NIDA - Director's Report - May, 2011 NIDA Home > Publications > Director's Reports Director's Report to the National Advisory Council on Drug Abuse - May, 2011 Report Index Index Report for February, 2011 Research Findings Report for September, 2010 Basic Neurosciences Research Report for May, 2010 Basic Behavioral Research Report for February, 2010 Behavioral and Brain Development Research Older Reports - go to the Archives Clinical Neuroscience Research Epidemiology and Etiology Research Prevention Research Behavioral and Integrative Treatment Research NACDA Research on Pharmacotherapies for Drug Abuse Legislation Research on Medical Consequences of Drug Abuse and Co-Occurring Infections (HIV/AIDS, HCV) Services Research Clinical Trials Network Research International Research Intramural Research Program Activities Extramural Policy and Review Activities Congressional Affairs International Activities Meetings and Conferences Media and Education Activities Planned Meetings Publications Staff Highlights Grantee Honors https://archives.drugabuse.gov/DirReports/DirRep511/[11/18/16, 11:39:34 AM] NIDA - Director's Report - May, 2011 Archive Home | Accessibility | Privacy | FOIA (NIH) | Current NIDA Home Page The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , a component of the U.S. Department of Health and Human Services. Questions? _ See our Contact Information. https://archives.drugabuse.gov/DirReports/DirRep511/[11/18/16, 11:39:34 AM] NIDA - Director's Report - May, 2011 NIDA Home > Publications > Director's Reports > May, 2011 Index Director's Report to the National Advisory Council on Drug Abuse - May, 2011 Index Research Findings - Basic Neuroscience Research Research Findings Cocaine Dynamically Regulates Heterochromatin and Repetitive Basic Neurosciences Element Unsilencing In Nucleus Accumbens Research Basic Behavioral Research Repeated cocaine exposure induces persistent alterations in genome-wide transcriptional regulatory networks, chromatin remodeling activity and, Behavioral and Brain ultimately, gene expression profiles in the brain's reward circuitry. Virtually all Development Research previous investigations have centered on drug-mediated effects occurring Clinical Neuroscience throughout active euchromatic regions of the genome, with very little known Research concerning the impact of cocaine exposure on the regulation and maintenance Epidemiology and Etiology of heterochromatin in adult brain. Here, the authors report that cocaine Research dramatically and dynamically alters heterochromatic histone H3 lysine 9 trimethylation (H3K9me3) in the nucleus accumbens (NAc), a key brain reward Prevention Research region. Furthermore, they demonstrate that repeated cocaine exposure causes Behavioral and Integrative persistent decreases in heterochromatization in this brain region, suggesting a Treatment Research potential role for heterochromatic regulation in the long-term actions of Research on cocaine. To identify precise genomic loci affected by these alterations, Pharmacotherapies for Drug chromatin immunoprecipitation followed by massively parallel DNA sequencing Abuse (ChIP-Seq) was performed on NAc. ChIP-Seq analyses confirmed the existence Research on Medical of the H3K9me3 mark mainly within intergenic regions of the genome and Consequences of Drug identified specific patterns of cocaine-induced H3K9me3 regulation at repetitive Abuse and Co-Occurring genomic sequences. Cocaine-mediated decreases in H3K9me3 enrichment at Infections (HIV/AIDS, HCV) specific genomic repeats [e.g., long interspersed nuclear element (LINE)-1 repeats] were further confirmed by the increased expression of LINE-1 Services Research retrotransposon-associated repetitive elements in NAc. Such increases likely Clinical Trials Network reflect global patterns of genomic destabilization in this brain region after Research repeated cocaine administration and open the door for future investigations International Research into the epigenetic and genetic basis of drug addiction. Maze I, Feng J, Wilkinson MB, Sun H, Shen L, Nestler EJ. Cocaine dynamically regulates Intramural Research heterochromatin and repetitive element unsilencing in nucleus accumbens. Proc Program Activities Natl Acad Sci U S A. 2011 Feb 15; 108(7): 3035-3040. Extramural Policy and HDAC3 is a Critical Negative Regulator of Long-Term Memory Review Activities Formation Congressional Affairs Gene expression is dynamically regulated by chromatin modifications on histone tails, such as acetylation. In general, histone acetylation promotes International Activities transcription, whereas histone deacetylation negatively regulates transcription. The interplay between histone acetyltranserases and histone deacetylases Meetings and Conferences (HDACs) is pivotal for the regulation of gene expression required for long-term memory processes. Currently, very little is known about the role of individual Media and Education HDACs in learning and memory. The authors examined the role of HDAC3 in Activities long-term memory using a combined genetic and pharmacologic approach. They used HDAC3-FLOX genetically modified mice in combination with adeno- Planned Meetings https://archives.drugabuse.gov/DirReports/DirRep511/DirectorReport1.html[11/18/16, 11:39:41 AM] NIDA - Director's Report - May, 2011 associated virus-expressing Cre recombinase to generate focal homozygous deletions of Hdac3 in area CA1 of the dorsal hippocampus. To complement this Publications approach, we also used a selective inhibitor of HDAC3, RGFP136 [N-(6-(2- amino-4-fluorophenylamino)-6-oxohexyl)-4-methylbenzamide]. Staff Highlights Immunohistochemistry showed that focal deletion or intrahippocampal delivery of RGFP136 resulted in increased histone acetylation. Both the focal deletion of Grantee Honors HDAC3 as well as HDAC3 inhibition via RGFP136 significantly enhanced long- term memory in a persistent manner. Next they examined expression of genes implicated in long-term memory from dorsal hippocampal punches using quantitative reverse transcription-PCR. Expression of nuclear receptor subfamily 4 group A, member 2 (Nr4a2) and c-fos was significantly increased in the hippocampus of HDAC3-FLOX mice compared with wild-type controls. Memory enhancements observed in HDAC3-FLOX mice were abolished by intrahippocampal delivery of Nr4a2 small interfering RNA, suggesting a mechanism by which HDAC3 negatively regulates memory formation. Together, these findings demonstrate a critical role for HDAC3 in the molecular mechanisms underlying long-term memory formation. McQuown SC, Barrett RM, Matheos DP, Post RJ, Rogge GA, Alenghat T, Mullican SE, Jones S, Rusche JR, Lazar MA, Wood MA. HDAC3 is a critical negative regulator of long-term memory formation. J Neurosci. 2011 Jan 12; 31(2): 764-774. Adolescent Opioid Exposure In Female Rats: Transgenerational Effects On Morphine Analgesia and Anxiety-Like Behavior In Adult Offspring The use of narcotics by adolescent females is a growing problem, yet very little is known about the long-term consequences for either the user or her future offspring. In the current study, the authors utilized an animal model to examine the transgenerational consequences of opiate exposure occurring during this sensitive period. Female rats were exposed to increasing doses of morphine or its saline vehicle twice daily during adolescent development (postnatal days 30-40), after which they remained drug free. At 60 days of age, all females were mated and their adult offspring were tested for anxiety- like behavior and sensitivity to morphine. Specifically, offspring of adolescent morphine (MOR-F1)- or saline (SAL-F1)-exposed mothers were tested for acute locomotor responses in an open field, followed by testing of acute or chronic morphine analgesia on the hot plate. Open field testing indicated alterations in anxiety-like behavior in MOR-F1 female offspring, with effects dependent upon the stage of the estrus cycle. Hot plate testing revealed sex differences in baseline pain threshold and morphine sensitivity in all offspring, regardless of maternal exposure. However, when compared to their SAL-F1 counterparts, MOR-F1 male offspring demonstrated significantly increased sensitivity to the analgesic effects of acute morphine, and developed analgesic tolerance more rapidly following chronic morphine treatment. The findings indicate that prior opiate exposure during early adolescence in females produces sex-specific alterations of both emotionality and morphine sensitivity in their progeny. Byrnes JJ, Babb JA, Scanlan VF, Byrnes EM. Adolescent opioid exposure in female rats: transgenerational effects on morphine analgesia and anxiety-like behavior in adult offspring. Behav Brain Res. 2011 Mar 17; 218(1): 200-205. Structure of the Human Dopamine D3 Receptor In Complex With A D2/D3 Selective Antagonist Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R- https://archives.drugabuse.gov/DirReports/DirRep511/DirectorReport1.html[11/18/16, 11:39:41 AM] NIDA - Director's Report - May, 2011 selective antagonist,