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The regular use of cannabis during adolescence has been associated with a number of negative life outcomes, including psychopathology and cognitive impairments. However, the exact molecular mechanisms that underlie these outcomes are just beginning to be understood. Moreover, very little is known about the spatio-temporal molecular changes that occur following cannabinoid exposure in adolescence. To understand these changes, we exposed mid-adolescent male rats to a synthetic cannabinoid (WIN 55,212-2 mesylate; WIN) and, following drug abstinence through late adolescence, we subjected the synaptosomal fractions of the prefrontal cortex (PFC) to proteomic analyses. A total of N = 487 differentially expressed proteins were found in WIN-exposed animals compared to controls. Gene ontology analyses revealed enrichment of terms related to the gamma-aminobutyric acid (GABA)-ergic neurotransmitter system. Among the top differentially expressed proteins was the synaptic Ras GTPase-activating protein 1 (SYNGAP1). Using Western blotting experiments, we found that the WIN-induced upregulation of SYNGAP1 was spatio-temporal in nature, arising only in the synaptosomal fractions (not in the cytosol) and only following prolonged drug abstinence (not on abstinence day 1). Moreover, the SYNGAP1 changes were found to be specific to WIN-exposure in adolescence and not adulthood. Adolescent animals exposed to a natural cannabinoid (Δ 9 -tetrahydrocannabinol; THC) were also found to have increased levels of SYNGAP1 in the PFC. THC exposure also led to a pronounced upregulation of SYNGAP1 in the amygdala, but without any changes in the dorsal striatum, hippocampus, or nucleus accumbens. To our knowledge, this is the first study to uncover a link between cannabinoid exposure and changes in SYNGAP1 that are spatio-temporal and developmental in nature. Future studies are needed to investigate the putative role of SYNGAP1 in the negative behavioral consequences of cannabis use in adolescence.

The effects of social isolation on an individual's behavior is an important field of research, especially as public health officials encourage social distancing to prevent the spread of pandemic disease. In this study we evaluate the effects of social isolation on physical activity in mice. Utilizing a pixel-based tracking system, we continuously monitored the movement of isolated mice compared with paired cage mates in the home cage environment. We demonstrate that mice that are socially isolated dramatically decrease their movement when separated from their cage mate, and especially in the dark cycle, when mice are normally most active. When isolated mice are re-paired with their original cage mate, this effect is reversed, and mice return to their prior levels of activity. These findings suggest a close link between social isolation and physical activity, and are of particular interest in the wake of coronavirus disease 2019, when many are forced into isolation. Social isolation may affect an individual's overall activity levels in humans too, which may have unintended effects on health that deserve further consideration., (© 2020 Wiley Periodicals LLC.)

Importance: Limited information is available regarding the association between parental and adolescent medical prescription opioid use and misuse in the US., Objective: To examine the associations between parental and adolescent prescription opioid medical use and misuse., Design, Setting, and Participants: This cross-sectional, nationally representative study included 15 200 parent-adolescent dyads from the annual 2015-2017 National Survey on Drug Use and Health. Data were collected from January 6, 2015, to December 20, 2017, and analyzed from October 4, 2019, to October 15, 2020., Exposures: Parental past 12-month exclusive medical prescription opioid use and any misuse (ie, using without a prescription or in any way not directed by a physician)., Main Outcomes and Measures: Adolescent past 12-month medical prescription opioid use or misuse. Multivariable regressions estimated associations between parental and offspring medical prescription opioid use or misuse, controlling for sociodemographic and psychosocial variables., Results: Respondents included 9400 mother-child and 5800 father-child dyads in the same household; children were aged 12 to 17 years (52.8% male; mean [SD] age, 14.5 [1.7] years). Controlling for other factors, parental medical prescription opioid use was associated with adolescent prescription opioid medical use (adjusted odds ratio [aOR], 1.28; 95% CI, 1.06-1.53) and misuse (aOR, 1.53; 95% CI, 1.07-2.25), whereas parental misuse was not. Parental medical prescription stimulant use was associated with adolescent medical prescription opioid use (aOR, 1.40; 95% CI, 1.02-1.91). Parental marijuana use (aOR, 1.84; 95% CI, 1.13-2.99), parent-adolescent conflict (aOR, 1.26; 95% CI, 1.05-1.52), and adolescent depression (aOR, 1.75; 95% CI, 1.26-2.44) were associated with adolescent prescription opioid misuse. Adolescent delinquency (aOR, 1.55; 95% CI, 1.38-1.74) and perceived schoolmates' drug use (aOR, 2.87; 95% CI, 1.95-4.23) were also associated with adolescent misuse and more weakly with medical use (aORs, 1.13 [95% CI, 1.05-1.22] and 1.61 [95% CI, 1.32-1.96], respectively)., Conclusions and Relevance: Youth use of prescription opioids is in part a structural/environmental issue. The findings of this study suggest that parental medical prescription opioid use is associated with offspring prescription opioid use, whereas parental misuse is not. Restricting physicians' opioid prescribing to parents is a crucial public health goal. In addition, parents could be educated on the risks of their prescription opioid use for offspring and on practices to mitigate risk, including safe medication storage and disposal. Screening for parental prescription opioid use could be part of pediatric practice. Addressing adolescent mental health could also reduce adolescent prescription opioid misuse.

A recurrent and devastating feature of addiction to a drug of abuse is its persistence, which is mediated by maladaptive long-term memories of the highly pleasurable experience initially associated with the consumption of the drug. We have recently found that members of the CPEB family of proteins (Cytoplasmic Polyadenylation Element-Binding Proteins) are involved in the maintenance of spatial memory. However, their possible role in the maintenance of memories that sustain addictive behavior has yet to be explored. Little is known about any of the mechanisms for maintaining memories for addictive behavior. To address the mechanisms whereby addictive behavior is maintained over time, we utilized a conditional transgenic mouse model expressing a dominant-negative version of CPEB1 that abolishes the activity in the forebrain of two of the four CPEB isoforms (CPEB1 and CPEB3). We found that, following cocaine administration, these dominant-negative (DN) CPEB mice showed a significant decrease, when compared to wild type (WT) mice, in both locomotor sensitizations and conditioned place preference (CPP), two indices of addictive behavior. Supporting these behavioral results, we also found a difference between WT and DN-CPEB1-3 mice in the cocaine-induced synaptic depression in the core of the Nucleus Accumbens (NAc). Finally, we found that (1) CPEB is reduced in transgenic mice following cocaine injections and that (2) FosB, known for its contribution to establishing the addictive phenotype, when its expression in the striatum is increased by drug administration, is a novel target of CPEBs molecules. Thus, our study highlights how CPEB1 and CPEB3 act on target mRNAs to build the neuroadaptative implicit memory responses that lead to the development of the cocaine addictive phenotypes in mammals., (Copyright © 2020 Drisaldi, Colnaghi, Levine, Huang, Snyder, Metzger, Theis, Kandel, Kandel and Fioriti.)

The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain's initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as Npas2 Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK/MAPK-targets like gephyrin, and modulates the synaptic AMPAR/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC-NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Objectives. To characterize prescription opioid medical users and misusers among US adults. Methods. We used the 2016-2017 National Surveys on Drug Use and Health to compare medical prescription opioid users with misusers without prescriptions, misusers of own prescriptions, and misusers with both types of misuse. Multinomial logistic regressions identified substance use characteristics and mental and physical health characteristics that distinguished the groups. Results. Among prescription opioid users, 12% were misusers; 58% of misusers misused their own prescriptions. Misusers had higher rates of substance use than did medical users. Compared with with-prescription-only misusers, without-and-with-prescription misusers and without-prescription-only misusers had higher rates of marijuana use and benzodiazepine misuse; without-and-with-prescription misusers had higher rates of heroin use. Compared with without-prescription-only misusers, without-and-with-prescription and with-prescription-only misusers had higher rates of prescription opioid use disorder. Most misusers, especially with-prescription-only misusers, used prescription opioids to relieve pain. Misusers were more likely to be depressed than medical users. Conclusions. Prescription opioid misusers who misused both their own prescriptions and prescription opioid drugs not prescribed to them may be most at risk for overdose. Prescription opioid misuse is a polysubstance use problem.

Background: To date, intergenerational patterns of nonmedical prescription opioid (NMPO) use have not been examined. We investigate the association between parental and adolescent NMPO use in the United States., Methods: Data are from 35 000 parent-child dyads with an adolescent aged 12 to 17 years from the 2004-2012 nationally representative National Surveys on Drug Use and Health. Using multivariable logistic regression models, we estimated the association between self-reported parental and adolescent lifetime NMPO use, controlling for parental and adolescent use of other drugs, attitudes about drug use, parental and adolescent psychosocial risk factors, and sociodemographic characteristics., Results: Controlling for other factors, parental NMPO use was associated with adolescent NMPO use (adjusted odds ratio [aOR] 1.30; 95% confidence interval [CI] 1.09-1.56). Mothers' use had a stronger association with adolescent use than fathers' use (aOR 1.62 [95% CI 1.28-2.056] versus aOR 0.98 [95% CI 0.74-1.24]). Associations between parental and adolescent NMPO use did not differ by adolescent sex or race and/or ethnicity. Parental lifetime smoking, low monitoring, and parent-adolescent conflict were uniquely associated with adolescent NMPO use (aOR 1.19-1.24) as were adolescent smoking, marijuana use, depression, delinquency, and perceived schoolmates' drug use (aOR 1.25-1.71). Perceived risk of drug use and religiosity were associated with lower rates of adolescent NMPO use (aOR 0.77-0.93). Use among older adolescents was higher than among younger adolescents (aOR 1.27; 95% CI 1.21-1.34)., Conclusions: Parent-based interventions targeted at adolescent NMPO use should address parental NMPO use and smoking and promote positive parenting., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Cannabis use is typically initiated during adolescence and is a significant risk factor for the development of cocaine use in adulthood. However, no preclinical studies have examined the effects of adolescent cannabinoid exposure on cocaine dependence in adulthood using the escalation model of cocaine self-administration and the assessment of negative emotional states. In the present study, we found that exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN) in adolescence produced irritability-like behavior and psychomotor cross-sensitization to cocaine in adolescence. In adulthood, rats were allowed to self-administer cocaine. The acquisition of cocaine self-administration was lower in rats with adolescent WIN exposure compared with controls. However, both WIN-exposed and control rats escalated their cocaine intake at the same rate, had similar responding under a progressive-ratio schedule of reinforcement, and had similar psychomotor responses to cocaine. Interestingly, the increase in irritability-like behavior that was previously observed in adolescence after WIN exposure persisted into adulthood. Whether the persisting increase in irritability-like behavior after WIN exposure has translational relevance remains to be studied. In summary, these results suggest that psychoactive cannabinoid exposure during adolescence is unlikely to have a major effect on the escalation of cocaine intake or the development of compulsive-like responding per se in adulthood in a rat model of cocaine self-administration. However, whether the persisting irritability-like behavior may predispose an individual to mood-related impairments in adulthood or predict such impairments warrants further investigation.

Reduced eukaryotic Initiation Factor 2 (eIF2)α phosphorylation (p-eIF2α) enhances protein synthesis, memory formation, and addiction-like behaviors. However, p-eIF2α has not been examined with regard to psychoactive cannabinoids and cross-sensitization. Here, we find that a cannabinoid receptor agonist (WIN 55,212-2 mesylate [WIN]) reduced p-eIF2α in vitro by upregulating GADD34 (PPP1R15A), the recruiter of protein phosphatase 1 (PP1). The induction of GADD34 was linked to ERK/CREB signaling and to CREB-binding protein (CBP)-mediated histone hyperacetylation at the Gadd34 locus. In vitro, WIN also upregulated eIF2B1, an eIF2 activator subunit. We next found that WIN administration in vivo reduced p-eIF2α in the nucleus accumbens of adolescent, but not adult, rats. By contrast, WIN increased dorsal striatal levels of eIF2B1 and ΔFosB among both adolescents and adults. In addition, we found cross-sensitization between WIN and cocaine only among adolescents. These findings show that cannabinoids can modulate eukaryotic initiation factors, and they suggest a possible link between p-eIF2α and the gateway drug properties of psychoactive cannabinoids., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study sought to specify (1) the position of nonmedical prescription opioids (NMPO) in drug initiation sequences among Millennials (1979-96), Generation X (1964-79), and Baby Boomers (1949-64) and (2) gender and racial/ethnic differences in sequences among Millennials., Methods: Data are from the 2013-2014 National Surveys on Drug Use and Health (n = 73,026). We identified statistically significant drug initiation sequences involving alcohol/cigarettes, marijuana, NMPO, cocaine, and heroin using a novel method distinguishing significant sequences from patterns expected only due to correlations induced by common liability among drugs., Results: Alcohol/cigarettes followed by marijuana was the most common sequence. NMPO or cocaine use after marijuana, and heroin use after NMPO or cocaine, differed by generation. Among successively younger generations, NMPO after marijuana and heroin after NMPO increased. Millennials were more likely to initiate NMPO than cocaine after marijuana; Generation X and Baby Boomers were less likely (odds ratios = 1.4;0.3;0.2). Millennials were more likely than Generation X and Baby Boomers to use heroin after NMPO (hazards ratios = 7.1;3.4;2.5). In each generation, heroin users were far more likely to start heroin after both NMPO and cocaine than either alone. Sequences were similar by gender. Fewer paths were significant among African-Americans., Conclusions: NMPOs play a more prominent role in drug initiation sequences among Millennials than prior generations. Among Millennials, NMPO use is more likely than cocaine to follow marijuana use. In all generations, transition to heroin from NMPO significantly occurs only when both NMPO and cocaine have been used. Delineation of drug sequences suggests optimal points in development for prevention and treatment efforts., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Addiction to cocaine is commonly preceded by experiences with legal or decriminalized drugs, such as alcohol, nicotine, and marijuana. The biological mechanisms by which these gateway drugs contribute to cocaine addiction are only beginning to be understood. We report that in the rat, prior alcohol consumption results in enhanced addiction-like behavior to cocaine, including continued cocaine use despite aversive consequences. Conversely, prior cocaine use has no effect on alcohol preference. Long-term, but not short-term, alcohol consumption promotes proteasome-mediated degradation of the nuclear histone deacetylases HDAC4 and HDAC5 in the nucleus accumbens, a brain region critical for reward-based memory. Decreased nuclear HDAC activity results in global H3 acetylation, creating a permissive environment for cocaine-induced gene expression. We also find that selective degradation of HDAC4 and HDAC5, facilitated by the class II-specific HDAC inhibitor MC1568, enhances compulsive cocaine self-administration. These results parallel our previously reported findings that the gateway drug nicotine enhances the behavioral effects of cocaine via HDAC inhibition. Together, our findings suggest a shared mechanism of action for the gateway drugs alcohol and nicotine, and reveal a novel mechanism by which environmental factors may alter the epigenetic landscape of the reward system to increase vulnerability to cocaine addiction.

Background: Prescription opioid (PO) overdose deaths increased sharply over the last decade. Changes in PO deaths in combination with other psychoactive substances may provide a partial explanation., Methods: PO deaths from the National Multiple-Cause-of-Death Files for 2002-03 (N=15,973) and 2014-15 (N=41,491) were analyzed. We calculated (1) changes in proportions of deaths in combination with benzodiazepines, antidepressants, heroin, alcohol, cocaine between the two periods, and (2) proportions of increase in deaths attributable to each substance among PO and synthetic opioids other than methadone (SO-M) deaths, by age, gender, race/ethnicity., Results: Between 2002-03 and 2014-15, PO deaths increased 2.6 times; SO-M deaths 5.6 times, especially for ages 18-34, males, African-Americans. For PO deaths, most frequent combinations at both periods were with benzodiazepines; for SO-M, benzodiazepines, antidepressants in 2002-03, heroin, benzodiazepines in 2014-15. The largest increases occurred in combination with heroin among all PO (4.6% to 15.4%, change ratio=3.3[95%CI=3.1-3.6]), but especially SO-M deaths (1.2% to 24.5%, change ratio=21.3[95%CI=15.0-30.3]). Deaths involving cocaine decreased among PO, increased among SO-M deaths. One-fifth of increased PO or SO-M deaths were attributable to any of the five substances. Increased PO deaths were equally attributable to benzodiazepines and heroin; deaths attributable to heroin were higher among ages 18-49, males, and non-Hispanic whites. Increased SO-M deaths were attributable mostly to heroin among all groups., Conclusions: Increased PO overdose deaths over the last decade may be partially explained by increased deaths in combination with other psychoactive substances. Use of other substances should be considered in efforts toward reducing prescription opioid overdoses., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: To estimate age-related patterns in nonmedical prescription opioid (NMPO) use in the US population and disorder among past-year users at ages 12-34 between 2002 and 2014, controlling for period and birth-cohort effects., Methods: Data are from 13 consecutive cross-sectional National Surveys on Drug Use and Health (N=542,556). Synthetic longitudinal cohorts spanning ages 12-34 were created and an age-period-cohort analysis was implemented based on the Intrinsic Estimator algorithm., Results: In every birth cohort, past-year NMPO use increases during adolescence, peaks at ages 18-21, decreases through ages 30-34; disorder among past-year users increases from ages 18-21 through 30-34. Use at ages 12-34 decreased from the 1984-87 birth cohorts to more recently-born cohorts. Peak prevalence of use at ages 18-21 has also decreased, and the rates of increase from ages 14-17 to ages 18-21 are slowing down. Disorder at ages 18-34 increased from the 1976-79 to 1992-95 cohorts, but decreased at ages 12-17 from the 1992-95 to the most recently-born 2000-02 cohorts. The years 2010-2014 were characterized by lower NMPO use but higher disorder than 2002-2009., Conclusions: Increasing NMPO disorder among users aged 18-34 warrants concern. However, declining NMPO use among 12-34 year-olds, a declining rate of increase from adolescence to early adulthood, and a suggestive decline in disorder among the most recent adolescent cohorts may forecast a potential reduction in the public health crisis associated with NMPO drugs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: To examine whether the drug behavior of adults from different birth cohorts is shaped by adolescent drug experiences and whether adult prevalence of marijuana and cocaine use depends on adolescent cigarette or alcohol use prevalence., Methods: We analyzed 18 birth cohorts comprising 8th, 10th, and 12th graders, sampled from 1991 to 2008, from Monitoring the Future, an annual nationally representative cross-sectional survey of high school students in the United States (n = 864 443)., Results: Within cohorts, lifetime rates of 8th and 10th grade cigarette use were significantly associated with subsequent lifetime rates of marijuana and cocaine use, controlling for trends in use and social norms toward drug use. Each percent increase (or decrease) in 8th and 10th grade smoking was associated with an 8% increase (or decrease) in prevalence of later marijuana use and 14% to 23% increase (or decrease) in prevalence of later cocaine use. Relationships were consistent by gender and race/ethnicity., Conclusions: Prevalences of smoking in 8th and 10th grade and of marijuana and cocaine use in 12th grade are associated. Public health campaigns should focus on early stages of adolescence, when drug use habits are forming.

Introduction: To examine the prospective associations of Diagnostic and Statistical Manual of Mental Disorders nicotine dependence (ND) and other individual and parental factors in adolescence on self-reported health symptoms in early adulthood., Methods: Multiethnic prospective longitudinal cohort of adolescents from grades 6-10 and a parent (N = 908) from the Chicago Public Schools. Adolescents were interviewed five times at 6-month intervals (Waves 1-5) and once 4.5 years later (Wave 6). Parents were interviewed annually three times (W1, W3, W5). Multivariate regressions estimated prospective associations of Diagnostic and Statistical Manual of Mental Disorders ND, other individual and familial risk factors in adolescence (mean age 16.6) on physical health symptoms in early adulthood (mean age 21.3), controlling for health symptoms in adolescence., Results: Levels of health symptoms declined from adolescence to early adulthood, except among dependent smokers. Nicotine dependent adolescents reported more health symptoms as young adults than nonsmokers and nondependent smokers, especially if depressed. ND and health symptoms in adolescence were the strongest predictors of health in early adulthood. These two adolescent factors, depression, and the familial factors of parental ND, depression and health conditions, each independently predicted health symptoms in young adulthood. Females reported more symptoms than males., Conclusions: There is continuity of health status over time. ND, depression, and parental factors in adolescence contribute to poor health in early adulthood. The findings highlight not only the role of adolescent behavior, but the importance of the family in the development of young adult health. Reducing smoking, particularly ND, and depression among adolescents and parents will decrease physical health burden., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We examined associations between parental and adolescent smoking and nicotine dependence in the United States., Methods: We used data from the 2004 to 2012 National Survey on Drug Use and Health, which ascertained smoking behaviors of 1 parent and 1 adolescent aged 12 to 17 years in 35 000 dyads. We estimated associations between parental and adolescent smoking behaviors, adjusted for covariates., Results: Parental current dependence was strongly associated with adolescents' lifetime smoking (adjusted odds ratio [AOR] = 2.96; 95% confidence interval [CI] = 2.47, 3.55), whereas parental current nondependent smoking (AOR = 2.26; 95% CI = 1.92, 2.67) and former smoking (AOR = 1.51; 95% CI = 1.31, 1.75) were less strongly associated. Only parental nicotine dependence was associated with adolescent nicotine dependence (AOR = 1.66; 95% CI = 1.00, 2.74). Associations between parental and adolescent smoking did not differ by race/ethnicity. Parents' education, marital status, and parenting and adolescents' mental health, beliefs about smoking, perception of schoolmates' smoking, and other substance use predicted adolescent smoking and dependence., Conclusions: Reducing parental smoking would reduce adolescent smoking. Prevention efforts should encourage parental smoking cessation, improve parenting, address adolescent mental health, and reinforce adolescents' negative beliefs about smoking.