Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5

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

Epidemiology and Correlates of Daily Smoking and Nicotine Dependence Among Young Adults in the United States

Objectives. We describe the epidemiology of smoking behaviors in a national young adult sample and identify common and unique demographic, social, and psychological correlates of daily smoking and lifetime and current nicotine dependence by race/ethnicity. Methods. Data are from the National Longitudinal Survey of Adolescent Health, wave III. Dependence was measured by the Revised Fagerström Test for Nicotine Dependence. Logistic regressions were estimated. Results. Hispanic ethnicity, low education, parental and peer smoking, novelty seeking, early age of smoking onset, and pleasurable initial smoking experiences are significantly correlated with daily smoking and lifetime nicotine dependence. Depressive symptoms are uniquely associated with lifetime and current dependence. Few factors are highly associated with current dependence. Initial sensitivity to smoking has a significantly greater impact on daily smoking than on dependence. Correlates of smoking behaviors are mostly common across racial/ethnic groups, although parental and peer smoking are significant for Whites and Hispanics but not for African Americans. Conclusions. There are more common than unique correlates of each smoking stage and across racial/ethnic groups. Primary prevention and interventions addressing the factors tested could be uniform for most chronic smokers irrespective of dependence status and race/ethnicity

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

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