Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability.
Hilarie C Tomasiewicz, Michelle M Jacobs, Matthew B Wilkinson, Steven P Wilson, Eric J Nestler, Yasmin L. Hurd
Biological Psychiatry November 15, 2012 DOI: 10.1016/j.biopsych.2012.04.026 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Rats exposed to THC during adolescence and THC-naive rats |
| Intervention | Δ(9)-tetrahydrocannabinol (THC) |
| Topics | Cannabis |
| Key findings | Regulation of the Penk gene in the nucleus accumbens shell directly regulates heroin self-administration: knockdown attenuated it in adolescent THC-exposed rats and overexpression potentiated it in THC-naive rats. Adolescent THC exposure reduced histone H3 lysine 9 methylation at the Penk gene, upregulating Penk and disrupting its normal developmental pattern, which the authors propose underlies long-term vulnerability to heroin. |
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 Δ(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.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 15
- Cannabis Use during Adolescent Development: Susceptibility to Psychiatric Illness Frontiers in Psychiatry 2013
- Divergent outcomes of delta 9 - tetrahydrocannabinol (THC) in adolescence on mesocortical dopamine and cognitive development in male and female mice. Psychopharmacology October 2025
- Long-term effects of THC exposure on reward learning and motivated behavior in adolescent and adult male rats. Psychopharmacology May 2023
- THC and CBD: Villain versus Hero? Insights into Adolescent Exposure. International Journal of Molecular Sciences March 9, 2023
- THC and CBD: Similarities and differences between siblings. Neuron February 1, 2023
and 10 more in the library
Cites 3
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- Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats. Neuropsychopharmacology March 2007