EXCEED THE SPACE PROVIDED. In order to understand cocaine craving/relapse in humans it is critical to identify 'plastic' changes that occur in the CNS following repetitive drug administration. Repeated, intermittent treatment of rats with cocaine results in enhanced motor responsiveness, or 'behavioral sensitization'. Sensitization is persistent and is an important form of long-lasting neuronal plasticity. The sensitivity and/or expression of the dopamine trans- porter (DAT) is persistently altered, particularly in the nucleus accumbens (NAc), after repeated exposure to cocaine, suggesting that DAT regulation in this brain region may be key to the enduring expression of sensi- tization. This competing renewal application focuses on this idea. To prove that changes in DAT are required, behavior and DAT activity must be measured concurrently. DAT activity can be altered via post-translational, as well as translational, mechanisms. Therefore, it is critical to also understand post-translational modifications by which cocaine could regulate DAT activity and expression. The proposed work will test the hypotheses that: (1) persistent changes in DAT sensitivity to cocaine in NAc contribute to the expression of behav- ioral sensitization and (2) protein kinase C (PKC) and Ca +/calmodulin-dependent protein kinase II (CaM kinase II) mediate cocaine-induced changes in DAT activity and/or expression.
Aim #1 will ad- dress the relationship between the persistent expression of behavioral sensitization and cocaine-induced changes in DAT activity using concurrent measures of locomotor activity and DA clearance, measured with in vivo electrochemical recording in NAc and caudate-putamen (CPu) of freely-moving rats. DAT expression will be determined using quantitative autoradiographic analysis of [ H]WIN 35,428 binding. Treatment regi- mens using repeated intermittent i.p. and i.v. injections, as well as continuous infusion, of cocaine will be compared.
Aim #2 will use in vitro brain slices containing NAc and CPu to address whether the persistent cocaine-induced changes hi DA clearance are unique to NAc, DAT and psychostimulants.
Aim #3 will focus on PKC and CaM kinase II as molecular mechanisms that regulate the activity and/or expression of human (h) DAT expressed in Xenopus oocytes. Measures of hDAT-mediated transport and reverse transport, as well as cocaine sensitivity, will be compared. By combining information about DAT at the systems level (behavioral measurements), cellular level (DA clearance studies), and molecular level (studies in expression systems), the relationship between cocaine behavioral sensitization and the transporter should be elucidated. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA004216-17
Application #
6878942
Study Section
Special Emphasis Panel (NSS)
Program Officer
Pilotte, Nancy S
Project Start
1987-04-01
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
17
Fiscal Year
2005
Total Cost
$274,077
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Yamamoto, Dorothy J; Zahniser, Nancy R (2012) Differences in rat dorsal striatal NMDA and AMPA receptors following acute and repeated cocaine-induced locomotor activation. PLoS One 7:e37673
Liu, Xinjian; Li, Fang; Stubblefield, Elizabeth A et al. (2012) Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. Cell Res 22:321-32
Nelson, Anna M; Kleschen, Melissa J; Zahniser, Nancy R (2010) Individual differences in cocaine-induced locomotor activity of male Sprague-Dawley rats are not explained by plasma corticosterone levels. Neurosci Lett 476:9-13
Mandt, Bruce H; Zahniser, Nancy R (2010) Low and high cocaine locomotor responding male Sprague-Dawley rats differ in rapid cocaine-induced regulation of striatal dopamine transporter function. Neuropharmacology 58:605-12
Zahniser, Nancy R; Sorkin, Alexander (2009) Trafficking of dopamine transporters in psychostimulant actions. Semin Cell Dev Biol 20:411-7
Richards, Toni L; Zahniser, Nancy R (2009) Rapid substrate-induced down-regulation in function and surface localization of dopamine transporters: rat dorsal striatum versus nucleus accumbens. J Neurochem 108:1575-84
Nelson, Anna M; Larson, Gaynor A; Zahniser, Nancy R (2009) Low or high cocaine responding rats differ in striatal extracellular dopamine levels and dopamine transporter number. J Pharmacol Exp Ther 331:985-97
Goodwin, J Shawn; Larson, Gaynor A; Swant, Jarod et al. (2009) Amphetamine and methamphetamine differentially affect dopamine transporters in vitro and in vivo. J Biol Chem 284:2978-89
Price, David A; Sorkin, Alexander; Zahniser, Nancy R (2009) Cyclin-dependent kinase 5 inhibitors: inhibition of dopamine transporter activity. Mol Pharmacol 76:812-23

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