NIDA - Director's Report - September, 2008 NIDA Home > Publications > Director's Reports Director's Report to the National Advisory Council on Drug Abuse - September, 2008 Index Research Findings Cross-Divisional Research Basic Neurosciences Research Basic Behavioral Research Behavioral and Brain Development Research Clinical Neuroscience Research Epidemiology and Etiology Research Prevention Research Research on Behavioral and Combined Treatments for Drug Abuse Research on Pharmacotherapies for Drug Abuse 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/DirRep908/Default.html[11/17/16, 11:11:47 PM] NIDA - Director's Report - September, 2008 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/DirRep908/Default.html[11/17/16, 11:11:47 PM] NIDA - Director's Report - September, 2008 NIDA Home > Publications > Director's Reports > September, 2008 Index Director's Report to the National Advisory Council on Drug Abuse - September, 2008 Index Research Findings - Cross-Divisional Research Research Findings A NIDA DBNBR and DESPR Cross-Divisional Supported Study Cross-Divisional Research Highlights the CHRNA5-A3-B4 Region is a Risk Factor for Age- Basic Neurosciences Dependent Nicotine Addiction Research The research examined the hypothesis that associations between nicotinic Basic Behavioral Research acetylcholine receptor subunit gene variants and nicotine dependence assessed Behavioral and Brain in adulthood would be stronger among smokers who began daily nicotine Development Research exposure during adolescence. This group examined 2,827 subjects from three Clinical Neuroscience European American cohorts with a mean age of 49.6 years. All were either Research current or previous daily cigarette smokers, with only 8% who had not smoked Epidemiology and Etiology for at least 2 years prior to the study. Participants began daily smoking at a Research mean age of 17.3 and smoked 28.3 cigarettes per day for a mean of 30.7 years. The mean Fagerstrom Test of Nicotine Dependence test score was 5.7. Prevention Research Smokers were dichotomized into Òearly onsetÓ (age 16 or younger) and Òlate Research on Behavioral and onsetÓ (age 17 or older). Using a candidate gene approach, the SNP panel Combined Treatments for screen included common coding variants and haplotypes detected in eight Drug Abuse alpha and three beta nicotinic subunit receptor genes. Of the 2,827 long-term Research on smokers examined, common susceptibility and protective haplotypes at the Pharmacotherapies for Drug chromosome 15 CHRNA5-A3-B4 locus were associated with nicotine Abuse dependence severity (OR=1.82; 95%CI 1.39-2.39, p=2 x 10-5) in subjects who began daily smoking at or before the age of 16. This effect was not seen in Research on Medical subjects who began daily smoking after the age of 16, marking a period of Consequences of Drug exposure vulnerability that results in a more severe form of adult nicotine Abuse and Co-Occurring dependence. The interaction of a common genetic risk factor, age, and onset of Infections (HIV/AIDS, HCV) daily smoking supports the notion that it is important to understand gene x Services Research environment x development factors. This finding needs independent replication, Clinical Trials Network but it points to how genetic studies of complex disease phenotypes can bolster Research public health approaches to disorders such as addictions, because the risk is amenable to both intervention and prevention. Weiss, R.B., Baker, T.B., International Research Cannon, D.S., von Niederhausern, A., Dunn, D.M., Matsunami, N., Singh, N.A., Intramural Research Baird, L., Coon, H., McMahon, W.M., Piper, M.E., Fiore, M.C., Scholand, M.B., Program Activities Connett, J.E., Kanner, R.E., Gahring, L.C., Rogers, S.W., Hoidal, J.R., and Leppert, M.F. A Candidate Gene Approach Identifies the CHRNA5-A3-B4 Region Extramural Policy and as a Risk Factor for Age-Dependent Nicotine Addiction. PLOS Genetics, 4(7), Review Activities pp. 1-11, 2008. Congressional Affairs International Activities Meetings and Conferences https://archives.drugabuse.gov/DirReports/DirRep908/DirectorReportA.html[11/17/16, 11:11:50 PM] NIDA - Director's Report - September, 2008 Media and Education Activities Planned Meetings Publications Staff Highlights Grantee Honors 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/DirRep908/DirectorReportA.html[11/17/16, 11:11:50 PM] NIDA - Director's Report - September, 2008 NIDA Home > Publications > Director's Reports > September, 2008 Index Director's Report to the National Advisory Council on Drug Abuse - September, 2008 Index Research Findings - Basic Neuroscience Research Research Findings Voluntary Oral Cross-Divisional Research Basic Neurosciences Nicotine Intake in Mice Down-Regulates Glur2 But Not Depression-Like Research Behaviors Dr. Marina Picciotto and her colleagues at Yale University have continued their studies on the adaptive changes in brain and behavior that Basic Behavioral Research accompany repeated exposure to nicotine. Some of these adaptive changes are Behavioral and Brain thought to be mediated by glutamate receptors (GluR) and cAMP response Development Research element-binding protein (CREB) in the nucleus accumbens. Dr. Picciotto studied Clinical Neuroscience the effects of nicotine exposure via the drinking water on nicotine preference, Research locomotor activity, and anxiety and depression-like behaviors in inbred mice. She and her colleagues reported few behavioral changes following extended Epidemiology and Etiology nicotine exposure, but clear down-regulation of GluR2 in the mesolimbic Research system. When given a choice between nicotine and control solutions, mice Prevention Research showed a significant preference for nicotine. Dr. Picciotto interpreted these Research on Behavioral and findings to indicate that voluntary nicotine drinking induces nicotine preference Combined Treatments for in mice with accompanying down regulation of GluR, but that differences are Drug Abuse not sufficient to explain preference for nicotine. Vieryra-Reyes, P. Picciotto, M., and Mineur, Y. Voluntary Oral Nicotine Intake in Mice Down-regulates GluR2 Research on but Does Not Modulate Depression-like Behaviors. Neuroscience Letters, 434, Pharmacotherapies for Drug pp. 18-22, 2008. Abuse Research on Medical Improved Synthesis of the ORL Antagonist, 1-[(3R, 4R)-1- Consequences of Drug Cyclooctylmethyl-3-ethoxycarbonyl-4-piperidinyl]-3-ethyl-1,3- Abuse and Co-Occurring dihydro-2H-benzimidazol-2-one (J-113397) Infections (HIV/AIDS, HCV) Services Research Four subtypes of opioid receptors have been identified based upon structural Clinical Trials Network homology. These include the classical mu, delta, and kappa receptors (MOP, Research DOP, and KOP, respectively) and the more recently identified opioid-receptor- International Research like-1 (ORL-1), which is termed NOP. The endogenous ligand for NOP is a heptapeptide named as nociceptin by one group of investigators and orphanin Intramural Research FQ (N/OFQ) by another group. Several studies have shown that NOP may be Program Activities involved in pain regulation, drug dependence, anxiety and stress, depression, learning and memory, motor activity, epilepsy/seizures, cardiovascular effects, Extramural Policy and urinary incontinence, cough and immunoregulation. A number of ORL-1 (NOP) Review Activities receptor agonists and antagonists have been synthesized and used to characterize the pharmacological effects of the NOP system. The first and most Congressional Affairs studied small molecule antagonist is 1-[(3R, 4R)-1-Cyclooctylmethyl-3- ethoxycarbonyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J- International 113397). The synthesis of this molecule has been reported previously. In two Activities reports the optical resolution of the racemate of J-113397 was achieved by chromatography with a chiral column, and in another report a new synthesis of Meetings and (+)- and (-)- J-113397 was reported. In the present study the authors have Conferences avoided the expense of large scale chiral column and provided an alternate https://archives.drugabuse.gov/DirReports/DirRep908/DirectorReport1.html[11/17/16, 11:11:53 PM] NIDA - Director's Report - September, 2008 practical synthesis of (+/-)-J113397 by separating the racemic compound into Media and Education individual (+) - and (-)-isomers using a chiral auxiliary. Carroll, F.I. and Activities Brieaddy, L.E. Improved Synthesis of the ORL Antagonist 1-[(3R,4R)-1- Cyclooctylmethyl-3-ethoxycarbonyl-4-piperidinyl]-3-ethyl-1,3-dihydro-2H- Planned Meetings benzimidazol-2-one (J-113397). Synthetic