in heavy cannabis use (HCU). This study employed a longitudinal design to investigate CT changes in young adults with HCU from baseline (BL) to 3-year follow-up (FU). The results showed a significant group effect in the left lateral orbitofrontal cortex (OFC), and a significant time effect revealed CT changes in several brain regions, including the left lateral frontal cortex, bilateral medial frontal cortex, bilateral posterior cingulate cortex and bilateral insula. Simple effects analysis further demonstrated that the CT of left lateral OFC in young adults with HCU decreased significantly at FU compared with their BL and was also lower than control group at FU. Furthermore, a significant positive correlation was observed between the total score of Cannabis Use Disorders Identification Test at FU and the CT of left lateral OFC. These findings suggest that prolonged cannabis use may disrupt the structural integrity of the left lateral OFC, impairing decision-making, impulse control and emotional processing, thereby exacerbating addictive behaviours. This study provides key evidence for understanding the neural mechanisms underlying cannabis addiction.

In Taiwan, amphetamines are the main drug of abuse. While drug abuse is often related to individual risky decision-making, how this relates to underlying neural mechanisms in amphetamine abusers remains unclear. The current study was carried out to help better understand this. A Balloon Analogue Risk Task (BART) was used to examine individual risky decision-making in conjunction with event-related potential (ERP) recording and presentation of questionnaires relating to behavioural control. Compared with healthy controls, amphetamine users had a lower score on the Behavioural Inhibition System (BIS) scale and showed reduced amplitudes in feedback-related negativity (FRN) and error-related negativity (ERN) ERP components following negative feedback on the task. Amphetamine users were less sensitive to punitive or aversive stimuli. This reduced sensitivity might lead to a higher tendency for risky decision-making, with them less able to learn from mistakes and thus repeatedly engage in risky behaviours.

Alcohol use disorder (AUD) is associated with changes in endocrine and immune system function. This study is a secondary analysis aimed at investigating changes in circulating immune and endocrine biomarkers in blood samples from three groups: (1) healthy controls (HC, N = 12), (2) AUD—currently drinking, nontreatment seeking (CD, N = 9), and (3) AUD—abstinent, treatment-seeking (AB, N = 10; abstinent for at least 6 weeks). We hypothesized that both immune and endocrine biomarker concentrations would be different in AUD groups compared to healthy controls. Immune biomarkers included IL-8, IL-18, CCL2, TNF-α, IL-1RA, IL-6, and IL-10. Endocrine biomarkers included brain-derived neurotrophic factor (BDNF), glucagon-like peptide 1 (GLP-1), ghrelin, gastric inhibitory peptide (GIP), growth hormone, leptin, and insulin. Biomarker concentrations were compared between the three groups while controlling for age and sex, and associations between biomarker concentrations and behavioral measures were explored. IL-8 concentrations were elevated in AB compared to CD and HC (F(2,29) = 6.33, p = 0.006, ƞ_p² = 0.318). BDNF concentrations were lower in AB compared to HC (F(2,30) = 4.34, p = 0.02, ƞ_p² = 0.266). GLP-1 concentrations were higher in AB compared to HC (F(2,25) = 4.22, p = 0.03, ƞ_p² = 0.287). Exploratory analyses in combined groups showed that measures of past drinking, AUD severity, and anxiety/depression positively correlated with IL-18 and TNF-α and negatively correlated with BDNF. These results demonstrate that circulating concentrations of both immune and endocrine proteins are altered in abstinent individuals with a history of severe AUD (AB group) compared to healthy controls. In contrast, no group differences were observed for any biomarker between the nontreatment seeking, currently drinking people with AUD and the HC group. Our findings highlight the importance of accounting for AUD severity, comorbidities, and treatment-seeking status, especially when studying alcohol-related biomarkers.

Theoretical models propose that interoception plays a role in addictive disorder. However, this assumption has been mostly tested using the heartbeat counting task (HCT), which is known to be contaminated by estimation strategies. An adapted version of the HCT (in which respondents report only felt heartbeats) has been developed to reduce estimation biases. Here, we examined the validity of the classical and adapted HCT versions in samples presenting alcohol use disorders. We recruited a clinical sample of 48 patients with severe alcohol use disorder (SAUD), matched with 41 healthy controls (HC), and a subclinical sample of 32 binge drinkers (BD), matched with 30 HC. Participants performed the classical HCT, adapted HCT, and a time estimation task. We additionally assessed mental health variables theoretically related to interoception (alexithymia, anxiety, childhood trauma, depression and emotion regulation). In all groups, HCT scores were smaller in adapted than classical HCT. Patients with SAUD, but not BD, showed lower HCT scores than matched controls, independently of the task. We found no correlation between HCT scores and psychological constructs. Heartbeats reported during classical HCT correlated with seconds reported during time estimation task for SAUD and matched HC, suggesting the use of time estimation strategies to perform the task. The largely reduced HCT performance in the adapted version, the association between HCT performance and time estimation performance and the lack of theoretically expected associations between HCT scores and psychological variables extend doubts on the validity of these tasks for measuring interoceptive accuracy in problematic alcohol consumption.