Several literature reviews have examined tolerance and sensitization in the extended cocaine abuse withdrawal syndrome, and its relevance for recidivism. However, the potential for manipulating mechanisms underlying tolerance and sensitization for therapeutic purposes remains unclear. Our goal in this project is to examine the mechanisms underlying chronic cocaine tolerance at one week after withdrawal. Our focus is on an examination of the robust presynaptic dopamine autoreceptor mechanisms, along with parallel assessment of changes in dopamine reuptake parameters. Rats made tolerant by continuous cocaine administration will be compared with two control groups: 1) a positive drug control group made supersensitive to the behavioral effects of cocaine by daily intermittent injections of the same daily dose, and 2) saline controls. Our previous studies have established that tolerance extends out to at least seven days of withdrawal and is accompanied by dopamine autoreceptor supersensitivity as measured by several different methods ranging from behavioral, to in vitro HPLC and voltammetric, to antisense ODN probes. We are now proposing a set of experiments that further, and more extensively, characterize dopamine autoreceptor function during withdrawal from continuous or intermittent cocaine administration, using these same methods: 1) Behavior to examine the functional consequences of autoreceptor supersensitivity, 2) Voltammetry, with its ultra-fast temporal and spatial resolution allows for the assessment of both DA release and reuptake parameters in specific, localized brain areas, and 3) Antisense ODN's to reduce messenger RNA transcription of DA D2 receptors, to further assess the ODN effects on autoreceptor control of dopamine synthesis, neuronal firing rates, and dopamine mediated behaviors.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010327-03
Application #
2837877
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Pilotte, Nancy S
Project Start
1997-02-01
Project End
2001-11-30
Budget Start
1999-01-15
Budget End
1999-11-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Duke University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Szabo, Steven T; Fowler, J C; Froeliger, Brett et al. (2014) Time-dependent changes in nicotine behavioral responsivity during early withdrawal from chronic cocaine administration and attenuation of cocaine sensitization by mecamylamine. Behav Brain Res 262:42-6
Lee, Tong H; Szabo, Steven T; Fowler, J Corey et al. (2012) Pharmacologically-mediated reactivation and reconsolidation blockade of the psychostimulant-abuse circuit: a novel treatment strategy. Drug Alcohol Depend 124:11-8
Zhang, Xiuwu; Lee, Tong H; Davidson, Colin et al. (2007) Reversal of cocaine-induced behavioral sensitization and associated phosphorylation of the NR2B and GluR1 subunits of the NMDA and AMPA receptors. Neuropsychopharmacology 32:377-87
Davidson, Colin; Chen, Qiang; Zhang, Xiuwn et al. (2007) Deprenyl treatment attenuates long-term pre- and post-synaptic changes evoked by chronic methamphetamine. Eur J Pharmacol 573:100-10
Chen, Qiang; Lee, Tong H; Wetsel, William C et al. (2007) Reversal of cocaine sensitization-induced behavioral sensitization normalizes GAD67 and GABAA receptor alpha2 subunit expression, and PKC zeta activity. Biochem Biophys Res Commun 356:733-8
Zhang, Xiuwu; Mi, Jing; Wetsel, William C et al. (2006) PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity. Biochem Biophys Res Commun 340:1144-50
Zhang, Xiuwu; Lee, Tong H; Xiong, Xueying et al. (2006) Methamphetamine induces long-term changes in GABAA receptor alpha2 subunit and GAD67 expression. Biochem Biophys Res Commun 351:300-5
Davidson, Colin; Lee, Tong H; Ellinwood, Everett H (2004) The NK(1) receptor antagonist WIN51708 reduces sensitization after chronic cocaine. Eur J Pharmacol 499:355-6
Davidson, Colin; Lazarus, Cindy; Lee, Tong H et al. (2004) Ondansetron, given during the acute cocaine withdrawal, attenuates oral cocaine self-administration. Eur J Pharmacol 503:99-102
Lee, T H; Gee, K R; Davidson, C et al. (2002) Direct, real-time assessment of dopamine release autoinhibition in the rat caudate-putamen. Neuroscience 112:647-54

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