Addiction Biology

ObjectivesWe aimed to determine whether chronic nicotine use, alcohol consumption, and gambling alters brain glucose metabolism. MethodsWe retrospectively analyzed data from 473 healthy men who participated in health checkups at Samsung Changwon Hospital Health Promotion Center during 2013 (baseline) and 2018 (follow-up). The health checks included a brain 18F-fluorodeoxyglucose positron emission tomography (PET), a questionnaire of tobacco use, the Alcohol Use Disorders Identification Test (AUDIT; Korean version), and the Problem Gambling Severity Index (PGSI). From brain PET scans, the mean uptake in regions-of-interest was scaled to the mean global cortical uptake by each individual, defining the standardized uptake value ratio. We established a model for tobacco use, AUDIT, and PGSI with regional SUVR as a dependent variable and tobacco use, AUDIT, and PGSI as predictors adjusted for age using Bayesian hierarchical modelling. Bayesian models were estimated using four Markov chains, each of which had 4,000 iterations including 1,000 warm-ups, thus totaling 12,000 post-warmup samples. The sampling parameters were slightly modified to facilitate convergence (max tree depth = 20). All data were analyzed using R (The R Foundation for Statistical Computing, Vienna, Austria). ResultsThis study included 131 healthy males (mean age at baseline and follow-up: 43.0 {+/-} 3.4, 48.1 {+/-} 3.3 years, respectively). Tobacco use was negatively associated with glucose metabolism in the caudate, thalamus, cingulate, and frontal lobe, and positively associated with the cerebellum, whereas AUDIT or PGSI were not associated. ConclusionTobacco use was associated with altered brain glucose metabolism in the caudate, thalamus, cingulate, frontal lobe, and the cerebellum. However, neither hazardous alcohol consumption, nor problem gambling showed any association with brain glucose metabolism. Our findings might provide new insights into the neural mechanisms of chronic nicotine use.

BackgroundCharting the clinical course of substance use disorders (SUDs) to identify etiologic contributors to milestone onset and progression could inform intervention efforts. MethodsWe calculated polygenic risk scores (PRS) in 5,692 European-ancestry individuals (EUR) (56.2% male) and 4,918 African-ancestry (AFR) individuals (54.9% male) using genome-wide association studies (GWAS) of alcohol use disorder (AUD), opioid use disorder (OUD), and smoking trajectory (SMK). Using Cox regression, we examined the association of polygenic risk with age of first substance use, regular use, reported problems, and dependence diagnosis and with progression from regular use to onset of problems and dependence. ResultsEUR and males reported earlier onset and shorter progression times than AFR and females, respectively. Among EUR, higher AUD PRS predicted earlier onset and more rapid progression to alcohol-related milestones (ps<0.0001) and although a stronger moderator of problem onset among females (p=0.0165), it was more predictive of the progression to problems among males (p=0.0054). OUD and SMK PRS in EUR also predicted earlier onset of the respective milestones (ps=0.0002). Among AFR, where power is lower, AUD PRS predicted age of regular alcohol use (p=0.039) and dependence (p=0.001) and progression from regular use to diagnosis (p=0.045), while SMK PRS predicted earlier age of initiation (p=0.036). ConclusionsGenetic risk for SUDs predicts milestones and symptom progression in EUR and, to a lesser extent, among AFR. Larger, diverse discovery GWAS and target samples are needed to enhance the power of PRS to personalize interventions for individuals at genetic risk of serious substance-related outcomes. DisclosureDr. Kranzler is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacologys Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, and Otsuka. Drs. Gelernter and Kranzler hold U.S. Patent 10,900,082: Genotype-guided Dosing of Opioid Receptor Agonists, 26 Jan. 2021. The other authors have no disclosures to make.

Excessive alcohol drinking is a leading cause of preventable death in the United States. High alcohol consumption and persistent drinking despite adverse events, also known as compulsive drinking, are key criteria that contribute to the development and progression of alcohol use disorder (AUD). There is a clear need to better understand the mechanisms that support these related but distinct behaviors. The serotonin (5-HT) system has been associated with alcohol consumption and risk of alcohol dependence, however given the complexity of this system, there remains much to discover regarding specific alcohol related phenotypes. The current study uses a combination of volitional home-cage drinking and operant conditioning to phenotype mice based on ethanol intake and persistence of alcohol drinking following quinine adulteration, a model to study compulsive drinking. Brain tissue of 10 regions known to be implicated in regulating executive function, reward, and stress was collected, and gene expression of serotonergic receptors, transporters, and enzymes was quantified. Three opioid receptors were included given their well-established roles in alcohol-related behaviors and interactions with the 5HT system. Region-specific gene expression patterns emerged, with serotonergic and opioid receptor expression differentially associated with alcohol drinking phenotype. 5-HT and opioid receptors displayed opposing directionality across regions, consistent with functional heterogeneity within the system. These findings identify region-specific molecular alterations following chronic alcohol that may contribute to individual differences in alcohol drinking phenotypes, highlighting candidate targets for biomarkers of increased alcohol use disorder susceptibility or as interventions aimed at preventing the progression of AUD.

ObjectivesTo explore the hypothesis that plasma levels of neurofilament light chain (NfL), a marker of neuroaxonal pathology, are elevated in chronic cocaine users (CU) and longitudinally associated with changes in cocaine use. MethodsAs part of the Social Stress Cocaine Study (SSCP), we assessed 35 CU and 35 stimulant-naive healthy controls (HC) at baseline and at a 4-month follow-up. Plasma NfL levels were determined from blood samples using single molecule array (SIMOA) technology. Substance use was subjectively assessed with an extensive interview and objectively measured via toxicological analysis of urine and 4-month hair samples. ResultsIn a generalized linear model corrected for sex, age, and body mass index, NfL plasma levels were elevated in CU compared to HC (p<0.05). A moderate positive correlation between cocaine hair concentration and NfL levels was also found in CU (r(s)=0.36, p=0.03). Changes in cocaine hair concentration (group analysis of increasers vs. decreasers) over the 4-month interval predicted NfL levels at follow-up (p=0.002), indicating a rise in NfL with increased cocaine use and a reduction with decreased use. No associations between use or change of use of other substances (including the cocaine adulterant levamisole) and NfL levels were found (r(s)[&le;]{+/-}0.27, p>0.05). ConclusionsOur findings demonstrate that NfL is a sensitive marker for assessing cocaine-related brain pathology, supporting the utility of blood NfL analysis in addiction research. The results also suggest that cocaine use should be considered a potential confounder in diagnostic applications and clinical studies using NfL.

Genetic research on nicotine dependence has utilized multiple assessments that are in weak agreement. We conducted a genome-wide association study of nicotine dependence defined using the Diagnostic and Statistical Manual of Mental Disorders (DSM-NicDep) in 61,861 individuals (47,884 of European ancestry, 10,231 of African ancestry, 3,746 of East Asian ancestry) and compared the results to other nicotine-related phenotypes. We replicated the well-known association at the CHRNA5 locus (lead SNP: rs147144681, p =1.27E-11 in European ancestry; lead SNP = rs2036527, p = 6.49e-13 in cross-ancestry analysis). DSM-NicDep showed strong positive genetic correlations with cannabis use disorder, opioid use disorder, problematic alcohol use, lung cancer, material deprivation, and several psychiatric disorders, and negative correlations with respiratory function and educational attainment. A polygenic score of DSM-NicDep predicted DSM-5 tobacco use disorder and 6 of 11 individual diagnostic criteria, but none of the Fagerstrom Test for Nicotine Dependence (FTND) items, in the independent NESARC-III sample. In genomic structural equation models, DSM-NicDep loaded more strongly on a previously identified factor of general addiction liability than did a "problematic tobacco use" factor (a combination of cigarettes per day and nicotine dependence defined by the FTND). Finally, DSM-NicDep was strongly genetically correlated with a GWAS of tobacco use disorder as defined in electronic health records, suggesting that combining the wide availability of diagnostic EHR data with nuanced criterion-level analyses of DSM tobacco use disorder may produce new insights into the genetics of this disorder.

Inefficient aldehyde metabolism by an aldehyde dehydrogenase 2 (ALDH2) genetic variant, ALDH2*2 (rs671), increases the risk of esophageal cancer with alcohol consumption. Here we tested the hypothesis that additional genetic differences in ALDH2 besides ALDH2*2 exist resulting in inefficient acetaldehyde metabolism after alcohol consumption. Human volunteers were recruited who self-reported flushing after alcohol. The first stage recruited East Asians and the second stage non-East Asians. After phone screening and ALDH2 sequencing, volunteers were subjected to an alcohol challenge (0.25g/kg). Physiological parameters and breath acetaldehyde levels were assessed. Twenty-six participants were given an alcohol challenge. In the first stage, when comparing the ALDH2*1/*2 genotype to ALDH2*1/*1 genotype, tachycardia (104{+/-}3* versus 73{+/-}4 beats per minute), increases in facial skin temperature (99.6{+/-}0.4* versus 95.9{+/-}0.50F), and increases in breath acetaldehyde (peak: 2.1{+/-}0.4* versus 0.2{+/-}0.3ppm, n=8/group, *p<0.01) occurred after alcohol consumption. In the second stage, heterozygotes for an ALDH2 intron variant (rs4646777, G>A) caused increases in facial skin temperature (98{+/-}1* versus 94{+/-}10F, n=4, *p<0.01) without tachycardia or acetaldehyde accumulation after alcohol consumption. Subjects self-identifying as non-East Asian genotyped with an ALDH2*1/*2 variant also displayed a characteristic ALDH2*1/*2 phenotype after alcohol consumption. Further, ALDH2 point mutations rs747096195 (R101G) and rs190764869 (R114W) showed reduced acetaldehyde metabolism and increases in facial skin temperature after an alcohol challenge relative to wild type ALDH2 subjects. Taken together, we developed a method to non-invasively phenotype genetic differences for ALDH2 in humans including quantifying aldehyde metabolism in single subjects. We also discovered genetic differences besides ALDH2*2 that cause inefficient aldehyde metabolism. Brief SummaryWe developed a method to phenotype genetic differences in ALDH2 and we discovered novel ALDH2 mutations that result in inefficient acetaldehyde metabolism after alcohol consumption.

BackgroundEnvironmental enrichment (EE) is a promising strategy to promote recovery from addiction, but its neurobiological mechanisms remain poorly understood. This study investigates how exposure to EE during abstinence dynamically affects brain neuroadaptations induced by voluntary intake of cocaine. MethodsUsing longitudinal 18FDG microPET imaging, we examined brain metabolic activity in rats following extended access cocaine self-administration. After establishing escalation of cocaine intake, rats were housed in either enriched or standard environments during a four-week abstinence period. Brain metabolic activity was assessed after one and four weeks of abstinence. ResultsCocaine self-administration produced widespread decreases in cortical metabolic activity, particularly in regions involved in executive function (orbitofrontal cortex, anterior cingulate) and interoception (insula), while increasing activity in emotional and motivational circuits (nucleus accumbens, amygdala, mesencephalon). EE selectively normalized these alterations through temporally distinct mechanisms: rapidly restoring nucleus accumbens and amygdala function while gradually affecting prefrontal cortical activity. After four weeks, rats housed in enriched environments showed significantly normalized metabolic activity in the orbitofrontal cortex and dorsolateral striatum compared to those in standard housing, with persistent changes in anterior cingulate cortex and ventral posterior hippocampus. ConclusionsOur findings reveal circuit-specific and temporally distinct effects of environmental enrichment on cocaine-induced brain alterations. These insights could inform the development of more targeted therapeutic approaches for addiction recovery.

Addiction is viewed as maladaptive glutamate-mediated neuroplasticity that is regulated, in part, by calcium-permeable AMPA receptor (CP-AMPAR) activity. However, the contribution of CP-AMPARs to alcohol-seeking behavior remains to be elucidated. We evaluated CP-AMPAR activity in the basolateral amygdala (BLA) as a potential target of alcohol that also regulates alcohol self-administration in C57BL/6J mice. Operant self-administration of sweetened alcohol increased spontaneous EPSC frequency in BLA neurons that project to the nucleus accumbens as compared to behavior-matched sucrose controls indicating an alcohol-specific upregulation of synaptic activity. Bath application of the CP-AMPAR antagonist NASPM decreased evoked EPSC amplitude only in alcohol self-administering mice indicating alcohol-induced synaptic insertion of CP-AMPARs in BLA projection neurons. Moreover, NASPM infusion in the BLA dose-dependently decreased the rate of operant alcohol self-administration providing direct evidence for CP-AMPAR regulation of alcohol reinforcement. Since most CP-AMPARs are GluA1-containing, we asked if alcohol alters the activation state of GluA1-containing AMPARs. Immunocytochemistry results showed elevated GluA1-S831 phosphorylation in the BLA of alcohol as compared to sucrose mice. To investigate mechanistic regulation of alcohol self-administration by GluA1-containing AMPARs, we evaluated the necessity of GluA1 trafficking using a TET-ON AAV encoding a dominant-negative GluA1 c-terminus (GluA1ct) that blocks activity-dependent synaptic delivery of native GluA1-containing AMPARs. GluA1ct expression in the BLA reduced alcohol self-administration with no effect on sucrose controls. These results show that CP-AMPAR activity and GluA1 trafficking in the BLA mechanistically regulate the reinforcing effects of sweetened alcohol. Pharmacotherapeutic targeting these mechanisms of maladaptive neuroplasticity may aid medical management of alcohol use disorder.

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.

ImportanceAlcohol genome-wide association studies (GWAS) have generally focused on alcohol consumption and alcohol use disorder (AUD); few have examined habitual drinking behaviors like maximum habitual alcohol intake (MaxAlc). ObjectiveIdentify MaxAlc loci and elucidate the genetic architecture across alcohol traits. DesignThe MaxAlc GWAS was performed in Million Veteran Program (MVP) participants enrolled from January 10, 2011 to September 30, 2020. Ancestry-specific GWAS were conducted in European (EUR) (n=218,623) and African (AFR) (n=29,132) ancestry subjects, then meta-analyzed (N=247,755). Linkage-disequilibrium score regression (LDSC) was used to estimate SNP-heritability and genetic correlations (rg) with other alcohol and psychiatric traits. Genomic structural equation modeling (gSEM) was used to evaluate genetic relationships between MaxAlc and other alcohol traits. Mendelian randomization (MR) was used to examine causal relationships. MTAG (multi-trait analysis of GWAS) was used to analyze MaxAlc and problematic alcohol use (PAU) jointly. SettingThe study was performed in a sample of U.S military Veterans. ParticipantsParticipants were 92.68% male and had mean age=65.92 (SD=11.70). 36.92% reported MaxAlc [&ge;] the binge-drinking threshold. Main Outcomes(s) and Measure(s)MaxAlc was defined from survey item: "in a typical month, what is/was the largest number of drinks of alcohol you may have had in one day?" with ordinal responses from 0 [&ge;] 15 drinks. ResultsThe MaxAlc GWAS resulted in 15 genome-wide significant (GWS) loci. Top associations in EUR and AFR were with known functional variants ADH1B*rs1229984 (p=3.12x10-104) and rs2066702 (p=6.30x10-17), respectively. Multiple novel associations were found. The SNP-heritability was 6.65% (s.e.=0.41%) in EUR and 3.42% (s.e.=1.46%) in AFR. MaxAlc was positively correlated with PAU (rg=0.79; p=3.95x10-149) and AUD (rg=0.76; p=1.26x10-127), and had negative rg with "alcohol usually taken with meals" (rg=-0.53; p=1.40x10-50). For psychiatric traits, MaxAlc had the strongest rg with suicide attempt (rg=0.40; p=3.02x10-21). gSEM supported a two-factor model with MaxAlc loading on a factor with PAU and AUD, and other alcohol consumption measures loading a separate factor. MR supported a small causal effect of MaxAlc on the liver enzyme gamma-glutamyltransferase ({beta}=0.012; p=2.66x10-10). MaxAlc MTAG resulted in 31 GWS loci. Conclusions and RelevanceMaxAlc closely aligns genetically with the etiology of problematic alcohol use traits. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the genetic etiology of maximum habitual alcohol intake (MaxAlc) and how does it compare to other alcohol consumption measures. FindingsThis MaxAlc study in 247,455 European and African ancestry individuals identified 15 genome-wide significant loci, including multiple novel associations. MaxAlc was strongly genetically correlated (rg) with measures of alcohol-related problems, demonstrated significantly different rg with psychiatric traits compared to other alcohol consumption traits, and loaded on a factor with alcohol problem traits while alcohol consumption state measures loaded on a separate factor. MeaningMaxAlc is genetically different from trait consumption measures in relation to problematic alcohol use.

BackgroundSubstance use disorders (SUDs), including alcohol and drug dependence, and smoking, pose a public health threat with their high prevalence and comorbidity with other diseases, and contribution to mortality. SUDs are highly correlated, and their genetic background is shared to some degree. ObjectivesWe aimed to investigate the genetic associations of previously reported loci for a wide range of SUDs in an unstudied Ukrainian population. MethodsWe collected data from 595 individuals (339 women, 253 men), including 321 participants from two rehab centres. Based on clinical review and questionnaire data we defined drug dependence, alcohol dependence, alcohol abuse, binge drinking, smoking, opiate, amphetamine, cannabis, and hallucinogen use, along with several intermediary alcohol use and smoking variables considering the amount of use and the level of dependence. We genotyped COMT-rs4680, ADH1B-ADH1C-rs1789891, and HTR2A-rs6313, and applied logistic and ordered logistic regression assuming an additive inheritance model, controlling for the recruitment group, other substance uses, age, and sex, in the association analyses. ResultsWe replicate (P<0.05) the associations at COMT-rs4680 with smoking status (OR[95% CI]=1.56[1.01-2.41], P=0.047) and heaviness (1.37[1.04-1.80], P=0.026), and at ADH1B-ADH1C-rs1789891 and HTR2A-rs6313 with alcohol dependence (1.69[1.03-2.76], P=0.038 and 0.66[0.47-0.92, P=0.016], respectively). Furthermore, we provide evidence for an association at HTR2A-rs6313 with hallucinogen use (0.58[0.35-0.98], P=0.040). ConclusionIn this study on multiple SUDs we shed light on the genetic background of SUDs in Ukrainians and provide further evidence that variation at COMT is mainly associated with smoking, at ADH1B-ADH1C with alcohol-related variables, whereas HTR2A is a more general SUD-associated locus. HighlightsO_LIWe present the first genetic study of substance use disorders in Ukrainians C_LIO_LIWe replicate the associations at COMT-rs4680 with smoking status and heaviness, and ADH1B-ADH1C-rs1789891 and HTR2A-rs6313 with alcohol dependence C_LIO_LIWe provide evidence for an association at HTR2A-rs6313 with hallucinogen use C_LI

Drug predictive cues and contexts exert powerful control over behavior and can incite drug seeking and taking. This association and the behavioral output are encoded within striatal circuits, and regulation of these circuits by G-protein coupled receptors affects cocaine-related behaviors. Here, we investigated how opioid peptides and G-protein coupled opioid receptors expressed in striatal medium spiny neurons (MSNs) regulate conditioned cocaine seeking. Augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP). In contrast, opioid receptor antagonists attenuate cocaine CPP and facilitate extinction of alcohol CPP. However, whether striatal enkephalin is necessary for acquisition of cocaine CPP and maintenance during extinction remains unknown. We generated mice with a targeted deletion of enkephalin from dopamine D2-receptor expressing MSNs (D2-PenkKO) and tested them for cocaine CPP. Low striatal enkephalin levels did not attenuate acquisition or expression of CPP; however, D2-PenkKOs showed faster extinction of cocaine CPP. Single administration of the non-selective opioid receptor antagonist naloxone prior to preference testing blocked expression of CPP selectively in females, but equally between genotypes. Repeated administration of naloxone during extinction did not facilitate extinction of cocaine CPP for either genotype, but rather prevented extinction in D2-PenkKO mice. We conclude that while striatal enkephalin is not necessary for acquisition of cocaine reward, it maintains the learned association between cocaine and its predictive cues during extinction learning. Further, sex and pre-existing low striatal enkephalin levels may be important considerations for use of naloxone in treating cocaine use disorder.

Preclinical and clinical work suggests that mifepristone (glucocorticoid receptor antagonist), may be a viable treatment for alcohol use disorder (AUD). The aim of this work was to translate our preclinical mifepristone study using yohimbine (2 receptor antagonist) stress-induced reinstatement of alcohol-seeking to a clinical setting. This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD (N=32). We investigated the safety, alcohol craving and consumption after oral administration of mifepristone (600mg daily for a week) in a human laboratory study comprised of administration of yohimbine in a cue-reactivity procedure and alcohol self-administration. Outcomes were assessed using Generalized Estimating Equations and mediation and moderation analyses assessed mechanisms of action and precision medicine targets. We did not observe serious adverse events related to the study drugs or study procedure and mild to moderate non-serious adverse events were reported by both study conditions. Also, there was no statistically-significant difference between the mifepristone and placebo in the hemodynamic response, alcohol subjective effects and pharmacokinetics parameters. Mifepristone significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Moderation analysis with family history density of AUD (FHDA) and mifepristone, suggested that reduced craving was present in individuals with low, but not high FHDA. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a preclinical paradigm to a human laboratory study confirming safety, tolerability and efficacy of mifepristone in an alcohol paradigm. Mediation analysis showed that the effect of mifepristone on craving was not related to mifepristone-induced increases in cortisol and moderation of FHDA suggested the importance of evaluating AUD endophenotypes for pharmacotherapies. Clinical trial registrationClinicaltrials.gov; NCT02243709 IND/FDA121984, mifepristone and yohimbine (Holder: Haass-Koffler)

Synthetic opioids like fentanyl are highly potent and prevalent in the illicit drug market, leading to tolerance, dependence, and opioid use disorder (OUD). Chronic opioid use disrupts sleep and circadian rhythms, which persist even during treatment and abstinence, increasing the risk of relapse. The bodys molecular clock, regulated by transcriptional and translational feedback loops, controls various physiological processes, including the expression of endogenous opioids and their receptors. The circadian transcription factor NPAS2, highly expressed in the nucleus accumbens, may have a crucial function in opioid-related behaviors. Our study found sex-specific roles for NPAS2-mediated reward behaviors in male and female mice, including in fentanyl seeking and craving. We also identified specific cell types and transcriptional targets in the nucleus accumbens of both mice and humans by which NPAS2 may mediate the impact of fentanyl on brain physiology and in opioid reward-related behaviors. Ultimately, our findings begin to uncover the mechanisms underlying circadian rhythm dysfunction and opioid addiction.

Alcohol use disorder (AUD) affects over 28 million people in the U.S and is associated with neurobiological alterations, including in the basal ganglia. Within the basal ganglia, the caudate nucleus (caudate) and putamen are implicated in AUD due to their roles in ethanol reinforcement, with the caudate receiving inputs from cortico-associative areas and the putamen receiving inputs from somatosensory areas, supporting goal-directed and habitual behaviors respectively. These distinct behavioral roles are supported by dopamine signaling, including phasic dopamine, involved in assessing action-outcome associations, and tonic dopamine, which reflects ongoing dopaminergic tone that biases action initiation. Intrastriatal dopamine release is modulated by cholinergic interneurons via nicotinic acetylcholine receptors. Dysregulation of these mechanisms can contribute to the transition from occasional to habitual ethanol drinking. Here, we used in-vitro fast-scan cyclic voltammetry to measure dopamine signaling in male (n=6) and female (n=6) rhesus macaques following six months of ethanol self-administration. In putamen, ethanol increased tonic dopamine in both sexes, with females exhibiting greater release and faster dopamine uptake rates than males. In the caudate, ethanol self-administration enhanced dopamine uptake rates only in males. Phasic dopamine release was enhanced in caudate of both sexes but only putamen in males. nAChR blockade revealed that phasic dopamine release in males, but not females, was dependent on cholinergic modulation. These results demonstrate basal and sex-specific dopamine release and uptake are uniquely altered in rhesus macaque caudate and putamen in conjunction with chronic ethanol drinking.

ImportanceValid biomarkers that can predict longitudinal clinical outcomes at low cost are a holy grail in psychiatric research, promising to ultimately be used to optimize and tailor intervention and prevention efforts. ObjectiveTo determine if baseline linguistic markers in natural speech, as compared to non-speech clinical and demographic measures, can predict drug use severity measures at future sessions in initially abstinent individuals with cocaine use disorder (iCUD). DesignA longitudinal cohort study (August 2017 - March 2020), where baseline measures were used to predict outcomes collected at three-month intervals for up to one year of follow-up. ParticipantsEighty-eight initially abstinent iCUD were studied at baseline; 57 (46 male, age 50.7+/-7.9 years) came back for at least another session. Main Outcomes and MeasuresOutcomes were self-reported symptoms of withdrawal, craving, abstinence duration and frequency of cocaine use in the past 90 days at each study session. The predictors were derived from 5-min recordings of vocal descriptions of the positive consequences of abstinence and the negative consequences of using cocaine; the baseline cocaine and other common drug use measures, demographic and neuropsychological variables were used for comparison. ResultsModels using the non-speech variables showed the best predictive performance at three(r>0.45, P<2x10-3) and six months follow-up (r>0.37, P<3x10-2). At 12 months, the natural language processing-based model showed significant correlations with withdrawal (r=0.43, P=3x10-2), craving (r=0.72, P=5x10-5), days of abstinence (r=0.76, P=1x10-5), and cocaine use in the past 90 days (r=0.61, P=2x10-3), significantly outperforming the other models for abstinence prediction. Conclusions and RelevanceAt short time intervals, maximal predictive power was obtained with models that used baseline drug use (in addition to demographic and neuropsychological) measures, potentially reflecting a slow rate of change in these measures, which could be estimated by linear functions. In contrast, short speech samples predicted longer-term changes in drug use, implying deeper penetrance by potentially capturing non-linear dynamics over longer intervals. Results suggest that, compared to the common outcome measures used in clinical trials, speech-based measures could be leveraged as better predictors of longitudinal drug use outcomes in initially abstinent iCUD, as potentially generalizable to other substance use disorders and related comorbidity. Key PointsO_ST_ABSQuestionC_ST_ABSCan natural language processing be leveraged to predict longitudinal drug use outcomes in individuals with substance use disorder? FindingsIn this prospective study that included initially abstinent individuals with cocaine use disorder (iCUD), models using demographics, neuropsychological measures and drug use patterns at baseline were compared to those using minimally structured short natural speech samples relating the positive consequences of abstinence and the negative consequences of using drugs, showing a differential prediction of outcomes measured up to one year later. At three and six months, the former outperformed speech models, including approximately 50% of the variability in craving and 40% in abstinence duration. At 12 months from baseline, speech models were superior, predicting 50% of the variability in abstinence duration. MeaningSpeech variables derived through natural language processing can predict clinically meaningful drug use outcome measures in addiction, with greater value at longer intervals. The applicability of language modeling to aid in assessing treatment response and risk in drug addiction warrants further investigation in clinical settings.

Uncovering the neurobiological processes underlying substance use disorder informs future therapeutic interventions. Prior research implicates the corticotropin releasing factor (CRF) system as a major player in a wide variety of substance use disorder-like phenotypes. However, the complexity of the CRF system in regard to brain region specific effects and experience-dependent changes in activity is poorly understood. Employing a cocaine self-administration paradigm that induces escalation of cocaine consumption in a subset of subjects, we investigated the role of CRF activity in the Nucleus Accumbens (NAc) in cocaine-taking patterns both before and after chronic cocaine experience. Our results showed that pharmacologically inhibiting CRF-R1 in the NAc did not reduce cocaine consumption following escalation and genetically deleting CRF-R1 from cells in the NAc did not prevent escalation. Overall, this suggests that any effect of CRF activity driving escalation or high levels of cocaine consumption is not through its actions on CRF-R1 in the NAc.

BackgroundWhile most research into predictors of problematic alcohol use has focused on adolescence, young adults are also at elevated risk, and differ from adolescents and adults in terms of exposure to alcohol and neurodevelopment. Here we examined predictors of alcohol use among young adults at a 1-year follow-up using a broad predictive modelling approach. MethodsData in four modalities were included from 128 men aged between 18 and 25 years; functional MRI regions-of-interest from 1) a beer-incentive delay task, and 2) a social alcohol cue-exposure task, 3) grey matter data, and 4) non-neuroimaging data (i.e. psychometric and behavioural). These modalities were combined into an ensemble model to predict follow-up Alcohol Use Disorder Identification (AUDIT) scores, and were tested separately for their contribution. To reveal specificity for the prediction of future AUDIT scores, the same analyses were carried out for current AUDIT score. ResultsThe ensemble resulted in a more accurate estimation of follow-up AUDIT score than any single modality. Only removal of the social alcohol cue-exposure task and of the non-neuroimaging data significantly worsened predictions. Reporting to need a drink in the morning to start the day was the strongest unique predictor of future drinking along with anterior cingulate cortex and cerebellar activity. ConclusionsAlcohol-related task fMRI activity is a valuable predictor for future drinking among young adults alongside non-neuroimaging variables. Multi-modal prediction models best predict future drinking among young adults and may play an important part in the move towards individualized treatment and prevention efforts.

Cannabis use during adolescence and young adulthood has been associated with brain structure and functional connectivity, yet despite a rapid increase in cannabis use among older adults in the past decade, the impact on brain structure and function in this population remains understudied. We examined 3,641 lifetime cannabis users (mean age = 61.00 years, standard deviation (SD) = 7.07) and 12,255 controls (mean age = 64.49 years, SD = 7.51) from the UK Biobank. Insufficient data were available on cannabis use disorders in the UK Biobank to perform an analysis. Brain structure and functional connectivity were measured using multiple imaging-derived phenotypes. Associations with cannabis use were assessed using multiple linear regression while controlling for potential confounders. Additionally, we conducted a two-sample Mendelian randomization analysis to investigate the potential causal relationship. After correcting for false discovery rate for multiple testing, participants with lifetime cannabis use had significantly lower fractional anisotropy and higher mean diffusivity in the genu of the corpus callosum. A weaker resting-state functional connectivity was observed in brain regions underlying the default mode and central executive networks. Furthermore, bidirectional two-sample Mendelian randomization analyses found no support for a causal relationship between either cannabis use or cannabis dependence and brain structure or function. Our findings indicate that associations between lifetime cannabis use and later life brain structure and function are not likely causal in nature and may represent residual confounding.

Any increase in alcohol use is associated with an increase in risk of illness and mortality and consequences of chronic alcohol use include cancer, hypertension, heart and liver disease, and Alcohol Use Disorder. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective anti-glycemic and weight-loss medications with a strong safety record. There is substantial preclinical evidence and mounting retrospective and prospective randomized controlled trial evidence that GLP-1RAs could be effective for reducing alcohol consumption. However, the mechanism by which GLP-1RAs reduce alcohol intake remains unclear. While medications that reduce alcohol intake such as naltrexone and acamprosate have central nervous system action, disulfiram reduces alcohol intake through peripheral mechanisms. Here, we test whether GLP- 1RAs alter alcohols peripheral pharmacokinetics as a potential mechanism of action for their alcohol intake suppressive effects. In this pilot study, twenty participants with obesity in the GLP-1RA or control group consumed a challenge dose of alcohol, and we measured breath alcohol (BrAC) and the subjective effects of alcohol. We observed a delayed rise in BrAC and subjective effects in the GLP-1RA group as compared to controls, that was not explained by nausea. These data provide preliminary evidence that GLP-1RAs could act through peripheral mechanisms to suppress alcohol intake.