The goal of this proposal is to establish a genetic profile of neuronal excitability as it relates to psychostimulant addiction. To accomplish this aim we will be using the most advanced oligonucleotide high density microarray technology combined with patch-clamp electrophysiology. Affymetrix Gene Chips allow for genome wide scans of the entire mouse genome for genes susceptible to chronic psychostimulant administration. In order to understand neural information procession in the brain reward circuitry as it relates to addiction, it is necessary to understand how individual neurons within this system code reward-related information. This project uses both DNA microarrays and patch-clamp electrophysiology to establish a molecular and functional characterization of nucleus accumbens, prefrontal cortical pyramidal neurons and ventral subicular hippocampal pyramidal neurons after repeated psychomotor stimulant injections in rats and mice.
Specific aim 1 is to look for voltage and ligand-gated ion-channel genes that are subject to modulation by psychostimulants in the accumbens, subiculum and prefrontal cortical neurons.
Specific aim 2 is to determine the functional manifestations of those changes within each structure.
Specific aim 3 involves individual neuron gene expression profiling of electrophysiologically classified neurons (e.g. Interneurons and pyramidal bursting and nonbursting). Together these experiments will help us understand how drugs of abuse induce long-lasting neuroadaptations within the brain reward circuitry. With greater understanding of addiction-associated plasticity it may be possible to develop pharmacological or gene profiling strategies to screen for addiction vulnerability and possible therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DA017750-03
Application #
7229041
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Koustova, Elena
Project Start
2005-05-15
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$163,994
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Dobelis, Peter; Staley, Kevin J; Cooper, Donald C (2012) Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons. PLoS One 7:e41108
Varela, Juan A; Wang, Jungang; Christianson, John P et al. (2012) Control over stress, but not stress per se increases prefrontal cortical pyramidal neuron excitability. J Neurosci 32:12848-53
Coque, Laurent; Mukherjee, Shibani; Cao, Jun-Li et al. (2011) Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the Clock?19 mouse model of mania. Neuropsychopharmacology 36:1478-88
Cao, Jun-Li; Vialou, Vincent F; Lobo, Mary Kay et al. (2010) Essential role of the cAMP-cAMP response-element binding protein pathway in opiate-induced homeostatic adaptations of locus coeruleus neurons. Proc Natl Acad Sci U S A 107:17011-6
Mukherjee, Shibani; Coque, Laurent; Cao, Jun-Li et al. (2010) Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. Biol Psychiatry 68:503-11
Ables, Jessica L; Decarolis, Nathan A; Johnson, Madeleine A et al. (2010) Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells. J Neurosci 30:10484-92
Cao, Jun-Li; Covington 3rd, Herbert E; Friedman, Allyson K et al. (2010) Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J Neurosci 30:16453-8
Cadle, Brian A; Rasmus, Kristin C; Varela, Juan A et al. (2010) Cellular phone-based image acquisition and quantitative ratiometric method for detecting cocaine and benzoylecgonine for biological and forensic applications. Subst Abuse 4:21-33
Park, Jin-Yong; Remy, Stefan; Varela, Juan et al. (2010) A post-burst after depolarization is mediated by group i metabotropic glutamate receptor-dependent upregulation of Ca(v)2.3 R-type calcium channels in CA1 pyramidal neurons. PLoS Biol 8:e1000534
Sidiropoulou, Kyriaki; Lu, Fang-Min; Fowler, Melissa A et al. (2009) Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity. Nat Neurosci 12:190-9

Showing the most recent 10 out of 15 publications