Dataset Information

Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability.

ABSTRACT: Marijuana use by teenagers often predates the use of harder drugs, but the neurobiological underpinnings of such vulnerability are unknown. Animal studies suggest enhanced heroin self-administration (SA) and dysregulation of the endogenous opioid system in the nucleus accumbens shell (NAcsh) of adults following adolescent ?(9)-tetrahydrocannabinol (THC) exposure. However, a causal link between proenkephalin (Penk) expression and vulnerability to heroin has yet to be established.To investigate the functional significance of NAcsh Penk tone, selective viral-mediated knockdown and overexpression of Penk was performed, followed by analysis of subsequent heroin SA behavior. To determine whether adolescent THC exposure was associated with chromatin alteration, we analyzed levels of histone H3 methylation in the NAcsh via chromatin immunoprecipitation at five sites flanking the Penk gene transcription start site.Here we show that regulation of the Penk opioid neuropeptide gene in NAcsh directly regulates heroin SA behavior. Selective viral-mediated knockdown of Penk in striatopallidal neurons attenuates heroin SA in adolescent THC-exposed rats, whereas Penk overexpression potentiates heroin SA in THC-naïve rats. Furthermore, we report that adolescent THC exposure mediates Penk upregulation through reduction of histone H3 lysine 9 (H3K9) methylation in the NAcsh, thereby disrupting the normal developmental pattern of H3K9 methylation.These data establish a direct association between THC-induced NAcsh Penk upregulation and heroin SA and indicate that epigenetic dysregulation of Penk underlies the long-term effects of THC.

SUBMITTER: Tomasiewicz HC

PROVIDER: S-EPMC3440551 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability.

Tomasiewicz Hilarie C HC Jacobs Michelle M MM Wilkinson Matthew B MB Wilson Steven P SP Nestler Eric J EJ Hurd Yasmin L YL

Biological psychiatry 20120608 10

<h4>Background</h4>Marijuana use by teenagers often predates the use of harder drugs, but the neurobiological underpinnings of such vulnerability are unknown. Animal studies suggest enhanced heroin self-administration (SA) and dysregulation of the endogenous opioid system in the nucleus accumbens shell (NAcsh) of adults following adolescent Δ(9)-tetrahydrocannabinol (THC) exposure. However, a causal link between proenkephalin (Penk) expression and vulnerability to heroin has yet to be establishe ...[more]

PMID: 22683090

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Project description:ObjectivesStudies examining the impact of adolescent and young adult cannabis use on structural outcomes have been heterogeneous. One already-identified moderator is sex, while a novel potential moderator is extent of aerobic fitness. Here, we sought to investigate the associations of cannabis use, sex, and aerobic fitness levels on brain volume. Second, we explored brain-behavior relationships to interpret these findings.MethodsSeventy-four adolescents and young adults (36 cannabis users and 38 controls) underwent 3 weeks of monitored cannabis abstinence, aerobic fitness testing, structural neuroimaging, and neuropsychological testing. Linear regressions examined cannabis use and its interaction with sex and aerobic fitness on whole-brain cortical volume and subcortical regions of interests.ResultsNo main-effect differences between cannabis users and nonusers were observed; however, cannabis-by-sex interactions identified differences in frontal, temporal, and paracentral volumes. Female cannabis users generally exhibited greater volume while male users exhibited less volume compared to same-sex controls. Positive associations between aerobic fitness and frontal, parietal, cerebellum, and caudate volumes were observed. Cannabis-by-fitness interaction was linked with left superior temporal volume. Preliminary brain-behavior correlations revealed that abnormal volumes were not advantageous in either male or female cannabis users.ConclusionsAerobic fitness was linked with greater brain volume and sex moderated the effect of cannabis use on volume; preliminary brain-behavior correlations revealed that differences in cannabis users were not linked with advantageous cognitive performance. Implications of sex-specific subtleties and mechanisms of aerobic fitness require large-scale investigation. Furthermore, present findings and prior literature on aerobic exercise warrant examinations of aerobic fitness interventions that aimed at improving neurocognitive health in substance-using youth.

Project description:Adolescence is a time of rapid neurodevelopment and the endocannabinoid system is particularly prone to change during this time. Cannabis is a commonly used drug with a particularly high prevalence of use among adolescents. The two predominant phytocannabinoids are Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which affect the endocannabinoid system. It is unknown whether this period of rapid development makes adolescents more or less vulnerable to the effects of cannabis on brain-network connectivity, and whether CBD may attenuate the effects of THC. Using fMRI, we explored the impact of vaporized cannabis (placebo, THC: 8 mg/75 kg, THC + CBD: 8 mg/75 kg THC & 24 mg/75 kg CBD) on resting-state networks in groups of semi-regular cannabis users (usage frequency between 0.5 and 3 days/week), consisting of 22 adolescents (16-17 years) and 24 young adults (26-29 years) matched for cannabis use frequency. Cannabis caused reductions in within-network connectivity in the default mode (F[2,88] = 3.97, P = 0.022, η² = 0.018), executive control (F[2,88] = 18.62, P < 0.001, η² = 0.123), salience (F[2,88] = 12.12, P < 0.001, η² = 0.076), hippocampal (F[2,88] = 14.65, P < 0.001, η² = 0.087), and limbic striatal (F[2,88] = 16.19, P < 0.001, η² = 0.102) networks compared to placebo. Whole-brain analysis showed cannabis significantly disrupted functional connectivity with cortical regions and the executive control, salience, hippocampal, and limbic striatal networks compared to placebo. CBD did not counteract THC's effects and further reduced connectivity both within networks and the whole brain. While age-related differences were observed, there were no interactions between age group and cannabis treatment in any brain network. Overall, these results challenge the assumption that CBD can make cannabis safer, as CBD did not attenuate THC effects (and in some cases potentiated them); furthermore, they show that cannabis causes similar disruption to resting-state connectivity in the adolescent and adult brain.

Project description:Background: Among youth already using cannabis, legalization of medical cannabis may influence cannabis-related attitudes and behaviors, including increasing access through use of someone else's medical cannabis (diversion). Objective: To examine cannabis-related attitudes and behaviors (including diverted cannabis use) in cannabis-using youth in the four years following medical cannabis legalization. Additionally, we investigated characteristics of youth who used vs. did not use diverted medical cannabis. Methods: Data were collected in Boston from 2013 (when medical cannabis legislation took effect in Massachusetts) through 2016 (when recreational cannabis use became legal in Massachusetts). Cannabis-using youth (age 13-24) presenting to an outpatient adolescent substance use treatment program (ASUTP) or recruited for an adolescent medicine clinic study (AMCS) completed a confidential survey on demographic characteristics and cannabis use behaviors and attitudes. We used multiple logistic regression to analyze changes in attitudes and behaviors over three years versus the reference year (2013), controlling for demographics. We used chi-square to compare characteristics of youth reporting use of diverted medical cannabis versus those not. Results: The sample included 273 cannabis-using youth (ASUTP n = 203, AMCS n = 70; 2013 n = 67, 2014 n = 67, 2015 n = 77, 2016 n = 62). Mean ± SD age was 18.2 ± 2.5 years, 32% were female, 58% were White non-Hispanic, and 70% had college-graduate parents. In 2013, most youth reported that cannabis was easy to obtain (97.9%), and that occasional cannabis use had "no" or "slight" risk of harm (89.4%), with little change across years. In 2016, 44% of youth reported using someone else's medical cannabis, versus 15% in 2013 (aOR 4.66, 95% CI 1.81, 11.95). Youth using diverted medical cannabis had higher likelihood of reporting riding with a driver, or driving themselves, after cannabis use (both p < .01). Conclusion: Among at-risk youth in Massachusetts, use of diverted medical cannabis increased after medical cannabis legalization, and those using diverted medical cannabis reported higher risk for cannabis-related traffic injury.

Dataset Information

Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability.

Publications

Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability.

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