? The transition from drug abuse to the addicted state is characterized by the escalation of drug intake during self-administration, and markedly increased craving in withdrawal. Both drug-taking and drug-seeking behaviors are differentially regulated by D1 and D2 dopamine receptors in the nucleus accumbens (NAc). Drug-induced up-regulation of cAMP/PKA signaling may contribute to escalation and relapse, possibly by differentially altering dopamine receptor-responsiveness in the NAc. To investigate this hypothesis, studies will measure changes in NAc cAMP-dependent protein phosphorylation in vivo produced by chronic cocaine, heroin, and ethanol self-administration. Additionally, studies will measure alterations in sensitivity to D1 and D2 receptor-regulation of cAMP-dependent protein phosphorylation after chronic cocaine self-administration. Changes in cAMP-dependent protein phosphorylation in both core and shell subregions of NAc will be compared to individual propensities for escalating cocaine self-administration and relapse to cocaine seeking in withdrawal. In vivo phosphoprotein measures will include pGluR1 and pNR1 subunits of AMPA and NMDA receptors, pDARPP-32, pCREB, and pD1 receptor using a novel site-specific antibody. These studies are aimed at understanding molecular mechanisms that underlie drug and alcohol addiction, and may identify targets for therapeutic intervention. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DA016472-02
Application #
6798831
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Babecki, Beth
Project Start
2003-10-01
Project End
2006-09-30
Budget Start
2004-10-01
Budget End
2005-09-30
Support Year
2
Fiscal Year
2004
Total Cost
$29,402
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
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Edwards, Scott; Graham, Danielle L; Whisler, Kimberly N et al. (2009) Phosphorylation of GluR1, ERK, and CREB during spontaneous withdrawal from chronic heroin self-administration. Synapse 63:224-35
Gabra, Bichoy H; Smith, Forrest L; Navarro, Hernan A et al. (2008) mGluR5 antagonists that block calcium mobilization in vitro also reverse (S)-3,5-DHPG-induced hyperalgesia and morphine antinociceptive tolerance in vivo. Brain Res 1187:58-66
Edwards, Scott; Whisler, Kimberly N; Fuller, Dwain C et al. (2007) Addiction-related alterations in D1 and D2 dopamine receptor behavioral responses following chronic cocaine self-administration. Neuropsychopharmacology 32:354-66
Carroll, F Ivy; Kotturi, Sharadsrikar V; Navarro, Hernan A et al. (2007) Synthesis and pharmacological evaluation of phenylethynyl[1,2,4]methyltriazines as analogues of 3-methyl-6-(phenylethynyl)pyridine. J Med Chem 50:3388-91
Edwards, Scott; Graham, Danielle L; Bachtell, Ryan K et al. (2007) Region-specific tolerance to cocaine-regulated cAMP-dependent protein phosphorylation following chronic self-administration. Eur J Neurosci 25:2201-13