Abstract

Compulsive cocaine (COC) abuse in humans is associated with an intermediate withdrawal phase (3-10 days after withdrawal), which may be related to a high rate of recidivism. Understanding neurobiological alterations characterizing this phase may be critical in formulating a rational treatment/prevention of repeated COC abuse. We hypothesize that withdrawal from chronic COC exposure is associated with time-dependent alterations in auto-inhibition of single dopamine (DA) neurons, effects analogous to those observed with amphetamine withdrawal. Establishing that these changes occur following continuous (vs. intermittent) COC will help in elucidating possible mechanisms underlying the COC recidivism. We will determine responses of nigrostriatal and mesoaccumbens DA neurons to apomorphine (mixed D1 and D2 agonist) and B-HT 920 (selective D2 agonist) during withdrawal from continuous or intermittent COC exposures. The single-unit data will be supplemented by determining the locomotor inhibition by low doses of agonists (a behavioral index of autoreceptor function), which should parallel the single-unit data. As the nigrostriatal and mesoaccumbens DA pathways differ in their acute and chronic responses to various DA agents, the projection area of each recorded neuron will be identified. In vivo, this task will be achieved by antidromic stimulation from the terminal regions. For in vitro recordings, a novel recording technique utilizing a priori labelling of DA cell bodies will be developed during the first year of this project. By injecting rhodamine-labelled fluorescent microspheres (a fluorescent retrograde tracer) into the terminal regions, DA neurons projecting to different terminal regions will be readily identified without a significant decrement in viability. Following its development, the in vitro technique will be used to examine chronic COC-induced changes. Data from these studies are expected to facilitate a rational approach to understanding and treating withdrawal from compulsive COC abuse in humans.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006519-03
Application #
3213151
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1990-05-01
Project End
1993-04-30
Budget Start
1992-05-12
Budget End
1993-04-30
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

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
Nah, Seong-Yeol; Bhatia, Kamal S; Lyles, Johnnie et al. (2009) Effects of ginseng saponin on acute cocaine-induced alterations in evoked dopamine release and uptake in rat brain nucleus accumbens. Brain Res 1248:184-90
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
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
Davidson, Colin; Lazarus, Cindy; Xiong, Xueying et al. (2002) 5-HT2 receptor antagonists given in the acute withdrawal from daily cocaine injections can reverse established sensitization. Eur J Pharmacol 453:255-63
Davidson, Colin; Lazarus, Cindy; Lee, Tong H et al. (2002) Behavioral sensitization is greater after repeated versus single chronic cocaine dosing regimens. Eur J Pharmacol 441:75-8
Ellinwood, Everett H; Davidson, Colin; Yu, Guo-Zhong et al. (2002) Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens. Eur Neuropsychopharmacol 12:407-15
Davidson, Colin; Lee, Tong H; Xiong, Zhiping et al. (2002) Ondansetron given in the acute withdrawal from a repeated cocaine sensitization dosing regimen reverses the expression of sensitization and inhibits self-administration. Neuropsychopharmacology 27:542-53
Davidson, C; Gow, A J; Lee, T H et al. (2001) Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Brain Res Rev 36:1-22

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