Emerging lines of evidence suggest that interactions between genes and the environment play a critical role in individual vulnerability to psychiatric disorders including drug addiction. The epigenome is influenced by environment and thus is a highly relevant biological candidate to maintain persistent aberrant neuronal processing as a result of developmental drug exposure. The developing brain may be particularly sensitive to epigenetic influences, given the dynamic neuroplasticity characteristic of this period. Marijuana (Cannabis sativa) is the illicit drug most commonly used by pregnant women and teenagers. Our studies of human fetuses with maternal cannabis use revealed selective alterations of striatal preproenkephalin (PENK) and dopamine receptor D2 gene expression (predominantly enriched in striatopallidal neurons), but not prodynorphin or dopamine D1 receptors (enriched in striatonigral neurons). Similar gene expression patterns were detected in the ventral striatum of rats exposed to ?-tetrahydrocannabinol (THC), the psychoactive component of cannabis, prenatally as well as during adolescence. Importantly, PENK and D2 gene expression impairments persisted into adulthood following either prenatal or adolescent THC exposure and the animals exhibited increased heroin self-administration and inhibitory control deficit, phenotypes predictive of drug addiction vulnerability. Epigenetic modifications are capable of maintaining modified gene expression states that can persist throughout development and it is an intriguing possibility that such mechanisms would underlie the long-term effects of cannabis exposure. In this project, we propose to study chromatin modification at specific regulatory regions of the PENK and D2 genes in the ventral striatum of adult rats with developmental THC exposure. The fact that PENK and D2 genes are preferentially expressed in subpopulations of striatal neurons that constitutes the striatopallidal pathway suggests a potential THC-sensitivity of genes aligned to this circuit. We set out to discover novel striatopallidal genes that are affected by developmental THC exposure and explore the epigenetic mechanisms that regulate their expression. Furthermore, we will investigate the causal relationship between THC-sensitive striatopallidal genes and addiction-related behaviors by use of gene manipulation in the ventral striatum. Overall, these studies will provide important mechanistic insights into the long-term impact of developmental THC exposure that would enable the development of targeted treatment interventions for addiction vulnerability and other related psychiatric disorders associated with developmental insults.

Public Health Relevance

Marijuana is the illicit drug most used by pregnant women and teens. Expanding knowledge regarding the long-term impact of developmental marijuana exposure on specific neurobiological events causally linked to behavioral disturbances will provide significant insights as to the discrete neurobiological mechanisms that may underlie the vulnerability to neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA030359-03
Application #
8490327
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (02))
Program Officer
Wu, Da-Yu
Project Start
2011-09-30
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$413,292
Indirect Cost
$156,275
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Miller, M L; Ren, Y; Szutorisz, H et al. (2018) Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Mol Psychiatry 23:1328-1335
Miller, Michael L; Chadwick, Benjamin; Dickstein, Dara L et al. (2018) Adolescent exposure to ?9-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons. Mol Psychiatry :
Mazzone, C M; Pati, D; Michaelides, M et al. (2018) Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior. Mol Psychiatry 23:143-153
Szutorisz, Henrietta; Hurd, Yasmin L (2018) High times for cannabis: Epigenetic imprint and its legacy on brain and behavior. Neurosci Biobehav Rev 85:93-101
Michaelides, Michael; Miller, Michael L; DiNieri, Jennifer A et al. (2017) Dopamine D2 Receptor Signaling in the Nucleus Accumbens Comprises a Metabolic-Cognitive Brain Interface Regulating Metabolic Components of Glucose Reinforcement. Neuropsychopharmacology 42:2365-2376
Miller, Michael L; Hurd, Yasmin L (2017) Testing the Gateway Hypothesis. Neuropsychopharmacology 42:985-986
Szutorisz, Henrietta; Egervári, Gabor; Sperry, James et al. (2016) Cross-generational THC exposure alters the developmental sensitivity of ventral and dorsal striatal gene expression in male and female offspring. Neurotoxicol Teratol 58:107-114
Szutorisz, Henrietta; Hurd, Yasmin L (2016) Epigenetic Effects of Cannabis Exposure. Biol Psychiatry 79:586-94
Urban, Daniel J; Zhu, Hu; Marcinkiewcz, Catherine A et al. (2016) Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons. Neuropsychopharmacology 41:1404-15
Parsons, Loren H; Hurd, Yasmin L (2015) Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci 16:579-94

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