Alcohol

RationalePrenatal alcohol exposure (PAE) can result in Fetal Alcohol Spectrum Disorder (FASD), which consists of a group of diagnosable medical conditions that can include an increased risk for anxiety disorders and/or alcohol misuse, and sensory issues, such as increased mechanical sensitivity. ObjectiveThis study investigated how a single moderate PAE on gestational day 12 (G12) alters anxiety-like behavior, ethanol (EtOH) intake, and mechanical sensitivity across the lifespan of Sprague Dawley rats. MethodsPregnant dams were exposed to vaporized EtOH or room air (control) for 6 hours (BECs [~]108 mg/dL). Testing in male and female offspring began at three different ages: juveniles ([~]postnatal day (P) 25), adolescents ([~]P45) and adults ([~]P80). ResultsThe greatest PAE effects were observed in adolescent animals, with alterations in anxiety-like behaviors demonstrated in the light-dark box and elevated plus maze. Additionally, adolescent female animals consumed more sweetened EtOH compared to males. However, PAE adolescent animals consuming less sweetened EtOH compared to their counterparts, which was also observed in adult PAE females. Interestingly, this effect is reversed in juvenile and adolescent males when tested with unsweetened EtOH, with juvenile females consuming more EtOH also. Finally, PAE and air animals exhibited increased mechanical sensitivity following post-natal EtOH consumption across all ages. ConclusionThese data demonstrate that there are age- and sex-specific effects of PAE on anxiety-like behaviors, EtOH intake, and mechanical sensitivity that are more distinct in adolescent animals.

BackgroundAlcohol use disorder is a chronic relapsing condition characterized by excessive drinking and withdrawal symptoms. Alcohol dependence disrupts function across multiple brain regions, and recent evidence implicates the cortical amygdala (CoA) as a critical node in alcohol-related circuits. However, how CoA activity influences alcohol intake and brain-wide network function during withdrawal remains unclear. MethodsAlcohol dependence was induced using chronic intermittent ethanol vapor (CIE). In one cohort, electrophysiological activity of CoA neurons was assessed during withdrawal. In a second cohort, mice underwent CIE paired with two-bottle choice drinking, and inhibitory DREADDs (hM4Di) were used to suppress CoA activity during drinking and withdrawal while behavioral outcomes were measured. Brains were then collected for Fos immunolabeling and iDISCO+ based whole-brain activity mapping to determine how CoA inhibition during withdrawal altered network organization. ResultsRepeated CIE increased alcohol sensitivity in CoA neurons during withdrawal. Chemogenetic inhibition of the CoA reduced alcohol intake in dependent mice without affecting withdrawal-related behaviors. Whole-brain Fos mapping showed that CoA inhibition reduced activity within the CoA while enhancing functional connectivity across multiple brain regions, particularly in the isocortex, thalamus, and anterior hypothalamic nucleus. During withdrawal without CoA inhibition, thalamic regions exhibited negative connectivity, consistent with disrupted network function; CoA inhibition reversed this pattern, producing strongly positive thalamic and medial prefrontal cortex connectivity. ConclusionsThese findings demonstrate that alcohol dependence alters CoA sensitivity, alcohol dependence-induced drinking and brain-wide network organization during withdrawal. The CoA appears to selectively regulate withdrawal-associated alcohol drinking, and its inhibition may reduce intake by restoring thalamic and cortical connectivity. HighlightsO_LIThis study identifies the cortical amygdala as a previously underexplored brain region involved in alcohol-related behaviors. C_LIO_LIBy integrating chemogenetic inhibition with brain-wide network analysis, the study reveals candidate circuit connections through which the CoA may regulate alcohol dependence-related brain activity. C_LIO_LIThis study establishes the CoA as a potential driver of excessive alcohol drinking and alcohol-related network dysfunction. C_LI

Background: Alcohol use disorder (AUD) is associated with altered gene expression across diverse cell types in reward-related brain regions, including the ventral tegmental area (VTA), which is rich in dopaminergic neurons. The VTA plays a central role in reward processing, learning, and memory; however, cell type-specific gene expression changes within the VTA remain uncharacterized. Methods: We applied single-nucleus RNA sequencing (snRNA-seq) to profile transcriptomic alterations associated with AUD in the VTA. Postmortem VTA samples from four individuals of European ancestry [two with AUD (one male, one female) and two matched controls (one male, one female)] were analyzed using the 10X Genomics Chromium Fixed RNA Profiling protocol. Differentially expressed genes (DEGs) were identified using Seurat, and enriched KEGG pathways was assessed by gene set enrichment analysis. Results: Nuclei were classified into six major cell types: astrocytes, endothelial cells, mature neurons, microglia, oligodendrocytes, and oligodendrocyte precursor cells (OPCs). At thresholds of P < 0.05 and |fold change| > 2.0, we identified 547 DEGs in astrocytes, 727 DEGs in endothelial cells, 715 DEGs in mature neurons, 421 DEGs in microglia, 263 DEGs in oligodendrocytes, and 432 DEGs in OPCs. DEGs across VTA cell types were enriched for pathways related to mitochondrial function, neurodegeneration, and synaptic signaling. Notably, DEGs in mature neurons were enriched for addiction-related pathways. Further subdivision of mature neurons into dopaminergic, GABAergic, glutamatergic, and unclassified subtypes revealed 526, 930, 896, and 569 DEGs, respectively. Neuronal DEGs indicate a convergence on mitochondrial/oxidative phosphorylation and neurodegeneration-related pathways across subtypes, whereas addiction- and synapse-related pathways show dopaminergic neuron-specific enrichment. Conclusions: This study provides the first cell type-resolved transcriptomic profiling of the human VTA, revealing AUD-associated gene expression alterations across neuronal, glial, and endothelial cells. The observed cell type-specific changes in synaptic plasticity and addiction-related genes offer new insights into molecular mechanisms underlying AUD pathophysiology.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are chronic psychiatric disorders that have overlapping symptomology and risk factors, including altered motivation and impulsive behavior. Inescapable exposure to a predator odor stressor (2,3,5-Trimethyl-3-Thiazoline (TMT)) produces PTSD-like symptomology in rats. Individual differences in stress-coping behaviors such as freezing and defensive digging during TMT exposure can predict long-term differences in alcohol-related behaviors and altered neurobiology. Here, we sought to evaluate the relationship between stress coping behavior during TMT exposure and different aspects of decision making. In Experiment 1, male and female rats were trained on an adjusting-amounts delay discounting task, and delay discounting curves were established before and >2 weeks after TMT exposure. In Experiment 2, female rats were trained to self-administer alcohol and sucrose in a concurrent choice procedure. Lever responses and preference for alcohol over sucrose were evaluated before and >2 weeks after TMT exposure, and then motivation for competing reinforcers was evaluated using progressive ratios. Active coping (digging) during TMT exposure was correlated with increased post-TMT impulsive choice (Experiment 1), reduced sucrose lever responses both before and after TMT exposure (Experiment 2), and reduced sucrose lever breakpoint (Experiment 2). Additionally, TMT-exposed rats had increased motivation for both alcohol and sucrose self-administration when available concurrently (Experiment 2). Overall, these findings suggest that behavior prior to and during a stressful experience can predict susceptibility to negative effects on decision making, which may help future studies identify the neurobiology underlying risk for aberrant reward-related behaviors after a traumatic event.

Individuals with Fetal Alcohol Spectrum Disorders (FASDs) show reduced subicular volume, and preclinical studies compliment this by demonstrating that third-trimester-equivalent ethanol exposure induced apoptosis in corticolimbic regions, including the subiculum. The subiculum mediates hippocampal-cortical communication critical for long-term memory consolidation. Within the distal dorsal subiculum, a population of bursting neurons uniquely express VGLUT2 and they play a key role in memory processing. We hypothesized that third-trimester-equivalent ethanol exposure would reduce neuronal and VGLUT2+ cell density in the dorsal subiculum and reduce the excitability of bursting neurons, providing a mechanism for long-term memory impairments observed in FASD. To test this, postnatal day (P)7 mice received a subcutaneous injection of ethanol and long-term effects were assessed in adolescence (P35-62). Using transgenic mice with fluorescently labeled VGLUT2+ neurons, and immunohistochemistry we observed a significant reduction in neuronal density in males and an increase in VGLUT2+ cell density in females. Using whole-cell patch clamp electrophysiology, we observed a reduction in action potentials per burst in both sexes. Additionally, females showed reduced overall excitability, and a subset of neurons exhibited a shift to regular spiking. These findings suggest that development ethanol exposure disrupts subicular output by impairing burst firing, potentially weaking hippocampal-cortical communication and contributing to the cognitive deficits associated with FASD. HighlightsO_LIThird-trimester ethanol targets VGLUT2+ neurons in the dorsal subiculum C_LIO_LIEthanol reduced neuronal density in male dorsal subiculum C_LIO_LIEthanol increases VGLUT2+ cell density in females C_LIO_LIEthanol reduces action potential per burst in both sexes C_LIO_LIFemales show reduced excitability and loss of bursting in some cells C_LI

Excessive alcohol consumption remains a major public health challenge with limited therapeutic options. Both glucagon-like peptide-1 (GLP-1) and fibroblast growth factor-21 (FGF21) independently regulate alcohol intake through complementary metabolic and reward pathways, but their combined potential has not been explored. Here, we report that a long-acting dual agonist, GLP1-ELP-FGF21 modulates behavioural, neurophysiological, and cognitive components of alcohol seeking in mice. A single GLP1-ELP-FGF21 dose reversibly reduces voluntary alcohol intake for at least 72 hours in male mice, has sustained effects in female mice, and markedly blunts nucleus accumbens dopamine transients aligned to the initiation and termination of lick bouts during alcohol consumption. To assess its effects on decision-making, we used a novel two-choice (alcohol versus food) decision task modelled with evidence-accumulation frameworks. Alcohol choice behaviour conformed to evidence accumulation decision models: Linear Ballistic Accumulator (LBM) and Racing diffusion models (RDM). Critically, GLP1-ELP-FGF21 selectively reduces choices for alcohol and slows the latent accumulation rate for alcohol options, without affecting food-directed choice or non-decision processes. Sensory-specific satiety devaluation confirms that reductions in reward value are explained by reductions in accumulation rates. Together, these results highlight GLP1-ELP-FGF21 as a therapeutic strategy for alcohol use disorder via modulation of central reward pathways and decision-making when confronted with alcohol rewards.

BackgroundChronic alcohol use disorder (AUD) is associated with profound dysregulation of immune function, neuroinflammation, and systemic stress responses, which contribute to both the maintenance of addiction and alcohol-related organ damage. While brain transcriptomic studies have established neuroimmune signaling and synaptic remodeling as central features of AUD, peripheral blood signatures during early withdrawal and recovery remain underexplored. Understanding the dynamic transcriptional changes in peripheral blood accompanying supervised withdrawal therapy is critical for identifying reversible molecular processes versus persistent trait-like alterations. MethodsRNA sequencing (RNA-seq) was performed on peripheral blood from individuals with alcohol use disorder (AUD, n = 100) and healthy controls (n = 74) at baseline and after three weeks of supervised withdrawal therapy. Differentially expressed genes (DEGs) were identified using linear mixed models assessing main effects of group, time, and their interaction. Functional enrichment and co-expression network analyses were performed to identify coordinated biological processes. ResultsAt baseline, more than 1,000 genes were differentially expressed between AUD and control participants, showing robust dysregulation of immune-related pathways. After three weeks of withdrawal, the number of DEGs decreased markedly to 141, indicating partial transcriptomic normalization. Nevertheless, immune dysregulation persisted despite treatment, particularly linked to B cell activation and cell-cell junctions. Interaction analyses (group x time) identified 16 genes whose expression dynamically changed with therapy, highlighting strong enrichment for fatty acid pathways. Co-expression network analysis revealed that baseline modules were enriched for genes associated with secretory granules and immune signaling, while therapy-related co-expression shifts involved coagulation and platelet activation processes. ConclusionsAUD is associated with widespread but partly reversible transcriptomic dysregulation in peripheral blood. These findings support a system-level view of AUD as a disorder of intertwined immune, metabolic, and coagulation biology and suggest that longitudinal blood transcriptomics may help identify both rapidly therapy-responsive and more stable molecular targets for relapse prevention.

Unpredictable and insufficient access to food, known as food insecurity, is associated with the development of obesity. However, causal mechanisms underlying this paradoxical relationship remain poorly understood. Using a rat model of food insecurity, this study investigated whether food insecurity causes dysregulated feeding behaviours, specifically impaired gut signal sensitivity and enhanced cue-driven appetitive responses. Adolescent female rats were assigned to receive either ad libitum chow access (Food secure), 90% caloric restriction (Food restricted) or unpredictable quantity and timing of food access (Food insecure), for 4 weeks. After which, rats were returned to an ad libitum chow diet for the remainder of the study. To examine gut signal sensitivity, we measured the effects of cholecystokinin (CCK) on 10% sucrose intake. To examine cue-driven feeding behaviours, we used Pavlovian appetitive conditioning and measured appetitive responses towards a food-predictive cue. Results showed that prior food insecure rats were less sensitive to the intake inhibitory effects of CCK and exhibited enhanced cue-induced appetitive behaviours, when compared to food secure and food restricted groups. Anxiety-like behaviours or learning and memory was not different between groups. At the end of the study, adolescent caloric restriction resulted in reduced fat mass, plasma leptin levels and body weight when compared to food secure, but not food insecure rats, suggesting that adolescent food insecurity somewhat overcame these metabolic effects. Taken together, our findings suggest that adolescent food insecurity impaired gut signal sensitivity and heightened food cue sensitivity, which may cause enduring metabolic and behavioural adaptations that promote overeating and weight gain.

Background: Despite the significant risks associated with online substance procurement (SP), few researchers have examined this practice in U.S. youth. The studies that do exist are cross-sectional and cannot temporally connect specific digital behaviors to online SP. This longitudinal cohort study examined youth SP and digital media habits to determine whether use of certain smartphone applications correlated with increased odds of online SP or being contacted online about procuring drugs or alcohol. Methods: A cohort of U.S. youth (aged 15-20) with a history of non-daily substance use in the 3 months prior to enrollment was recruited to use the digital phenotyping smartphone application EARS for 90 days. On a nightly basis, participants were asked to complete surveys about online experiences related to SP and instances of substance use. Smartphone-generated screen use data were also collected passively each day. Results: Out of 112 enrolled participants, 106 were able to be included in analyses. Over approximately 3 months, 28.3% of participants (n=30) reported a collective 91 instances where they used social media to acquire drugs or alcohol. Screen use data demonstrated temporal relationships between social media SP and applications previously connected to the social media drug-purchasing process (e.g., TikTok, encrypted apps), as well as other school-specific social media. Discussion: Our results provide critically needed research evidence to support a body of literature composed predominantly of anecdotal reports. Despite measures taken by social media companies to prevent use of their platforms for drug procurement, underage youth continue to engage in this practice.

BackgroundDisturbance of circadian rhythms is a hallmark of substance use disorders, with depressant drugs often causing soporific effects such as reduced sleep latency. The suprachiasmatic nucleus (SCN) of the hypothalamus is the central circadian pacemaker in mammals, regulating daily rhythms in physiology and behavior. However, the cellular mechanisms through which depressants alter SCN function remain poorly defined. MethodsWe used whole-cell patch clamp electrophysiology in acute brain slices to examine how alcohol and opioids modulate excitatory glutamatergic transmission onto SCN neurons. Ethanol effects were examined both acutely and following chronic exposure paradigms. Optogenetic stimulation was used to activate either RHT input or -opioid receptor-expressing (MOR) terminals, and MOR agonists were used to assess opioid-mediated effects on synaptic transmission. ResultsWe show that acute application of ethanol paradoxically enhances SCN firing rates. In contrast, chronic alcohol exposure reduces glutamatergic drive. We also found that activating MOR+ terminals produced bidirectional modulation of SCN firing and that MOR+ inputs formed functional glutamatergic synapses onto SCN neurons. Notably, this transmission could be suppressed by the MOR agonists DAMGO and fentanyl. ConclusionsTogether, these findings reveal that both alcohol and opioids modulate glutamatergic input to the SCN. This work establishes the SCN as a novel target of depressant substances and highlights glutamatergic transmission as a key point of vulnerability in circadian dysregulation associated with substance use.

BackgroundAn overwhelming body of evidence suggests neuroimmune dysfunction as a key underlying mechanism of FASD-associated adverse CNS outcomes. While few studies have highlighted the lingering effects of prenatal alcohol exposure (PAE) on producing specific immune factors, others suggest a primed neuroimmune state in adulthood, in which a proinflammatory bias is unmasked following subsequent immune activation in later-life. However, the PAE-induced neuroimmune landscape in adulthood remains poorly defined. We hypothesized that PAE induces long-term changes in gene expression linked to neuroimmune function that may be brain region-specific. MethodsUsing long-read next-generation RNA sequencing of brain tissues from a previously established model of a moderate PAE in mice, we compared across six regions: medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), hypothalamus, hippocampus, midbrain, and medulla. A comprehensive bioinformatics analysis investigated PAE-induced changes, dysregulated gene pathways, and transcriptional regulators with a focus on neuroimmune function. ResultsOur data identified at least 60 differentially expressed genes per brain region, many of which were associated with neuroimmune function. Upregulation of multiple proinflammatory factors and pathways was observed, suggesting ongoing baseline neuroimmune activation, potentially involving PXR, TNF, TLR4, the complement pathway, and various cytokine and chemokine signaling. A comparative analysis identified multiple upstream transcriptional regulators across multiple brain regions, including MECP2, TCF7L2, and IL-4. Importantly, this unbiased analysis revealed heterogeneity across brain regions in the activation of canonical immune pathways and highlighted previously unprecedented roles of pathways such as PXR, matrix metalloproteases, and cytokine signaling (e.g., IL-15, IL-27, IL-17) in PAE. ConclusionsPAE creates a unique inflammatory signature in the adult brain, even in the absence of secondary injury, with novel patterns of region-specific changes in genes implicated in glial-immune function. These data identified potential immune targets to elucidate the mechanisms underlying behavioral dysfunction and provide a framework for future therapeutic interventions.

Background: Alcohol use disorder (AUD) is marked by high relapse rates often driven by craving, yet less is known about whether in vivo, social, and place-based alcohol cues are differentially associated with craving across affective states. This study examined independent and affect-contingent associations of these cues with momentary craving in adults with AUD enrolled in an alcohol intervention study. Methods: Thirty-three adults with AUD completed up to four daily ecological momentary assessments (EMA) for 28 days. EMA prompts assessed craving, in vivo alcohol exposure, being around usual drinking partners, being in usual drinking places, and high-arousal positive affect (PA) and negative affect (NA). Multilevel mixed-effects models adjusted for demographics, intervention phase (1 = post, 0 = pre), AUD severity, and temporal and contextual covariates. Results: EMA compliance was high (median per-participant = 86.6%). Within-person elevations in in vivo alcohol exposure and being around usual drinking partners were independently associated with greater momentary craving, whereas being in usual drinking places was not. In vivo alcohol exposure was more strongly associated with craving during higher-than-usual PA ({beta} = 0.08, p = .032), whereas being in usual drinking places was more strongly associated with craving during higher-than-usual NA ({beta} = 0.06, p = .036), adjusting for intervention phase, which was associated with lower craving. Conclusions: Findings support the need for personalized just-in-time adaptive interventions tailored to high-risk, momentary cue-affect contexts in AUD, beyond low-frequency clinician-delivered feedback that may reduce average craving but not fully address real-time risk. ClinicalTrials.gov registration: NCT05135767.

Relapse to alcohol use is frequently triggered by re-exposure to alcohol-associated cues, and extinction-based interventions reduce relapse vulnerability. However, the cellular mechanisms through which extinction suppresses alcohol seeking remain unclear. Using a mouse model of operant alcohol self-administration, we examined how extinction training alters activity of defined striatal direct-pathway medium spiny neuron (dMSN) populations in the dorsomedial striatum (DMS). Extinction significantly reduced cue-induced reinstatement and decreased reactivation of acquisition-recruited dMSN ensembles during relapse. Chemogenetic activation of acquisition-recruited dMSN ensembles during extinction impaired extinction learning and enhanced subsequent reinstatement, even in the absence of manipulation at test, indicating that suppression of these ensembles is required for effective extinction. In contrast, selective activation of striosomal dMSNs during extinction accelerated extinction learning and further reduced reinstatement without affecting locomotor activity. These findings demonstrate that extinction suppresses alcohol seeking through coordinated modulation of distinct striatal dMSN populations, involving both reduced engagement of acquisition-related ensembles and recruitment of striosomal circuits. Together, these findings provide mechanistic insight into how extinction reshapes striatal circuitry to suppress relapse-related behavior and highlight defined striatal dMSN populations as potential substrates for enhancing extinction-based interventions.

Background: Cannabis use is highly prevalent among emerging adults (18-25 years), a developmental period marked by ongoing neurodevelopment and heightened risk for cannabis use disorder (CUD). Structural alterations in the orbitofrontal cortex (OFC) and medial prefrontal/anterior cingulate cortex (mPFC/ACC) have been linked to cannabis use, though findings remain inconsistent in directionality. To address this, we examined cortical thickness and surface area of the OFC and mPFC/ACC subregions using the high-resolution Glasser atlas, allowing for more granular characterization of associations with CUD severity. Method: One hundred eleven emerging adults (41% male, aged=20.6{+/-}1.1 years) reporting significant alcohol and/or cannabis use completed clinical assessments and structural MRI. The OFC and mPFC/ACC were segmented into seven and six subregions per hemisphere, respectively. Multiple linear regressions tested associations between cortical thickness or surface area and DSM-5 CUD symptom count, controlling for alcohol use and intracranial volume. Subregions surviving false discovery rate correction were examined in relation to depression, trauma-related symptoms, impulsivity, and cannabis use motives. Results: Greater CUD severity was associated with lower cortical surface area and greater cortical thickness in OFC and mPFC/ACC subregions. Lower OFC surface area was correlated with coping- and enhancement-related cannabis use motives. Lower mPFC/ACC surface area and greater thickness were associated with more severe depression, trauma-related symptoms, and impulsivity. Conclusion: In high-risk emerging adults, greater CUD symptom burden is associated with lower surface area and greater thickness in OFC and mPFC/ACC subregions. Using the high-resolution Glasser atlas, these findings provide a more precise characterization of structural correlates of CUD and highlight potential neurobiological markers linked to affective and motivational processes underlying cannabis use.

Relapse-prevention strategies aimed at reducing relapse following abstinence, primarily focus on reducing cravings that lead to drug-seeking triggered by stress, drug-related cues, or re-exposure to the drug. Because addictive drugs form persistent associative contextual memories, we investigated how reactivation of cocaine-related hippocampal memories influences subsequent drug-seeking. Here, we tagged dorsal dentate gyrus (dDG) memory ensembles involved in encoding either a first or fourth cocaine exposure (15mg/kg, i.p) in male and female c57BL/6 mice using a TetTag approach. Mice underwent cocaine conditioned place preference (CPP), extinction, and reinstatement. We assessed whether optical reactivation of tagged cocaine-related ensembles could substitute for a cocaine priming injection to reinstate CPP, whether reactivation altered cocaine-induced reinstatement, and if these effects differed depending on stage of drug exposure. We also compared these effects to reactivation of saline-associated ensembles. Cocaine produced robust locomotor activation during conditioning, and sensitization developed across repeated drug exposures. Reactivation of a cocaine-related engram alone did not reinstate CPP. However, reactivation of the first cocaine exposure engram attenuated cocaine-induced reinstatement. In contrast, reactivation of the fourth exposure engram did not confer this protective effect. Interestingly, reactivation of saline-associated ensembles also reduced cocaine-induced reinstatement specifically in females, suggesting dDG ensemble reactivation may modulate relapse-related behavior through interference or neuromodulatory disruption of cocaine-associated representations, consistent with our prior work. These findings raise the possibility that early contextual experiences form competing or destabilizing representations that interfere with later cocaine-seeking when reactivated. Females also displayed greater sensitivity to locomotor-inducing effects of cocaine memory reactivation, although this was dissociated from CPP. Together, these findings show that cocaine memories are distinct across drug experience and selective reactivation of dDG engrams can differentially influence drug-seeking.

Background: An increasing demand for organic food has risen due to perceived health benefits. Current evidence for the health effects of organic food is limited. Objective: To evaluate the association between organic food purchase as a proxy for organic food consumption and hypertension in a nationally representative population of the US. Methods: This was a cross-sectional study that included 9173 participants aged >= 18 and had available data of both organic food purchase and hypertension from the National Health and Nutrition Examination Survey 2007-2010. Organic food purchase and frequency were obtained from survey questionnaires. Hypertension was defined as having either a systolic BP >= 130 mm Hg/ diastolic BP >= 80 mm Hg, currently taking antihypertensive medication, or self-reported diagnosis of hypertension. We used multivariable logistic regression with sample weights and adjustment of potential confounders to assess associations (adjusted odds ratio [aOR] and 95% confidence intervals [CI]) between organic food purchase and hypertension status. Results: Findings suggest an 11% decrease in odds of hypertension (aOR = 0.89, 95% CI: 0.75-1.06) among organic food purchasers compared to non-purchasers. Lower odds of hypertension were observed across all categories of organic food purchasing frequency, with 13% lower among rarely purchasing organic food (aOR = 0.87, 95% CI: 0.67-1.14), 9% lower (aOR = 0.91, 95% CI: 0.71-1.16) among sometimes purchasing organic food, and 17% lower (aOR = 0.83, 95% CI: 0.55-1.27) among always or mostly purchasing organic food, as compared to those who never purchased organic food. Conclusion: Our findings suggest that organic food purchase, a proxy for organic food consumption, may be associated with lower odds of hypertension. These findings may reflect either the true benefits of organic food consumption, including lower pesticide amounts and higher nutrient content, or the health-seeking behaviors among health-conscious, healthy, and highly educated individuals.

RationaleThe progression of psychostimulant abuse is associated with a shift from recreational to habitual use (R2H-shift). Because this R2H-shift can be modeled using behavioral economics, we developed a novel Behavioral Economic model for the Analysis of Self-administration Time-curve (BEAST) to obtain R2H-shift variable(s). The relationship(s) between R2H-shift variables and drug intake (under normal and/or punishment conditions) is/are unknown. Our goal was to determine if the R2H-shift variable and intake variables obtained during the initial self-administration training phase were related to 1) drug intake at that time, and subsequent drug intake under 2) normal, 3) punishment, 4) post-punishment, and 5) price-constrained conditions. MethodLong Evans rats self-administered methamphetamine (METH, males n = 16, females n = 14), sucrose (males n = 22, females n = 22) and/or saline (males n = 3, females n = 10) under FR1 for 6 h per day for 20 days to obtain 1) followed by the assessment of subsequent drug intake under different conditions (2-5 above). We obtained all variables referenced above. We determined the relationships between all variables (multivariate analysis). ResultsThere were no sex differences detected in the METH and sucrose studies. For METH and sucrose, prior drug intake levels could predict drug intake under normal/punishment but not under price-constrained conditions. The R2H-shift variable could predict drug intake under a consumption-price curve but could not predict intake under normal/punishment conditions. ConclusionsWhile related to economic demand, the recreational-to-habitual shift rate was unrelated to drug intake levels (under normal and punishment conditions).

Current treatments for opioid use disorder (OUD) have major barriers to access. As such, researching new potential therapies for OUD is important to public health. Previous research has implicated glucagon-like peptide-1 (GLP-1) receptor agonists in decreasing the use of addictive substances by animals. In this study, female Wistar rats (N=32) were surgically implanted with jugular catheters and trained to self-administer fentanyl at a fixed-ratio 1 (FR1) schedule of reinforcement for 21 sessions under short- (ShA; 1 hour) or long-access (LgA; 8 hours) conditions. Next, the animals received injections of semaglutide (0.1 mg/kg, s.c.) or saline (0.9% NaCl, s.c.) prior to another FR1 session. The animals underwent a progressive ratio (PR) schedule of reinforcement while receiving saline (i.v.) or fentanyl (0.625-10 {micro}g/kg/inf, i.v.) and semaglutide (0.1 mg/kg, s.c.) or saline (s.c.). Next, the animals underwent a semaglutide (0-0.1 mg/kg, s.c.) dose response procedure at FR1 and a single dose of fentanyl (2.5 {micro}g/kg/inf, i.v.). Following drug discontinuation, spontaneous locomotor activity and withdrawal-like symptoms were measured. Semaglutide dose-dependently decreased fentanyl rewards under ShA and LgA conditions (p<0.05). Under a PR, semaglutide significantly decreased breakpoint (p<0.05), suggesting semaglutide decreases motivation to self-administer fentanyl. Semaglutide-treated ShA animals displayed significantly less withdrawal-like behavior (p<0.05) but not LgA animals. Overall, these findings suggest semaglutide may modulate motivation to seek opioid reward and could be useful in the development of pharmacotherapies to address OUD.

Standard rat housing may impede species-typical behaviors and impact rat welfare and research outcomes. This research investigated the effects of housing on behavioral and physiological outcomes of rats through the use of modified large animal cages for housing, and was conducted in two studies. Study A: 70 Sprague Dawley (SD) rats (34 males, 36 females; 5 wk old) were randomly assigned to standard polycarbonate shoebox cages (C: 733.9cm2) or modified stainless steel primate cages (T: 10,416cm2) for 18 days. In Study B: 48 SD rats (24 males, 24 females; 7.5 wk old) were held in T housing for 90 days to assess long term impacts. All rats received gentle handling for 15s 3x/week. Rats were assessed for body weight, anxiety-like behavior in an elevated plus maze, response during a voluntary human approach test, and overall home cage behavior, posture, and space usage. Data were analyzed using generalized linear mixed models, with sex and treatment as fixed effects, and cage as the random effect. The results of study A suggest that the modified large animal cages (T) had positive impacts on rat behavior and welfare. T rats were less anxious (P=0.038) and more active (P<0.0001) and explorative (P=0.0003) compared to C rats. In both groups, activity levels declined towards the end of the 18-day study period (P<0.0001). For study B, similar patterns were observed, with rats becoming more inactive (P<0.0001) over 90 days. However, rats spent significant time on elevated shelves in T housing, which increased throughout the study (P<0.0001), suggesting continued use of the resources the housing provided. In both studies, there were no differences in latency to approach humans (P>0.05), but T rats spent less time in contact with human handlers, suggesting differences in motivation to interact with humans that should be explored further.

ObjectivesTo examine the extent to which heat-related causes of death are recorded in fatal drug overdoses, how these patterns vary across states and over time, and how overdose characteristics differ between deaths with, versus without, heat involvement recorded. MethodsDeath certificate data for all drug overdose deaths in US residents from 2001 to 2024 (from the National Center for Health Statistics) were analyzed to identify whether a heat-related cause of death was also listed on the death certificate. Joinpoint regression, descriptive statistics, and nonparametric tests were used to examine temporal trends and compare overdose deaths with versus without recorded heat involvement. ResultsIn 2001, fewer than 10 drug overdose deaths with recorded heat involvement were identified, but this number increased to 558 in 2024. From 2013 to 2024, mortality rates increased significantly, with an estimated annual percent change of 30.1 (95% Confidence Interval, 26.5-47.1). The highest mortality rates and numbers of deaths were observed in residents of Arizona and Nevada. American Indian/Alaska Native, Mexican-heritage, and foreign-born populations accounted for larger shares of overdose deaths with, compared to without, heat involvement recorded. A street or highway was more frequently identified as the place of injury in overdose deaths with (18.9%), versus without (2.2%) heat involvement reported. Psychostimulants such as methamphetamine were involved in 85.9% of overdose deaths with, compared to 28.9% without, recorded heat involvement. ConclusionsAlthough representing only a fraction of all overdose deaths, fatal overdoses involving heat exposure have increased markedly over time and disproportionately impact certain states and demographic groups.