There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching three interrelated goals: 1) Identification of gene elements that confer cell-type specific expression and may thus allow targeting of introduced genetic material to appropriate brain regions; 2) Elucidation of gene elements yielding trans-synaptic gene regulation and thus allowing appropriate regulated expression of introduced genetic material; and 3) Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes. Dopaminergic systems involvement in central mechanisms of reward and reinforcement, and involvement of pre- and post-synaptic opioid peptide systems in the effects of opiate drugs has led to continuing focus on these systems during this year. Failure to reduce cocaine reward in DAT knockout mice, reported during last year, has also led to expansion of efforts to studies of SERT and NET knockout mice. Each of these assessments has provided novel data concerning the relationship between expression of each of these gene products at normal levels and drug-induced behavioral changes. In particular, studies of mice without combinations of DAT, VMAT2, SERT, NET or dopamine and serotonin receptor subtypes in providing striking evidence for mechanisms of cocaine and amphetamine reward and sleep/wake regulation. - knockout mice cocaine amphetamine morphine heroin

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000165-05
Application #
6289592
Study Section
Special Emphasis Panel (MNB)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Uhl, George R; Drgonova, Jana; Hall, F Scott (2014) Curious cases: Altered dose-response relationships in addiction genetics. Pharmacol Ther 141:335-46
Kitanaka, Nobue; Kitanaka, Junichi; Hall, F Scott et al. (2008) Alterations in the levels of heterotrimeric G protein subunits induced by psychostimulants, opiates, barbiturates, and ethanol: Implications for drug dependence, tolerance, and withdrawal. Synapse 62:689-99
Ide, Soichiro; Minami, Masabumi; Ishihara, Kumatoshi et al. (2008) Abolished thermal and mechanical antinociception but retained visceral chemical antinociception induced by butorphanol in micro-opioid receptor knockout mice. Neuropharmacology 54:1182-8
Perona, Maria T G; Waters, Shonna; Hall, Frank Scott et al. (2008) Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions. Behav Pharmacol 19:566-74
Onaivi, Emmanuel S; Ishiguro, Hiroki; Gong, Jian-Ping et al. (2008) Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS ONE 3:e1640
Uhl, George R; Drgon, Tomas; Johnson, Catherine et al. (2008) ""Higher order"" addiction molecular genetics: convergent data from genome-wide association in humans and mice. Biochem Pharmacol 75:98-111
Uhl, George (2007) Premature poking: impulsivity, cocaine and dopamine. Nat Med 13:413-4
Numachi, Yohtaro; Ohara, Arihisa; Yamashita, Motoyasu et al. (2007) Methamphetamine-induced hyperthermia and lethal toxicity: role of the dopamine and serotonin transporters. Eur J Pharmacol 572:120-8
Harburg, G C; Hall, F S; Harrist, A V et al. (2007) Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons. Neuroscience 144:77-87
Drgonova, Jana; Liu, Qing-Rong; Hall, F Scott et al. (2007) Deletion of v7-3 (SLC6A15) transporter allows assessment of its roles in synaptosomal proline uptake, leucine uptake and behaviors. Brain Res 1183:10-20

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