Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine.

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.

Normalization of Prevention Principles and Practices to Reduce Substance Use Disorders Through an Integrated Dissemination and Implementation Framework.

Major research breakthroughs over the past 30 years in the field of substance use prevention have served to: (1) enhance understanding of pharmacological effects on the central and peripheral nervous systems and the health and social consequences of use of psychoactive substances, particularly for children and adolescents; (2) delineate the processes that increase vulnerability to or protect from initiation of substance use and progression to substance use disorders (SUDs) and, based on this understanding, (3) develop effective strategies and practices to prevent the initiation and escalation of substance use. The challenge we now face as a field is to "normalize" what we have learned from this research so that it is incorporated into the work of those involved in supporting, planning, and delivering prevention programming to populations around the world, is integrated into health and social service systems, and helps to shape public policies. But we wish to go further, to incorporate these effective prevention practices into everyday life and the mind-sets of the public, particularly parents and educators. This paper reviews the advances that have been made in the field of prevention and presents a framework and recommendations to achieve these objectives generated during several meetings of prevention and implementation science researchers sponsored by the International Consortium of Universities for Drug Demand Reduction (ICUDDR) that guides a roadmap to achieve "normalization."

Synaptoproteomic Analysis of the Prefrontal Cortex Reveals Spatio-Temporal Changes in SYNGAP1 Following Cannabinoid Exposure in Rat Adolescence.

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 (Δ9-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.

Social isolation is closely linked to a marked reduction in physical activity in male mice.

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.

Medical Use and Misuse of Prescription Opioids in the US Adult Population: 2016-2017.

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.

Birth Cohorts Analysis of Adolescent Cigarette Smoking and Subsequent Marijuana and Cocaine Use.

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.

Nicotine Dependence in Adolescence and Physical Health Symptoms in Early Adulthood.

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.

Intergenerational Patterns of Smoking and Nicotine Dependence Among US Adolescents.

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.

The Gateway Hypothesis of substance abuse: developmental, biological and societal perspectives.

UNLABELLED: The Gateway Hypothesis describes how tobacco or alcohol use precedes marijuana and other illicit drug use. We review the epidemiological data, explore the underlying molecular mechanisms in mice and discuss the societal implications of the hypothesis, including the use of e-cigarettes by young people. CONCLUSION: Our mouse model identifies biological processes underlying the hypothesis, showing that nicotine is a gateway drug that exerts a priming effect on cocaine through increased global acetylation in the striatum.

D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus.

The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG.

Risk and protective factors for nicotine dependence in adolescence.

BACKGROUND: We investigated the role of psychosocial and proximal contextual factors on nicotine dependence in adolescence. METHODS: Data on a multiethnic cohort of 6th to 10th graders from the Chicago public schools were obtained from four household interviews conducted with adolescents over two years and one interview with mothers. Structural equation models were estimated on 660 youths who had smoked cigarettes by the first interview. RESULTS: Pleasant initial sensitivity to tobacco use, parental nicotine dependence (ND), adolescent ND and extensiveness of smoking at the initial interview had the strongest total effects on adolescent ND two years later. Perceived peer smoking and adolescent conduct problems were of lesser importance. Parental ND directly impacted adolescent ND two years later and had indirect effects through pleasant initial sensitivity and initial extensiveness of smoking. Parental depression affected initial adolescent dependence and depression but adolescent depression had no effect on ND. The model had greater explanatory power for males than females due partly to the stronger effect of conduct problems on dependence for males than females. CONCLUSIONS: The findings underscore the importance of the initial drug experience and familial factors on adolescent nicotine dependence and highlight the factors to be the focus of efforts targeted toward preventing ND among adolescents.

Assessment of Prescription Opioid Medical Use and Misuse Among Parents and Their Adolescent Offspring in the US.

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.

Cytoplasmic Polyadenylation Element Binding Proteins CPEB1 and CPEB3 Regulate the Translation of FosB and Are Required for Maintaining Addiction-Like Behaviors Induced by Cocaine.

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.

Nonmedical Prescription Opioid Use by Parents and Adolescents in the US.

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.

Developmental trajectories of criteria of nicotine dependence in adolescence.

We describe the nature and predictors of developmental trajectories of symptoms of DSM-IV nicotine dependence in adolescence following smoking initiation. Data are from a longitudinal cohort of 324 new smokers from grades 6-10 in the Chicago Public Schools, interviewed 5 times at 6-month intervals. Monthly data on DSM-IV symptoms of nicotine dependence were available for 36 months. Growth mixture modeling was applied to the monthly histories to identify trajectories of DSM-IV criteria of nicotine dependence. A four-class solution best fitted the data: no DSM criterion (47.7%); early onset/chronic course (19.8%); early onset/remission (17.3%); late onset (15.2%). Blunt use prior to cigarette use was associated with the three symptomatic trajectories. Conduct disorder and prior heavy smoking were associated with Class 2 (chronic). Conduct disorder differentiated Class 2 from Class 4 (late onset), while pleasant initial sensitivity to the first tobacco experience was associated with Classes 2 and 3 (remit) and differentiated Class 2 from Class 4. Novelty seeking characterized Class 3. Parental dependence differentiated chronicity (Class 2) from remission (Class 3) among those who developed symptoms early. Being Hispanic reduced membership in Classes 3 and 4, and being male for Class 3. The data highlight the importance of parental nicotine dependence as a risk factor for early and sustained nicotine dependence by the offspring, pleasant initial sensitivity and conduct disorder for early onset of dependence, and blunt use prior to smoking for all trajectories. The factors important for onset of dependence are not necessarily the same as those for sustained course.

Nonmedical prescription opioids and pathways of drug involvement in the US: Generational differences.

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.

Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood.

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.

Cannabinoid Modulation of Eukaryotic Initiation Factors (eIF2α and eIF2B1) and Behavioral Cross-Sensitization to Cocaine in Adolescent Rats.

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.