The literature on cocaine clearly suggests that several experimental factors have a profound influence on the subsequent behavioral effects of cocaine. For example, the continuous cocaine administration via osmotic minipump results in tolerance to the behavioral effects of cocaine. However, the dose and time dependency of these results, as well as the mechanistic bases of these effects, are not entirely understood. The present application proposes to systematically evaluate the factors that induce tolerance following continuous cocaine administration, as well as changes in DA autoreceptor function, and dopamine transporter (DAT) binding following different continuous cocaine administration regimens. Specifically, the present application will evaluate the dose-dependent nature of tolerance, as well as the time course of tolerance following continuous cocaine administration, as well as the corresponding changes in DA autoreceptor function. The present proposal will extend the data base regarding tolerance. The rats will be exposed to pretreatment regimen involving either the continuous infusion of saline or cocaine via osmotic minipump. The rats will then be withdrawn from this pretreatment regiment for 3, 7, 14 or 28 days, and assessed for behavioral, DA autoreceptor, and DAT and serotonin transporter (SET) binding changes. Specifically, the present application will examine, at three different levels of analysis: (1) the induction of tolerance, DA autoreceptor supersensitivity, and changes in DAT and SET binding, by the continuous administration 40 mg/kg cocaine via osmotic minipump for 5, 10, or 15 days. (2) the induction of tolerance, DA autoreceptor supersensitivity, and changes in DAT and SET binding, by the continuous administration of 0, 5, 10, 20 or 40 mg/kg cocaine, via osmotic minipump for 14 days. (3) the time course of DA autoreceptor supersensitivity (assessed behaviorally and voltammetrically), and changes in DAT and SET binding, following the continuous administration of 40 mg/kg cocaine, via osmotic minipump for 14 days. Over the last several years we have documented the residual effects of continuously administered, high dose cocaine. The present experiments are a logical extension of this research. Hence, the present experiments will further elucidate the parameters of cocaine tolerance, and the role of the DA autoreceptor in cocaine abuse and withdrawal, and may aid in the development of effective pharmacotherapies for the treatment of cocaine abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA010468-01A1
Application #
2013627
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Lin, Geraline
Project Start
1997-04-10
Project End
2002-02-28
Budget Start
1997-04-10
Budget End
1998-02-28
Support Year
1
Fiscal Year
1997
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
King, George R; Hillburn, Craig; Pinto, Gail et al. (2004) The effects of continuous cocaine dose, treatment, and withdrawal duration on the induction of behavioral tolerance and dopamine autoreceptor function. Pharmacol Biochem Behav 78:293-300
Matell, Matthew S; King, George R; Meck, Warren H (2004) Differential modulation of clock speed by the administration of intermittent versus continuous cocaine. Behav Neurosci 118:150-6
King, George R; Pinto, Gail; Konen, Jennifer et al. (2002) The effects of continuous 5-HT(3) receptor antagonist administration on the subsequent behavioral response to cocaine. Eur J Pharmacol 449:253-9
King, George R; Pinto, Gail; Konen, Jennifer et al. (2002) The effects of continuous cocaine duration on the induction of behavioral tolerance and dopamine autoreceptor function. Eur J Pharmacol 446:111-8
King, G R; Xiong, Z; Douglass, S et al. (2000) Long-term blockade of the expression of cocaine sensitization by ondansetron, a 5-HT(3) receptor antagonist. Eur J Pharmacol 394:97-101
King, G R; Xiong, Z; Ellinwood Jr, E H (1999) Withdrawal from continuous cocaine administration: time dependent changes in accumbens 5-HT3 receptor function and behavioral tolerance. Psychopharmacology (Berl) 142:352-9
King, G R; Xiong, Z; Ellinwood, E H (1999) Blockade of accumbens 5-HT3 receptor down-regulation by ondansetron administered during continuous cocaine administration. Eur J Pharmacol 364:79-87
King, G R; Xiong, Z; Douglas, S et al. (1999) The effects of continuous cocaine dose on the induction of behavioral tolerance and dopamine autoreceptor function. Eur J Pharmacol 376:207-15
King, G R; Xiong, Z; Ellinwood Jr, E H (1998) Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered during withdrawal from intermittent and continuous cocaine. Psychopharmacology (Berl) 135:263-9