Smoking addiction is a common mental disorder, and numerous imaging studies have shown that adolescents with smoking addiction exhibit abnormalities in brain function and structure. This study aims to investigate changes in the topological characteristics of the white matter (WM) functional network in young smokers. Forty-two young smokers and 42 age-, gender-, and education-matched nonsmokers were included in the study. The functional connectome of white matter and graph theory were used to study these participants. Two-sample t-test were used for the detection of the abnormal graph properties in young smokers. Pearson correlation was applied for the correlation analyses between properties and clinical indicators of smoking. The global level WM functional network analyses showed that the and values were higher in young smokers than in the control group, and the was positively correlated with the age of first smoking. At the node level, five nodes of the WM functional network exhibited abnormal node properties in the WM regions of the bilateral hippocampal parahippocampal gyrus (CGH), bilateral superior longitudinal fasciculus (SLF), bilateral inferior frontal gyrus (IFO), middle cerebellar peduncle (MCP), and the bilateral anterior commissure (ACR) in young smokers. The node degree centrality value of MCP was positively correlated with age of first smoking. Our neuroimaging findings provide evidence of WM functional alterations associated with nicotine addiction, which may enhance our understanding of the neural mechanisms underlying smoking addiction in young smokers.

ABSTRACTThe insular cortex (IC) is known to underlie drug seeking and relapse for multiple drug classes, yet the precise role the IC plays in opioid use disorder (OUD) remains unclear. In preclinical models of OUD, inhibition of the IC has produced conflicting results, such that in some cases the IC seems to promote opioid seeking whereas in others the IC seems to blunt opioid seeking. These results may be related to the heterogeneity of cortical output circuits, which can have opposing functions despite their relative proximity. Thus, here we examined the role of a specific IC output circuit, from the anterior IC (aIC) to the nucleus accumbens core (NAcc), for opioid seeking. We find in mice that following 14 days of heroin self‐administration and 3 days of forced abstinence, optogenetic inhibition of aIC➔NAcc terminals suppresses context‐associated opioid seeking. Furthermore, the same manipulation attenuates cued opioid seeking following extinction training. Importantly, we observed no effect of aIC➔NAcc terminal inhibition on sucrose seeking. Together, our results reveal that the IC selectively controls opioid seeking through a discrete population of NAcc projecting neurons, providing the first evidence for a projection‐specific role of IC circuitry in opioid seeking and relapse.

ABSTRACTCaffeine 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.

ABSTRACTFamily history (FH) of substance use disorders (SUDs) and stressful life events (SLEs) are known risk factors for SUDs in adolescents and young adults. Cross‐sectional studies suggest that FH and SLEs affect adolescent white matter (WM) development and form abnormal WM patterns. Here, we examined the effects of FH, SLEs and their interaction on WM integrity in youths in the Adolescent Cognitive Brain Development (ABCD) study at baseline and 2‐ and 4‐year follow‐ups. ABCD youths (N = 8939, age ± SD = 9.9 ± 0.6 years, 4302 female) completed baseline diffusion tensor imaging, of which 5661 repeated the scan at 2‐year follow‐up (age ± SD = 12.0 ± 0.7 years, 2634 female) and 2177 at 4‐year follow‐up (age ± SD = 14.1 ± 0.7 years, 1007 female). FH was measured as the weighted sum of biological parents and grandparents with alcohol and/or drug problems. SLEs were measured with parental report of life events. WM integrity was measured with fractional anisotropy (FA) of 23 WM tracts. Linear mixed effect models were used to examine the effects of FH, SLEs and their interaction on FA at baseline and longitudinally, modelling family and study site as random intercepts and correcting for multiple comparisons with false discovery rate (FDR) q = 0.05. At baseline, there were no significant effects of FH, SLEs and their interaction on FA after multiple comparison correction when controlling for race, family income and parental education. From baseline to 4‐year follow‐up, FH significantly negatively interacted with newly occurred SLEs on FA in 19 out of 23 tracts, so that FA at 4‐year was lower in youths with both FH and newly occurred SLEs when controlling for baseline FA (βinteraction = −0.049 − −0.018, pFDR = 6.2 × 10−5 − 4.7 × 10−2). These negative interactions were not significant with shorter time spans (baseline to 2‐year follow‐up and 2‐ to 4‐year follow‐up). In conclusion, we replicated findings from cross‐sectional cohorts of the effects of FH and SLEs on lower WM integrity in youths. The study utilized Big Data longitudinal design to show that FH‐by‐SLE interaction, rather than their independent effects was responsible for developmental WM changes associated with FH of SUDs and life stressors.

ABSTRACTThis 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.

ABSTRACTCigarette smoking is a prevalent and critical global health issue, with inconsistent findings for its effects on endogenous progesterone concentrations. This large multicentre study investigated the associations between various markers of smoking behaviour and plasma progesterone concentrations using a sex‐segregating approach. We studied 747 males aged 18–65 years and 158 peri−/postmenopausal females aged 50–65 years and assessed differences in plasma progesterone concentrations between smokers and never‐smokers and associations of plasma progesterone concentrations with the Fagerström Test for Nicotine Dependence (FTND) score, cigarette pack years, age at onset of regular smoking, number of cigarettes smoked daily, exhaled carbon monoxide (CO), plasma cotinine and the Questionnaire of Smoking Urges (QSU) score. In models adjusted for age, body mass index (BMI), years of education, Alcohol Use Disorder Identification Test (AUDIT) scores, intake of any medication and study centre, and after correction for multiple hypothesis testing, there were no significant differences in plasma progesterone concentrations between smokers and never‐smokers, and no significant associations between any of the mentioned markers of smoking behaviour and plasma progesterone concentrations in either males or females. The results suggest that smoking behaviour has no substantial effect on plasma progesterone concentrations and is not an important confounder in studies investigating progesterone.

ABSTRACTMethamphetamine (METH) abuse can inflict profound and enduring neurotoxic effects on the brain, culminating in cognitive dysfunction and impairment of learning and memory. Physical exercise can stimulate both structural and functional adaptations in the central nervous system. The primary objective of this study was to elucidate the safeguarding effect and underlying mechanisms of treadmill exercise intervention in the brains of METH‐addicted mice. Two‐month‐old adult mice were randomly assigned into three distinct groups: the control group (Group C), receiving intraperitoneal injections of saline; the METH treatment group (Group Ma), exposed to intraperitoneal METH administration; and the exercise group (Group Ea), which underwent a two‐week regimen of treadmill exercise intervention following intraperitoneal METH exposure. The conditioned place preference experiment was executed to evaluate METH addiction. The results showed that both Groups Ma and Ea mice became addicted to METH after METH administration (p < 0.05, n = 6). In the Y‐maze experiment, the exploration time of mice in Group Ea in the novel arm was significantly higher than that in Group Ma (p < 0.05, n = 6), indicating that exercise intervention improved the learning and memory capabilities of mice. Subsequently, the mouse brain specimens were harvested for transcriptome sequencing and real‐time fluorescence quantitative PCR analysis (n = 3). Transcriptome sequencing analysis identified 316 differentially expressed genes (DEGs) in Group Ma compared to Group C, while 156 DEGs were detected in Group Ea compared to Group Ma. Kyoto Encyclopedia of Genes and Genomes analysis outcomes underscored the substantial association of DEGs, discerned in exercise‐intervention mice compared to METH‐treated mice, with key signalling pathways, notably the PI3K‐Akt, mTOR and Wnt signalling pathways, among others. Cross‐analysis revealed 43 DEGs in exercise‐treated mice, such as NFKBIA, CXCL12 and Vav3. Our results revealed changes in the expression profile of the brain transcriptome of METH‐addicted mice and indicated that treadmill exercise intervention affects the expression changes of the brain transcriptome of METH‐addicted mice. The above research results provide unique insights into the further study of the mechanism of treadmill exercise intervention in improving the learning and memory abilities of METH‐induced mice.

ABSTRACTAlthough substance use is associated with a shortened lifespan, impeded health and accelerated biological ageing, the factors contributing to the associations between substance use and ageing are poorly understood. We used summary statistics from genome‐wide association studies (GWAS) to investigate whether substance involvement (N from 28K to 2M)—including alcohol, tobacco, cannabis and opioid use and use disorders—is genetically correlated with various ageing metrics (N from 162K to 2.7M) and whether these correlations reflect shared genetic etiologies or putative causal relationships. Using Linkage Disequilibrium Score Regression (LDSC), we found widespread evidence of genetic correlations between substance use/use disorders and indices of physical, cognitive and biological ageing. We then employed a series of Mendelian randomization–based approaches, finding significant causal effects of genetic predispositions to both tobacco use disorder and quantity of tobacco smoked on various markers of ageing. Causal effects of problematic alcohol use and cannabis use disorder were also found, though findings were mixed. Evidence of reverse causality (i.e., ageing causing substance use), meanwhile, was scant. Collectively, these results demonstrate strong triangulation across approaches and highlight the importance of integrating genetic insights into public health strategies for reducing the burden of SUDs across the lifespan.