Hurd Lab

Molecular Neuropsychopharmacology

Research

Yasmin HurdAt the Hurd Lab, our multi-prong research is focused on understanding the contribution and interplay of genes and the environment to the development of addictive disorders, and providing neurobiological insights that innovate and advance treatment and intervention. Translational research is the principal feature of our lab. Led by Dr. Yasmin Hurd, the Director of the Addiction Institute at the Mount Sinai Behavioral Health System, the research lab consists of a multi-disciplinary team of scientists who study addiction through a myriad of lenses: animal behavior, molecular biology, cell biology, pharmacology, psychology, neuroimaging, bioinformatics and biotechnology.

Dr. Yasmin Hurd is Professor in the Departments of Psychiatry, Neuroscience and Pharmacology and Systems Therapeutics. She is the Director of the Addiction Institute.

Contact Us

Hurd Laboratory
Yasmin Hurd, PhD
Professor, Neuroscience
Professor, Pharmacological Sciences
Professor, Psychiatry
Location
Lab: HESS 10-201
Phone
Office: 212.824.9313
Lab: 212.241.9975
Lab fax: 636.537.9598
Email

Areas of Research

At the Hurd Lab, our multi-prong research is focused on understanding the contribution and interplay of genes and the environment to the development of addictive disorders, and providing neurobiological insights that innovate and advance treatment and intervention. Translational research is the principal feature of our lab. Led by Dr. Yasmin Hurd, the Director of the Center for Addictive Disorders at the Mount Sinai Behavioral Health System, the research lab consists of a multi-disciplinary team of scientists who study addiction through a myriad of lenses: animal behavior, molecular biology, cell biology, pharmacology, psychology, neuroimaging, bioinformatics and biotechnology.

Genetic and Epigenetic Mechanisms

Combining standard molecular biological techniques such as in situ hybridization, qPCR, and biochemical assays with innovative methods such as next-generation sequencing and viral-mediated manipulations of discrete neuronal pathways, the Hurd lab investigates neurobiological disturbances associated addiction to variety of substances ( heroin, cannabis, cocaine). Epigenetic mechanisms including DNA methylation, histone modifications and microRNAs are also evaluated in relation to the regulation of gene expression within distinct neuronal populations of the mesocorticolimbic and striatal circuits.

Cutting-edge Molecular Neurobiology

Through our affiliation with the Friedman Brain Institute, the Hurd Lab has access to state-of-the-art technology in confocal and electron microscopy to analyze human and animal tissues at the single-cell level. Additionally, we use non-invasive neuroimaging techniques such as PET, fMRI and small animal MRI to determine real-time changes in neural activity, neurotransmitter levels and drug distribution, as well as structural changes in the brain. We pioneered the technique of DREAMM (DREADD-assisted metabolic mapping) combining molecular pharmacogenetic and in vivo imaging strategies to provide high-resolution quantitative mapping of functional brain circuits associated with disturbance of genes expressed in specific cell populations.

Animal Behavior Models

A large part of our research is committed to animal behavioral studies designed to mimic patterns of prenatal and adolescent THC exposure seen in humans in order to further explore the molecular basis for clinical symptoms observed in human subjects. The Hurd research group is a pioneering leader in the field studying developmental exposure to THC (the main psychoactive component of marijuana), and in particular, its transgenerational impact on neurocognitive development as it relates to vulnerability to addictive disorders and comorbid psychiatric disturbances such as anxiety and depression. We were the first to reveal that adolescent THC exposure may cause permanent changes in the mesocorticolimbic gene expression, receptor function and cellular activity transmitted through the parental germline to subsequent generations.

Human Brain Studies

Another significant part of our research engine is our long-standing translational efforts to study the neurobiological effects of human substance abuse through the direct examination of post-mortem human brain tissue. Through molecular, biochemical, and in vivo imaging studies of the human brain, we also work to understand the relationship of genetic polymorphisms to neurobiological systems underlying addictive and affective disorders.

Clinical Trials

Innovative translational research being the backbone of our research, some of our most exciting research efforts relate to clinical studies in addiction and intervention involving human subjects. Currently, we are conducting clinical research with cannabidiol, a cannabinoid compound from the marijuana plant that we identified from our animal studies to inhibit heroin-seeking behavior. We now study cannabidiol for its novel and potential role in preventing relapse in heroin and cocaine addiction, reducing anxiety, and improving overall cognitive function. We have successfully completed Phase I of this project and are carrying out Phase II studies.

Featured

Testing the Gateway Hypothesis

Cynthia Graber speaks to Yasmin L. Hurd in this Journal for Neuropsychopharmacology Podcast

Opioid Addiction FAQ: Experts' guide to the hard facts

As opioids claim an ever-greater number of American lives, the DAILY NEWS turned to the nation’s top medical specialists for what the addicted and their loved ones need to know. Frequently asked questions about opioid and opiate addiction and use.

Daily News – June 23, 2017

Time Magazine: The Great Pot Experiment

The recent push to legalize recreational and medical marijuana has put the spotlight on Dr. Yasmin Hurd and her pioneering work on the transgenerational effects of cannabis on the developing brain. Dr. Hurd’s research was featured on the cover story of TIME magazine on May 25, 2015: The Great Pot Experiment.

The Friedman Brain Institute

Game-changers in the field of Addiction. Addiction is a disorder of the brain, not one of morality. The Friedman Brain Institute actively seeks to discover what unique characteristics make certain individuals more vulnerable to addictive disorders and which treatments may be best suited to help that individual to overcome the disease.

Brain Venn Diagram

Drug Addiction: A brain disorder influenced by genetic and environmental factors

Three-dimensional DREAAM images

functional activation of the rat extended amygdala, cingulate cortex and olfactory tubercle regions after remote unilateral chemogenetic activation of prodynorphin-expressing neurons in the periamygdaloid cortex

Media

Humans of Earth: Humans of Earth We Need to Talk About Recreational Marijuana – Human Issues Special

Is Marijuana the Key to Solving the Opioid Crisis?

Just The Facts: The Science On Marijuana

The scientist is testing a marijuana ingredient as a way to prevent relapse. It’s a dauting task

Full CNN Documentary Weed Part 4 with Dr. Sanjay Gupta!

A Gene Links Impulsivity and Drug Use Vulnerability

Publications

2018

PMID-25122903

Egervari, G., Kozlenkov, A., Dracheva, S., and Hurd, Y.L. (2018b). Molecular windows into the human brain for psychiatric disorders. Mol Psychiatry.


PMID-25122903

Bassir Nia, A., and Hurd, Y.L. (2018). Cannabidiol, an Adjunct Player in the Antipsychosis Arsenal. Am J Psychiatry 175, 197-198.


PMID-25122903

Hurd, Y.L., and O’Brien, C.P. (2018). Molecular Genetics and New Medication Strategies for Opioid Addiction. Am J Psychiatry 175, 935-942.


PMID-25122903

Michaelides, M., Miller, M.L., Egervari, G., Primeaux, S.D., Gomez, J.L., Ellis, R.J., Landry, J.A., Szutorisz, H., Hoffman, A.F., Lupica, C.R., et al. (2018). Striatal Rgs4 regulates feeding and susceptibility to diet-induced obesity. Mol Psychiatry.


PMID-25122903

Miller, M.L., Chadwick, B., Dickstein, D.L., Purushothaman, I., Egervari, G., Rahman, T., Tessereau, C., Hof, P.R., Roussos, P., Shen, L., et al. (2018a). Adolescent exposure to Δ (9)-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons. Mol Psychiatry.


PMID-25122903

Szutorisz, H., and Hurd, Y.L. (2018). High times for cannabis: Epigenetic imprint and its legacy on brain and behavior. Neurosci Biobehav Rev 85, 93-101.


PMID-25122903

Egervari, G., Ciccocioppo, R., Jentsch, J.D., and Hurd, Y.L. (2018a). Shaping vulnerability to addiction – the contribution of behavior, neural circuits and molecular mechanisms. Neurosci Biobehav Rev 85, 117-125.


pmid-24231358

Mazzone, C.M., Pati, D., Michaelides, M., DiBerto, J., Fox, J.H., Tipton, G., Anderson, C., Duffy, K., McKlveen, J.M., Hardaway, J.A., 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.


PMID-25122903

Miller, M.L., Ren, Y., Szutorisz, H., Warren, N.A., Tessereau, C., Egervari, G., Mlodnicka, A., Kapoor, M., Chaarani, B., Morris, C.V., et al. (2018b). Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. Mol Psychiatry 23, 1328-1335.

2017

PMID-25122903

Hurd, Y.L. (2017). Cannabidiol: Swinging the Marijuana Pendulum From ‘Weed’ to Medication to Treat the Opioid Epidemic. Trends Neurosci 40, 124-127.


PMID-25122903

Miller, M.L., and Hurd, Y.L. (2017). Testing the Gateway Hypothesis. Neuropsychopharmacology 42, 985-986.


PMID-25122903

Cheer, J.F., and Hurd, Y.L. (2017). A new dawn in cannabinoid neurobiology: The road from molecules to therapeutic discoveries. Neuropharmacology 124, 1-2.


PMID-25122903

Michaelides, M., Miller, M.L., DiNieri, J.A., Gomez, J.L., Schwartz, E., Egervari, G., Wang, G.J., Mobbs, C.V., Volkow, N.D., and Hurd, Y.L. (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.


PMID-25122903

Egervari, G., Landry, J., Callens, J., Fullard, J.F., Roussos, P., Keller, E., and Hurd, Y.L. (2017). Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target. Biol Psychiatry 81, 585-594.

2016

PMID-25122903

Bassir Nia, A., Medrano, B., Perkel, C., Galynker, I., and Hurd, Y.L. (2016). Psychiatric comorbidity associated with synthetic cannabinoid use compared to cannabis. J Psychopharmacol 30, 1321-1330.


PMID-25122903

Egervari, G., Jutras-Aswad, D., Landry, J., Miller, M.L., Anderson, S.A., Michaelides, M., Jacobs, M.M., Peter, C., Yiannoulos, G., Liu, X., et al. (2016). A Functional 3’UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits. Neuropsychopharmacology 41, 2512-2520.


PMID-25122903

Szutorisz, H., and Hurd, Y.L. (2016). Epigenetic Effects of Cannabis Exposure. Biol Psychiatry 79, 586-594.


PMID-25122903

Szutorisz, H., Egervari, G., Sperry, J., Carter, J.M., and Hurd, Y.L. (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.

2015

PMID-25122903

Watson, C.T., Szutorisz, H., Garg, P., Martin, Q., Landry, J.A., Sharp, A.J., and Hurd, Y.L. (2015). Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated With Cross-Generational Effects of Adolescent THC Exposure. Neuropsychopharmacology 40, 2993-3005.


PMID-25122903

Parsons, L.H., and Hurd, Y.L. (2015). Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci 16, 579-594.


PMID-25122903

Manini, A.F., Yiannoulos, G., Bergamaschi, M.M., Hernandez, S., Olmedo, R., Barnes, A.J., Winkel, G., Sinha, R., Jutras-Aswad, D., Huestis, M.A., et al. (2015). Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med 9, 204-210.


PMID-25122903

Hurd, Y.L., Yoon, M., Manini, A.F., Hernandez, S., Olmedo, R., Ostman, M., and Jutras-Aswad, D. (2015). Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage. Neurotherapeutics 12, 807-815.


PMID-25122903

Michaelides, M., and Hurd, Y.L. (2015). DREAMM: a biobehavioral imaging methodology for dynamic in vivo whole-brain mapping of cell type-specific functional networks. Neuropsychopharmacology 40, 239-240.

2014

PMID-25122903

Xu, J., Lu, Z., Xu, M., Pan, L., Deng, Y., Xie, X., Liu, H., Ding, S., Hurd, Y.L., Pasternak, G.W., et al. (2014). A heroin addiction severity-associated intronic single nucleotide polymorphism modulates alternative pre-mRNA splicing of the mu opioid receptor gene OPRM1 via hnRNPH interactions. J Neurosci 34, 11048-11066.


PMID-25030704

Alpar, A., Tortoriello, G., Calvigioni, D., Niphakis, M.J., Milenkovic, I., Bakker, J., Cameron, G.A., Hanics, J., Morris, C.V., Fuzik, J., et al. (2014). Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nat Commun 5, 4421.


pmid-24584053

Maze, I., Chaudhury, D., Dietz, D.M., Von Schimmelmann, M., Kennedy, P.J., Lobo, M.K., Sillivan, S.E., Miller, M.L., Bagot, R.C., Sun, H., et al. (2014). G9a influences neuronal subtype specification in striatum. Nat Neurosci 17, 533-539.


pmid-24584053

Szutorisz, H., DiNieri, J.A., Sweet, E., Egervari, G., Michaelides, M., Carter, J.M., Ren, Y., Miller, M.L., Blitzer, R.D., and Hurd, Y.L. (2014). Parental THC exposure leads to compulsive heroin-seeking and altered striatal synaptic plasticity in the subsequent generation. Neuropsychopharmacology 39, 1315-1323.


pmid-24469251

Tortoriello, G., Morris, C.V., Alpar, A., Fuzik, J., Shirran, S.L., Calvigioni, D., Keimpema, E., Botting, C.H., Reinecke, K., Herdegen, T., et al. (2014). Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J 33, 668-685.


pmid-24410775

Trampush, J.W., Jacobs, M.M., Hurd, Y.L., Newcorn, J.H., and Halperin, J.M. (2014). Moderator effects of working memory on the stability of ADHD symptoms by dopamine receptor gene polymorphisms during development. Dev Sci 17, 584-595.


pmid-24057217

Kozlenkov, A., Roussos, P., Timashpolsky, A., Barbu, M., Rudchenko, S., Bibikova, M., Klotzle, B., Byne, W., Lyddon, R., Di Narzo, A.F., et al. (2014). Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites. Nucleic Acids Res 42, 109-127.


pmid-24057217

Mitchell, A.C., Bharadwaj, R., Whittle, C., Krueger, W., Mirnics, K., Hurd, Y., Rasmussen, T., and Akbarian, S. (2014). The genome in three dimensions: a new frontier in human brain research. Biol Psychiatry 75, 961-969.


pmid-24057217

Hurd, Y.L., Michaelides, M., Miller, M.L., and Jutras-Aswad, D. (2014). Trajectory of adolescent cannabis use on addiction vulnerability. Neuropharmacology 76 Pt B, 416-424.

2013

pmid-24231358

Michaelides, M., Anderson, S.A., Ananth, M., Smirnov, D., Thanos, P.K., Neumaier, J.F., Wang, G.J., Volkow, N.D., and Hurd, Y.L. (2013). Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks. J Clin Invest 123, 5342-5350.


pmid-24231358

Anderson, S.A., Michaelides, M., Zarnegar, P., Ren, Y., Fagergren, P., Thanos, P.K., Wang, G.J., Bannon, M., Neumaier, J.F., Keller, E., et al. (2013). Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression. J Clin Invest 123, 5334-5341.


pmid-24198352

Karatsoreos, I.N., Thaler, J.P., Borgland, S.L., Champagne, F.A., Hurd, Y.L., and Hill, M.N. (2013). Food for thought: hormonal, experiential, and neural influences on feeding and obesity. J Neurosci 33, 17610-17616.


pmid-24133461

Chadwick, B., Miller, M.L., and Hurd, Y.L. (2013). Cannabis Use during Adolescent Development: Susceptibility to Psychiatric Illness. Front Psychiatry 4, 129.


pmid-24057217

Lobo, M.K., Zaman, S., Damez-Werno, D.M., Koo, J.W., Bagot, R.C., DiNieri, J.A., Nugent, A., Finkel, E., Chaudhury, D., Chandra, R., et al. (2013). ΔFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli. J Neurosci 33, 18381-18395.


pmid-23806960

Keimpema, E., Alpar, A., Howell, F., Malenczyk, K., Hobbs, C., Hurd, Y.L., Watanabe, M., Sakimura, K., Kano, M., Doherty, P., et al. (2013). Diacylglycerol lipase alpha manipulation reveals developmental roles for intercellular endocannabinoid signaling. Sci Rep 3, 2093.


pmid-23702428

Sillivan, S.E., Whittard, J.D., Jacobs, M.M., Ren, Y., Mazloom, A.R., Caputi, F.F., Horvath, M., Keller, E., Ma’ayan, A., Pan, Y.X., et al. (2013). ELK1 transcription factor linked to dysregulated striatal mu opioid receptor signaling network and OPRM1 polymorphism in human heroin abusers. Biol Psychiatry 74, 511-519.


pmid-23494274

Manini, A.F., Jacobs, M.M., Vlahov, D., and Hurd, Y.L. (2013b). Opioid receptor polymorphism A118G associated with clinical severity in a drug overdose population. J Med Toxicol 9, 148-154.


pmid-23494274

Bergamaschi, M.M., Barnes, A., Queiroz, R.H., Hurd, Y.L., and Huestis, M.A. (2013). Impact of enzymatic and alkaline hydrolysis on CBD concentration in urine. Anal Bioanal Chem 405, 4679-4689.


pmid-23494274

Manini, A., Jacobs, M., Vlahov, D., and Hurd, Y. (2013a). On the role of genetic testing for personalized drug overdose management. J Med Toxicol 9, 294-295.


pmid-24231358

Jacobs, M.M., Okvist, A., Horvath, M., Keller, E., Bannon, M.J., Morgello, S., and Hurd, Y.L. (2013). Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels. Mol Psychiatry 18, 1205-1210.

2012

pmid-24231358

Tomasiewicz, H.C., Jacobs, M.M., Wilkinson, M.B., Wilson, S.P., Nestler, E.J., and Hurd, Y.L. (2012). Proenkephalin mediates the enduring effects of adolescent cannabis exposure associated with adult opiate vulnerability. Biol Psychiatry 72, 803-810.


pmid-22745721

Jutras-Aswad, D., Jacobs, M.M., Yiannoulos, G., Roussos, P., Bitsios, P., Nomura, Y., Liu, X., and Hurd, Y.L. (2012). Cannabis-dependence risk relates to synergism between neuroticism and proenkephalin SNPs associated with amygdala gene expression: case-control study. PLoS One 7, e39243.


pmid-22745721

Dinieri, J.A., and Hurd, Y.L. (2012). Rat models of prenatal and adolescent cannabis exposure. Methods Mol Biol 829, 231-242.

2011

PMID-25122903

DiNieri, J.A., Wang, X., Szutorisz, H., Spano, S.M., Kaur, J., Casaccia, P., Dow-Edwards, D., and Hurd, Y.L. (2011). Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring. Biol Psychiatry 70, 763-769.


PMID-25122903

Okvist, A., Fagergren, P., Whittard, J., Garcia-Osta, A., Drakenberg, K., Horvath, M.C., Schmidt, C.J., Keller, E., Bannon, M.J., and Hurd, Y.L. (2011). Dysregulated postsynaptic density and endocytic zone in the amygdala of human heroin and cocaine abusers. Biol Psychiatry 69, 245-252.


PMID-25122903

Morris, C.V., DiNieri, J.A., Szutorisz, H., and Hurd, Y.L. (2011). Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment. Eur J Neurosci 34, 1574-1583.

Meet the Team

James Callens, BA, BS

James Callens, BA, BS

Associate Researcher I

james.callens@mssm.edu

Annie Ly

Annie Ly

Associate Researcher

annie.ly@mssm.edu

Diana Akpoyibo

Diana Akpoyibo

PhD Student

diana.akpoyibo@icahn.mssm.edu

Anissa Bara, PhD

Anissa Bara, PhD

Postdoctoral Fellow

anissa.bara@mssm.edu

Randy Ellis

Randy Ellis

PhD Student

Philip Kamilar-Britt, B.A.

Philip Kamilar-Britt, B.A.

Clinical Research Coordinator

philip.kamilar-britt@mssm.edu

Jacqueline-Marie Ferland, PhD

Jacqueline-Marie Ferland, PhD

Postdoctoral Fellow

jacqueline-marie.ferland@mssm.edu

Henrietta Szutorisz, PhD

Henrietta Szutorisz, PhD

Assistant Professor

henrietta.szutorisz@mssm.edu

Noel Warren, PhD

Noel Warren, PhD

Postdoctoral Fellow

noel.warren@mssm.edu

Teddy Uzamere

Teddy Uzamere

Associate Researcher

teddy.uzamere@mssm.edu

Gregory Rompala

Gregory Rompala

Postdoctoral Fellow

gregory.rompala@mssm.edu

Joseph Landry, BS, MS

Joseph Landry, BS, MS

Research Program Coordinator

joseph.a.landry@mssm.edu

Tanni Rahman

Tanni Rahman

PhD Student

Tanni.rahman@icahn.mssm.edu

Anna Oprescu, MPH

Anna Oprescu, MPH

Project Manager

anna.oprescu1@mssm.edu

Nayana Patel, BS

Nayana Patel, BS

Associate Researcher I

nayana.patel@mssm.edu

Funding & Awards

Molecular Neurobiology of Human Drug Abuse - R01DA015446

Opiate addiction is now a national epidemic marked by an increased incidence of abuse and overdose of heroin and elevated misuse of prescription opioids which also bears a high incidence of overdose death. Despite this growing opiate problem there remains a lack of knowledge about the molecular neuropathology of this human disorder. A fundamental core of our reverse translational research efforts has thus been to fill critical gaps of knowledge by direct investigation of the brains of human heroin abusers. Such efforts have identified the transcription factor ets-like kinase 1 (ELK1) as a central candidate in human heroin abusers. ELK1 disturbance was downstream of the mu opioid receptor (the pharmacological target of heroin metabolites and prescription opiates) and mitogen-activated protein kinase (MAPK) pathway and it was found by in silico analysis of microarray data to target the promoters of a large percentage of down-regulated genes in the nucleus accumbens (NAc) of heroin abusers. Surprisingly, very limited knowledge exist about ELK1 in relation to drug abuse, but this transcription factor has been implicated in other fields in cellular differentiation and synaptic plasticity that are highly relevant to the pathophysiology of addiction disorders. We hypothesize that heroin abuse leads to dysregulated ELK1-mediated transcriptional activity of target genes involved in the reorganization of striatal synapses and that modulate drug-seeking behaviors. We propose: (1) to determine ELK1-mediated transcriptional regulation in neurons within striatal and mesocorticolimbic brain regions of human heroin abusers by conducting ELK1 ChIP in combination with high throughput sequencing (ChIP-seq) on the nucleus accumbens, dorsal striatum and medial orbitofrontal cortex of heroin abusers. This data will also be integrated with transcriptome analysis to determine the relationship to gene expression. (2) To identify the epigenetic landscape across the ELK1 gene that contributes to its dysregulation in heroin abusers. (3) To investigate the causal role of ELK1 in structural plasticity and heroin seeking behavior by use of animal models. The multidisciplinary approach will expand significant insights about novel targets for treatment interventions and the dataset accrued by this body of work will be a unique and valuable resource to the field given the current lack of such human brain data.

Cannabidol as treatment intervention for opiate relapse

Opioid abuse is a significant global public health problem. Of the over million opiate-dependent subjects today, only less than a quarter of such individuals receive treatment. Using a strategy of indirectly regulating neural systems to modulate opioid-related behavior, our preclinical rodent studies demonstrated that cannabidiol (CBD), a nonpsychoactive component of cannabis, specifically inhibits cue-induced heroin-seeking behavior. The fact that drug craving is generally triggered by exposure to conditioned cues suggests that CBD might be an effective treatment for heroin craving, specially given its protracted impact on behavior. It is the goal of this project to (1) determine the safety and basic pharmacokinetic characteristics of cannabidol when administered concomitantly with opiate in humans and (2) characterize the acute and short-term effects of cannabidol administration on cue-induced craving in drug-abstinent heroin-dependent subjects using a random double blind design.

Molecular Neurobiology of Drug Addiction/Project 4 - P01DA008227

The objective of this project is to elucidate transcriptional and epigenetic mechanisms underlying glutamatergic dysregulation in mesocorticolimbic circuits in heroin abuse, a chronic relapsing disorder. Aberrant glutamatergic transmission in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) is central to drug-seeking behavior and addiction vulnerability. Our research focuses on studies of the human brain for which limited molecular insights are available. Preliminary data from microarray analysis already revealed distinct impairments of NAc glutamate-related gene expression in heroin abusers. The majority of these genes are upregulated, indicating that transcriptional change may be predominantly activation. Bioinformatic prediction of potential transcriptional regulators of these gene alterations identified DNA-binding factors SP1 and CREB1 as most likely regulators. SP1 and CREB1 are known to interact with various molecules involved in histone modification, such as histone acetyltransferases (e.g., Ncoa1, Ncoa3) that were also affected in the heroin population, which is mechanistically consistent with the observed predominance of upregulated glutamatergic genes. We will validate these findings using a comprehensive view of the genome by RNA-seq next-generation sequencing (Program Core) in the NAc of another subset of heroin abusers and control subjects, and will also examine the transcriptome in the mPFC, which provides glutamatergic innervation to the NAc. Specific glutamatergic disturbances will be assessed within discrete striatal output pathways using laser capture microdissection. To interrogate the molecular mechanisms by which glutamatergic aberrations are maintained, we will perform parallel studies in the rat heroin self-administration model in which viral-mediated gene manipulation strategies will be used to evaluate causal relationship of gene targets to heroin-seeking and intake. ChIP-Seq will be conducted (Program Core) to map genome-wide binding of a select number of target transcription factors, chromatin modifiers and histone marks in the NAc and mPFC. Overall, the novel research in this Project, which is fully integrative with the Core and other Projects of the PPG, will advance molecular knowledge about the pathophysiology of addiction disorders.

Neurodevelopmental Effects of Cannabis and its Epigenetic Regulation - R01DA030359

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 stratial 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.