Abused drugs produce long-lasting changes in behaviors via biochemical mechanisms that are largely unknown. Drug-altered changes in expression of specific genes in the brain can provide a major window on possible biochemical substrates for ddiction. During this year, we have enhanced characterization of candidate genes and the families of genes whose expression is regulated by amphetamine, cocaine and morphine, especially those i chromosomal regions that make them candidates to contain human individual variants that migh predisopase to human addiction vulnerabilities. We have strengthened identification of human haplotypes in the morphine-regulated gene, NrCAM, that is associated with human substance abuse vulnerability in human genome scanning studies from this laboratory. During this year, we have reported the GBPI gene as a KEPI family member that is powerful inhibitor of protein phosphatase 1 activity when phosphorylated and is expressed in gut and in brain. We have identified drug-regulation of another """"""""cell adhesion"""""""" molecule gene, PTPRbeta; PTPRbeta haplotypes are also associated with individual differences in human addiction vulnerability. These data provide powerful substrates for further convergence with studies of human drug abuse vulnerability genome scans and with studies of mechanisms of addiction neurobiology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000157-09
Application #
6987725
Study Section
(MNRB)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2004
Total Cost
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Ishiguro, Hiroki; Liu, Qing-Rong; Gong, Jian-Ping et al. (2006) NrCAM in addiction vulnerability: positional cloning, drug-regulation, haplotype-specific expression, and altered drug reward in knockout mice. Neuropsychopharmacology 31:572-84
Liu, Qing-Rong; Gong, Jian-Ping; Uhl, George R (2005) Families of protein phosphatase 1 modulators activated by protein kinases a and C: focus on brain. Prog Nucleic Acid Res Mol Biol 79:371-404
Gong, J-P; Liu, Q-R; Zhang, P-W et al. (2005) Mouse brain localization of the protein kinase C-enhanced phosphatase 1 inhibitor KEPI (kinase C-enhanced PP1 inhibitor). Neuroscience 132:713-27
Liu, Qing-Rong; Zhang, Ping-Wu; Lin, Zhicheng et al. (2004) GBPI, a novel gastrointestinal- and brain-specific PP1-inhibitory protein, is activated by PKC and inactivated by PKA. Biochem J 377:171-81
Sokolov, Boris P; Polesskaya, Oxana O; Uhl, George R (2003) Mouse brain gene expression changes after acute and chronic amphetamine. J Neurochem 84:244-52
Kitanaka, Nobue; Kitanaka, Junichi; Walther, Donna et al. (2003) Comparative inter-strain sequence analysis of the putative regulatory region of murine psychostimulant-regulated gene GNB1 (G protein beta 1 subunit gene). DNA Seq 14:257-63
Kitanaka, Junichi; Kitanaka, Nobue; Takemura, Motohiko et al. (2002) Isolation and sequencing of a putative promoter region of the murine G protein beta 1 subunit (GNB1) gene. DNA Seq 13:39-45
Liu, Qing-Rong; Zhang, Ping-Wu; Zhen, Qiaoxi et al. (2002) KEPI, a PKC-dependent protein phosphatase 1 inhibitor regulated by morphine. J Biol Chem 277:13312-20