Nicotine & Tobacco Research

Introduction The Tobacco and Vapes Act 2026 provides the UK government powers to ban vaping in public places. Proposals include extending existing indoor smoke-free legislation to also being vape-free and making public children's playgrounds and outdoor areas of education settings vape-free. We examined adults' and adolescents' views on vape-free places. Methods Two UK-wide cross-sectional online surveys were conducted in 2026, one with adult (18+) current and former nicotine users (n=2,851), and one with adolescents aged 11-17 years (n=2,123). We measured (1) perceived acceptability of vaping in public places, (2) views on whether vapes should/should not be allowed in public places, and (3) perceived likelihood of public compliance with vaping bans. Results Adults considered it unacceptable to vape on public transport (85.9%), on school grounds (outdoors) (83.6%), outside hospital entrances (59.2%), and inside pubs (57.8%) and nightclubs (52.5%). A minority considered it unacceptable to vape at open air playparks (40.6%). Most adolescents viewed vaping as unacceptable in all locations. Perceived acceptability of vaping in each place was associated with current vaping and/or smoking. Adults and adolescents believed vaping should not be allowed on public transport (88.9%; 93.8%) or outdoors on school grounds (85.8%; 93.5%). Adults and adolescents perceived likely compliance on public transport, school grounds and in pubs, but not in nightclubs, outside hospital entrances and at open air playparks. Conclusion The findings indicate public support for some vape-free places among adults and adolescents, particularly on public transport and school grounds, and less so for a ban at open air playparks.

Objectives To compare hospital claims and costs for major tobacco associated diseases with ICD 10 F17 tobacco dependence coding in Indonesian national health insurance claims and to assess whether the insurer records tobacco addiction or mainly pays for its complications. Design Retrospective claims based observational study using routinely collected administrative claims reported according to STROBE and the RECORD extension. Setting Indonesian national health insurance scheme Jaminan Kesehatan Nasional including referral hospital and primary care claims from 2015 to 2023. Participants A national mental health claims sample of 54820 members with at least one ICD 10 mental or behavioral F code diagnosis weighted to 1032022 members and 2074277 referral hospital visits. Primary and secondary outcome measures The primary outcome was verified claim costs in USD for hospital visits with a primary diagnosis of chronic obstructive pulmonary disease J44 or tracheal bronchial or lung cancer C33 to C34 or ischemic heart disease I20 to I25 or stroke I60 to I69. Secondary outcomes were counts of ICD 10 F17 tobacco dependence coding and the disease to F17 coding ratio. Results The four tobacco associated disease groups accounted for 13946 visits among 5223 patients and USD 4.20 million in verified costs representing 6.0 percent of hospital spending in the sample. Weighted costs were USD 74.7 million of which cardiovascular and cerebrovascular disease accounted for 95 percent. F17 appeared in only 51 referral hospital encounters and 26 primary care encounters. Only 2 of 5223 patients with these tobacco associated diseases or 0.04 percent were ever coded with F17. Conclusions The Indonesian national insurer paid substantially for tobacco associated morbidity while tobacco dependence was almost never coded. Smoking related diseases were reimbursed but tobacco dependence treatment was not captured as a financed care target. Embedding brief cessation care reimbursable pharmacotherapy and routine F17 coding into primary care could help shift tobacco related expenditure from downstream complications toward addiction care. Keywords tobacco dependence smoking cessation F17 coding health expenditure administrative claims Indonesia

Objective To estimate the potential health and equity impacts of a tobacco free generation (TFG) and T21 policy (increasing the legal age of sale to 21) in Australia, in the context of a complex market including widespread illicit tobacco and e-cigarette product availability. Design A Markov macrosimulation model, parameterised with yearly net movements between legal smoking, illicit smoking, vaping, and dual use states, combined with a proportional multi-state lifetable. Setting The Australian population, modelled as an open cohort for 40-years. Intervention A 'business-as-usual' (BAU) scenario was compared to TFG and T21 policies, with both starting in 2026. Variations to policy impacts were tested under increasing background illicit market enforcement. Main outcome measures The model estimates the health-adjusted life years (HALYs) and deaths over 40 years, under each scenario, with differences across age and socioeconomic status (SES) presented. Results The TFG policy reduced daily smoking prevalence among 15-24-year-olds to 4.6% (95% uncertainty interval [UI] 3.8-5.7%) in 20 years' time, compared to 7.2% under the T21 policy and 7.9% under BAU trends. Vaping was minimally impacted by either policy. The TFG policy resulted in 178,000 (95% UI 87,800-314,000) HALYs being gained over 40 years. The policy impact was largest when accompanied by increased illicit market enforcement, reducing daily smoking among 15-24-year-olds to 1.4% within 20 years. Both policies had greater prevalence and health impacts on more disadvantaged compared to advantaged SES groups. Conclusion A TFG policy is expected to produce long-term benefits for the Australian population but would be most effective in combination with increased enforcement of illicit tobacco and e-cigarette markets. Novel strategies to increase quitting in addition to reducing uptake are needed to improve tobacco-related outcomes in the short to medium term.

Introduction: Pediatric nicotine exposures remain an important and preventable public health issue, particularly with the rapid expansion of electronic nicotine delivery systems. This study compared demographic characteristics, exposure circumstances, and clinical outcomes between pediatric cases involving nicotine devices and bottled liquids reported to U.S. poison centers. Method: This retrospective cohort study analyzed National Poison Data System cases from 2011-2022 involving children aged less than 6 years exposed to nicotine devices or bottled liquids. Analyses were limited to cases with definitive medical outcomes. The primary outcome was defined as a moderate or major clinical effect or death. Odds ratios with 95% confidence intervals were calculated, with a secondary analysis restricted to route-concordant exposures. Results: The final cohort included 15,497 cases: 10,168 device exposures and 5,329 liquid exposures. Demographic characteristics were similar between groups. Device exposures more frequently involved inhalation, while ingestion predominated overall. Clinical effects were typically mild and transient, with vomiting and coughing most commonly reported. The primary outcome occurred in 1.9% of device cases and 2.0% of liquid cases (OR = 1.05; 95% CI 0.82-1.34). A secondary analysis restricted to inhalation-only device exposures and ingestion-only liquid exposures similarly found no significant difference in clinically important outcomes (OR = 1.38; 95% CI 0.92-2.12). Two deaths occurred, one in each group. Conclusion: These findings suggest that, despite differences in formulation and route of exposure, nicotine devices and bottled liquids produce broadly similar clinical toxicity profiles in young children. Prevention strategies should address all household nicotine products rather than focusing on specific delivery systems.

Background: The UK Government aims to reduce smoking rates by implementing new, and investing in existing, tobacco control strategies including increased funding for Stop Smoking Services (SSS) in England. This study examined whether the additional funding starting in April 2024 was associated with a detectable increase in quit attempts supported by SSS and whether it was cost-effective. Methods: We used data from the Smoking Toolkit Study, a repeat cross-sectional survey conducted in 2021 to 2025. Adults aged [≥]18 years who smoked cigarettes and had made a quit attempt in the past year were included (weighted n=5,076). The outcome was monthly prevalence of past-year quit attempts supported by SSS. We fitted general additive models with a step change in April 2024 to represent the start of the increased funding. We adjusted for tobacco tax increases, the Swap-to-Stop scheme, age, gender, and a measure of socioeconomic position. In an unplanned analysis, we extended the time series back to 2006. For the cost-effectiveness, we estimated incremental cost-effectiveness ratios for the total population and age groups, accounting for future lifetime cessation. Results: In the primary model, the April 2024 step change was not statistically significant (adjusted odds ratio: 1.13; 95% CI: 0.52, 2.49). The cost-effectiveness analysis ranged from cost-effective to extremely ineffective (incremental cost-effectiveness ratio (ICER): GBP 104,126, 95% CI: 939,398 to 8,293). When using the extended time series, the adjusted odds ratio for the step change was 2.70 (95% CI: 2.03, 3.60) and the intervention was cost-effective (ICER: GBP 13,857; 21,393 to 9,620). Conclusions: Compared with the long-term trend, increased funding to SSS in England in 2024 appeared to lead to an increase in quit attempts supported by SSS at the population level. This result is somewhat uncertain because our primary pre-planned analyses assessing the impact relative to a more recent trend were insensitive.

Background: Cannabis is one of the most widely used psychoactive substances worldwide. {Delta}-tetrahydrocannabinol ({Delta}-THC) is the main contributor to cannabis-induced effects such as euphoria, anxiety, and psychotomimetic effects, and is metabolized by several hepatic enzymes, including CYP3A4. There are interindividual differences in how cannabis affects users, which have substantial genetic contributors. Methods: We examined how real-time effects of {Delta}-THC on psychotomimetic measures and on subjective effects of "high", sadness and anxiety in 188 healthy volunteers in a laboratory infusion paradigm, relate to polygenic risk scores (PRS) for cannabis lifetime use (CanLU), cannabis use disorder (CanUD), and CYP3A4 expression. Results: CYP3A4 expression PRS was significantly associated with {Delta}-THC-induced psychotomimetic effects. Genetic liability to use and misuse cannabis is potentially associated with lower {Delta}-THC-induced psychotomimetic symptoms. CanLU PRS nominally predicted enhanced {Delta}-THC-induced "high", while CanUD PRS predicted it to be lower. Conclusions: Our findings suggest that genetic liability to produce more CYP3A4 enzyme may be associated with faster {Delta}-THC degradation and the consequential diminution of the latter's effects. Nominal effects suggest that aversive outcomes may reduce cannabis use and use disorder genetic liability, and that CanUD subjects may need higher {Delta}-THC doses to experience euphoria ("high"). In total, this study provides novel insights regarding some of the specific genetic factors that influence interindividual variability in {Delta}-THC effects, mainly via {Delta}-THC metabolism.

Objective: To develop and validate clinically relevant polygenic scores (PGS) for alcohol (AUD), cannabis (CanUD), opioid (OUD), tobacco (TUD), and polysubstance use disorders (polySUD) across African (AA), European (EA), and Latinx (LA) ancestry populations. Methods: Using multiple genome-wide association study summary statistics and PGS methods, substance use disorder PGS were developed and evaluated in Indiana Biobank samples (IB, N: 1,356-24,989), then top-performing PGS were validated in All of Us Research Program samples (AOU, N: 62,389-209,952). Case and controls were defined using ICD-9/10 codes. All participants were aged 18 years or older (>=21 years for AUD controls). Clinical relevance was defined as an odds ratio (OR) >=2 for individuals with the highest PGS determined based on disorder prevalence compared to everyone else. Results: In EA and LA, all PGS achieved clinically relevant performance in both IB and AOU (ORs: 2.00-9.10; P <= 3.87E-4). In AA, PGS met this threshold in IB (ORs: 2.02-2.71; P <= 2.20E-4) but not in AOU (ORs: 1.28-1.56; P <=0.03). Overall, OUD PGS showed the strongest associations in most analyses, followed by CanUD and polySUD. Generally, compared to female PGS, male PGS had higher or comparable ORs, but the differences were not significant except AUD PGS in AOU LA. Conclusions: PGS demonstrated clinically meaningful risk prediction for substance use disorders in EA and LA, supporting the feasibility of future clinical implementation for population-level screening. However, reduced performance in AA underscores the urgent need for more genetic studies in that population.

Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising treatment for tobacco use disorder (TUD). Although at a group level, active stimulation outperforms sham, at an individual level, variability exists in clinical response. The behavioral and neurobiological factors that differentiate those who respond to rTMS from those who do not remain unclear. To explore individual factors that influence acute responses to rTMS, N = 60 human participants received one session of rTMS to the dorsolateral prefrontal cortex (DLPFC) and to a control region (visual cortex; V5) in a randomized order. They completed behavioral assessments and neuroimaging before and after rTMS sessions. Hypotheses involving behavioral and neuroimaging predictors of response were pre-registered prior to completion of data collection. rTMS to the DLPFC led to significant reductions in self-reported cigarette craving compared with rTMS to a control brain region (p = 0.0006) and participants were classified as n = 38 responders and n = 22 nonresponders. Responders used significantly more cigarettes per day (M = 11.441) compared to nonresponders (M = 7.952), reported higher levels of cigarette craving (d = 1.059), and more severe nicotine withdrawal (d = 0.803) prior to rTMS. Neuroimaging analyses based on preregistered hypotheses indicated that DLPFC-frontoparietal and insula whole-brain functional connectivity did not differ significantly between responders and nonresponders. However, exploratory analyses revealed that responders had reduced pre-rTMS functional connectivity between the insula and nucleus accumbens, precuneus, and occipital pole. These findings suggest that response to rTMS for TUD is associated with greater baseline cigarette consumption, craving, and withdrawal, in addition to distinct functional connectivity patterns related to salience, reward, and self-referential processes, providing candidate behavioral and neural markers for personalized rTMS interventions for TUD.

The ongoing opioid epidemic underscores the need for scalable and translational preclinical models of voluntary opioid intake and dependence. We therefore sought to establish and validate a voluntary two-bottle choice drinking-in-the-dark (DID) model of oral opioid intake in mice and to determine relationships between experimental parameters and behaviors during and after withdrawal. Male and female C57BL/6J mice were given daily access to two bottles during the dark phase for 24 drinking sessions over 5 weeks. Control mice received two bottles containing water. Experimental mice received one water bottle and one bottle containing oxycodone (0.1-1 mg/mL) or fentanyl (10-100 {micro}g/mL) under varying session durations and concentrations. On the final day, physical dependence was assessed using naloxone-precipitated withdrawal and then a behavioral battery to assess negative affect was performed in the following week. Mice voluntarily consumed both oxycodone and fentanyl without taste adulteration and maintained drug preference across most concentrations. Oxycodone intake produced minimal withdrawal symptoms. In contrast, fentanyl intake resulted in naloxone-precipitated withdrawal that was modulated by session duration and concentration. Four-hour sessions produced stronger withdrawal than two-hour sessions at equivalent concentrations. Escalating high-concentration fentanyl exposure revealed emerging sex differences, with females exhibiting greater intake and withdrawal at higher concentrations. Affective behavioral assays following withdrawal revealed minimal persistent alterations in any cohort. These findings establish key parameters for a scalable voluntary fentanyl model that produces dose- and session-dependent physical dependence in male and female mice. This paradigm provides a cost-effective and straightforward platform for future investigations of opioid use and dependence.

Alcohol use disorder demonstrates ~50% heritability, much of which remains unexplained by genetic sequence alone. Chronic alcohol exposure before conception changes offspring phenotypes through epigenetic mechanisms that are still being elucidated. Preconception ethanol exposure studies have focused on paternal exposure, neglecting maternal and biparental exposure. To address this, we exposed adult male and female mice to five cycles of chronic intermittent ethanol vapor interleaved with two bottle choice ethanol drinking and mated them to produce male and female F1 offspring with paternal, maternal, or biparental preconception ethanol exposure or controls. Whole blood and medial prefrontal cortex from adult, ethanol-naive offspring underwent RNA-sequencing. We also analyzed previously unpublished RNA-sequencing data from male and female preimplantation embryos derived from preconception ethanol-exposed sires. Here, we report transcriptomic patterns of preconception ethanol exposure that depend on the exposed parent, offspring sex, and tissue which suggest metabolic and immune dysfunction in offspring.

Alcohol drinking motives vary among individuals and shape experiences and beliefs about alcohol, influencing the processing of alcohol-related cues. In real-life settings, these cues are contextually rich, amplifying the role of such individualized drinking motives on cue processing. However, previous literature has primarily relied on images of alcohol, which lack contexts and differ significantly from real-life. Here, aiming to investigate real-life craving, we examined the role of alcohol drinking motives in craving in response to naturalistic alcohol-drinking videos. We asked fifty-three problematic alcohol users to speak about their reasons for drinking alcohol to capture unique alcohol drinking motives of each individual. Participants also underwent functional MRI while watching fifteen alcohol-drinking videos, and reported their subjective level of craving and self-relatedness for each video. Behavioral data analysis revealed that individuals with greater alcohol use severity tended to report greater cue-induced craving, but only when they reported that a video was related to themselves. Inter-subject representational similarity analysis showed that participants with similar alcohol drinking motives, reflected in shared drinking reasons and similar self-relatedness to the videos, exhibited synchronized craving-related neural responses during video-watching. Notably, these shared neural processes mediated the link between similar drinking motives and similar self-reported craving levels across participants. Together, our findings highlight the crucial role of alcohol drinking motives in shaping cue-induced alcohol craving, and provide deeper insights into craving in real-world contexts.

Short-form video platforms increasingly shape how young audiences encounter health information. Generative artificial intelligence can produce standardized avatar-based messages at scale, but randomized evidence for tobacco prevention is scarce. In this three-arm randomized online intervention study with pre-post assessment, participants aged 16 years or older were assigned to an AI avatar video emphasizing short-term smoking consequences, an AI avatar video presenting long-term cancer-related information matched to an American Cancer Society fact sheet, or the same fact sheet in written form. The primary outcome was post-intervention intention to avoid smoking and secondhand smoke exposure, adjusted for baseline intention. Among 400 randomized participants, 272 had complete data for the primary baseline-adjusted analysis. Intention increased from baseline to post-intervention in all conditions, with no statistically significant between-group differences. These findings support AI avatar videos as a scalable, social-media-compatible format for digital tobacco prevention, while not establishing superiority or equivalence.

Alcohol use disorder (AUD) is a widespread psychiatric condition, yet the molecular mechanisms underlying its development remain poorly understood. While prior studies have largely focused on protein-coding genes, long non-coding RNAs (lncRNAs) remain underexplored in AUD. Malat1, a highly abundant and evolutionarily conserved lncRNA, is elevated in post-mortem brain tissue of human AUD subjects and rodents chronically exposed to ethanol; however, its causal contribution to AUD-relevant behaviors remains unknown. Using CRISPR/Cas9 genome editing, we generated two complementary global Malat1 knockout models to assess its role in alcohol intake and related phenotypes. Constitutive knockout selectively attenuated acute functional tolerance rate and every-other-day two-bottle-choice alcohol intake in females. These results were supported by an inducible adult conditional global knockout model, which reduced ethanol consumption in females without altering taste preference. Together, our findings provide the first causal evidence that Malat1 regulates alcohol consumption in a sex-specific manner, supporting further investigation into its underlying mechanisms in AUD.

BackgroundPrenatal cannabis use is becoming increasingly more commonplace. However, cannabis exposure is linked to adverse pregnancy outcomes, including gestational hypertension, preeclampsia, and preterm birth. The aim of this study was to determine the morphological and molecular effects of prenatal cannabinoid exposure on the placenta. MethodsPregnant Sprague-Dawley rats were exposed daily to vaporized THC (100 mg/mL) starting at gestational day (GD)5 until GD19 when dams were sacrificed and fetuses and placentas collected. Fetuses were genotyped for genetic sex and transcriptomic analysis was performed on male and female THC-exposed and control placentas. ResultsOn GD19, both the fetuses and placentas from the THC group were significantly larger than the control. When separated by sex, both male and female THC fetuses were significantly larger; however, only male THC placentas were significantly larger than male control placentas with no significant difference in placental weight between female control and THC placentas. RNA-sequencing revealed enriched biological processes related to nutrient transport and lipid catabolism, protein-lipid complex formation, and lipoprotein particle remodeling and organization. Further transcriptomic analysis determined that the differentially expressed genes and enriched biological processes related to lipid metabolism were preferentially enriched in the female THC placentas compared to the male, suggesting a sex-specific effect. DiscussionCollectively, these data present sex-specific effects of prenatal cannabinoid exposure on placental growth and global gene expression. These data also suggest that sex influences gene expression of genes related to lipid metabolism in the THC-exposed placentas.

Polysubstance use is rising and linked to heightened overdose rates and increased treatment challenges, further exacerbated by increasing detection of adulterants (e.g., xylazine) in the street drug supply. Harm reduction groups provide sterile syringes in exchange for used ones, creating a unique opportunity to characterize prevalent polysubstance combinations and inform translational and preclinical research We analyzed residues from used syringes (N=3,168) obtained from several harm reduction organizations in Jefferson County, KY (Jan-Dec 2025) for the presence of substances using gas chromatography mass spectrometry (GC-MS). We classified compounds as adulterants (e.g., diphenhydramine [DPH]/Benadryl), byproducts/precursors of synthesis (e.g., 4-ANPP), and recreational drugs (e.g., meth). We excluded byproducts/precursors and determined the most frequent substance and pairs/trios containing one or more recreational substance. Results. Of 3,168 syringes, 2,522 (79.61%) tested positive for substances. Out of those positive, the top recreational substances were meth (n=1,387; 54.99%), fentanyl (n=1,220; 48.37%), and heroin (n=653; 25.89%). Top adulterants were DPH (n=1021; 40.48%), dimethyl sulfone (n=749; 29.69%), and lidocaine (n=736; 29.18%). The most common pairs were DPH+fentanyl (n=670; 26.57%), lidocaine+fentanyl (n=659; 26.13%), dimethyl sulfone+meth (n=621; 24.62%), and fentanyl+heroin (n=484; 19.19%). The most common trios were DPH+lidocaine+fentanyl (n=369; 14.63%), DPH+fentanyl+heroin (n=327; 12.97%), lidocaine+fentanyl+heroin (n=297; 11.77%), diphenhydramine+xylazine+fentanyl (n=273; 10.82%), and meth+lidocaine+fentanyl (n=262; 10.39%). Our findings highlight evolving patterns of multiple-opioid and opioid-stimulant polysubstance use, generating insights that can be rapidly applied to strengthen clinical, preclinical, and translational polysubstance research. These insights allow for investigations into biobehavioral mechanisms and consequences of emerging use patterns, accelerating development of novel therapeutics.

Background: High levels of sedentary behaviour are an emerging global public health concern, but its impact on cancer risk remains unclear. Methods: Within the Global Cancer Update Programme (CUP Global), we systematically searched the literature in PubMed and Embase until September 2024 for observational cohort studies on sedentary behaviour and adult cancer risk. Using dose-response meta-analyses, we investigated sedentary behaviour domains (total, occupational, recreational, transportation, and/or other) and dimensions (duration, frequency), and additionally pooled across domains. The quality of evidence was graded by the CUP Global Expert Panel (protocol registration: https://osf.io/7utbm/). Findings: We identified 62 publications from 27 cohorts comprising 162,902 incident cancer cases across 19 anatomical sites. There was evidence for a probable causal positive association between sedentary time (mixed definitions) and breast (RRper 2 hours/day=1.03; 95%CI=1.02-1.05; I2=10%; n=11 studies) and colon (RR=1.05; 95%CI=1.03-1.07; I2=0%; n=9) cancer risk, and between television watching time and colon cancer risk (RRper 2 hours/day=1.08; 95%CI=1.05-1.11; I2=0%; n=6). Limited suggestive evidence supported positive associations between sedentary time (mixed definitions) and lung (RR=1.04; 95%CI=1.00-1.09; I2=69%; n=7), ovarian (RR=1.06; 95%CI=1.01-1.10; I2=0%; n=7), premenopausal (RR=1.03; 95%CI=0.99-1.08; I2=20%; n=7) and postmenopausal breast (RR=1.02; 95%CI=1.00-1.04; I2=7%; n=11), and colorectal (RR=1.02; 95%CI=1.00-1.04; I2=47%; n=11) cancers, and between occupational sitting time and breast (RRper 2 hours/day=1.05; 95%CI=1.01-1.09; I2=0%; n=4) and colon (RR=1.08; 95%CI=1.02-1.15; I2=28%; n=2) cancers. An interactive evidence platform is available at: https://teacup.cc.ic.ac.uk/sedentary-behaviour-cancer.html. Interpretation: Evidence supports that prolonged sedentary behaviour is probably a cause of breast and colon cancers, while limited suggestive evidence supports positive associations for several other exposure-cancer pairs, including lung and ovarian cancers. This evidence should lead to revised cancer prevention recommendations. Future research should focus on device-based exposure assessments, repeated measurements, exposure substitution models, inclusion of diverse populations and investigation of biological mechanisms.

Background: Compulsive alcohol use despite negative outcomes is a defining characteristic of alcohol use disorder. Rats exposed to long-term intermittent alcohol access (IAA) demonstrate sustained motivation for ethanol despite presence of the bitter additive quinine, offering a useful preclinical model of compulsive alcohol use. However, little is known about the role of habenular circuitry in the development of this phenotype. Here, we employed chemogenetic techniques targeting basal forebrain (BF) input to the lateral habenula (LHb) to probe the involvement of this neural circuitry in aversion-resistant alcohol consumption. Methods: Following long-term IAA or control conditions, male and female Long-Evans rats underwent surgery for the expression of designer receptors in BF-to-LHb projections. We then excited this pathway in rats with IAA history, or inhibited this pathway in rats with more limited ethanol history, before testing consumption of unadulterated and quinine-adulterated ethanol as well as unadulterated and quinine-adulterated sucrose. Results: Long-term IAA elevated ethanol drinking in all rats and aversion-resistant ethanol preference in males. Chemogenetic activation of BF-to-LHb neurons in rats with IAA history produced different effects in males and females: excitation enhanced ethanol intake in females, but reduced ethanol preference in males, regardless of quinine adulteration. Activation also led to a relative insensitivity to quinine-adulteration of sucrose when compared to controls, particularly in females. Chemogenetic inhibition in rats with limited prior ethanol exposure did not alter either ethanol or sucrose consumption with or without quinine. Conclusions: Our results suggest a differential role for BF-to-LHb circuitry in ethanol drinking based on sex, and a potential role for this circuitry in the sensitivity to quinine in the context of natural reward consumption.

Adolescent use of alcohol, nicotine, and marijuana remains a major public health concern in the United States. Early identification of youth at elevated risk is critical for prevention before use begins or escalates. We developed and evaluated a longitudinal machine learning framework to predict alcohol, nicotine, and marijuana use at the next observed assessment wave. Data came from the Adolescent Brain Cognitive Development (ABCD) Study Release 6.0. The models incorporated predictors from multiple domains, including demographics, friends, family and community context, mental health, physical health, and prior substance-related behaviors. To reduce information leakage across individuals, we implemented a leakage-aware stacked ensemble. This ensemble combined diverse base learners through out-of-fold predictions and an elastic-net meta-learner. Across all three substances, the lagged stacked ensemble outperformed the cross-sectional stack and all single base learners. Adolescents identified as highest risk showed substantially higher observed rates of substance use than would be expected under random screening. Feature-importance analyses showed that the full longitudinal models were strongly influenced by developmental timing and prior-use history. Analyses restricted to current-wave features revealed distinct substance-specific risk patterns beyond prior-use history and developmental timing. Bootstrap stability analyses identified top-ranked features showing consistent positive predictive relevance across resampled adolescents. These findings suggest that longitudinal, leakage-aware machine learning can generate substance-specific risk estimates to support targeted prevention and screening in adolescent populations.

RationaleAppetitive Pavlovian cues can drive maladaptive reward seeking via stimulus-reward memories. Disrupting memory reconsolidation offers a potential strategy to reduce their influence, but evidence for {beta}-adrenergic blockade with propranolol is inconsistent across behavioural paradigms, particularly relative to NMDA receptor antagonism. ObjectivesWe tested whether propranolol disrupts reconsolidation of appetitive sucrose memories in a discriminative goal-tracking paradigm, and compared its effects with those of the most commonly used NMDA receptor antagonist, MK-801. MethodsAdult Lister hooded rats underwent discriminative Pavlovian conditioning. Thirty minutes before a brief memory reminder (non-reinforced or reinforced), rats received systemic drug treatment or saline control. In study 1, MK-801 (0.1 mg/kg) was administered to male rats. In study 2, propranolol (10 mg/kg) was administered to equal numbers of male and female rats. Goal-tracking was tested drug-free at 1 and 8 days. ResultsIn study 1, MK-801 impaired subsequent discriminated responding at test. These effects were observed not only when reminder was non-reinforced as in previous successful demonstrations, but also with reinforced reminder. In study 2, Propranolol also impaired subsequent goal-tracking, regardless of reminder type, and the effects were consistent across sexes. ConclusionsPropranolol can disrupt reconsolidation of appetitive goal-tracking memories to a similar extent as MK-801 under conditions that promote memory destabilisation. These findings demonstrate that {beta}-adrenergic blockade can impair appetitive memory reconsolidation in a goal-tracking paradigm, challenging prior null findings and revitalising the potential for propranolol-based interventions in maladaptive reward-seeking behaviours.

20% of Americans are at risk for environmental circadian rhythm disruptions (CRD) due to shift work, leading to substantial negative health outcomes. However, females are especially affected with greater vulnerability for substance use (SU) and adverse outcomes associated with pregnancy, including for offspring at birth and later in life. In mice, prenatal CRD (pCRD) recapitulates these risks, but it is unknown whether pCRD affects SU in mature offspring. To investigate this, C57BL/6J dams were disrupted by reversing the light/dark cycle during gestation. Following pCRD, reward- (cocaine conditioned place preference, intravenous self-administration) and mood-related behaviors (open field, elevated plus maze, light/dark box, forced swim) were measured in adult offspring. Adult female offspring of dams exposed to CRD developed an anhedonic-like phenotype with decreased food self-administration, cocaine intake and reinforcing properties of cocaine. Opposingly, pCRD male offspring showed a SU-like phenotype with increased cocaine preference, higher order food self-administration and cocaine reinforcement. Interestingly, these divergent behavioral outcomes were not specific to reward. While female pCRD mice showed increased anxiety-like behavior, pCRD males showed decreased anxiety/increased risk-taking behavior, as well as decreased immobility in the forced swim test. Rhythms in corticosterone were also sex-specifically affected by pCRD. These results suggest that pCRD may predispose individuals to distinct psychiatric disorders based on sex with mood disorders developing in females and SU disorders developing in males. By better understanding how disrupted rhythms during pregnancy affect behavior in adulthood, we can develop novel therapeutic approaches for SU and mood disorders in adults.