Repeated intermittent administration of cocaine results in behavioral sensitization. The overall goal of this project is to identify neurochemical alterations responsible for this persistent phenomenon. The experiments proposed in this application will test the hypotheses that persistent changes in dopamine (DA) and serotonin (5-HT) transporter function in specific brain regions, as well as persistent changes in cocaine disposition in the brain, contribute to the expression of cocaine- induced behavioral sensitization. The initial set of experiments will examine the role played by increased brain concentrations of cocaine in behavioral sensitization. Higher drug levels are achieved in the brain following repeated, as compared to acute, intraperitoneal (i.p.) administration of cocaine. This is not expected to be the case with intravenous (i.v.) administration. Brain cocaine levels will be measured following acute and repeated i.v. cocaine. Also, it will be investigated whether repeated i.v. cocaine administration produces changes similar to repeated i.p. administration in terms of behavior, DA clearance and DA transporter binding. During the past funding period, in vivo electrochemical (EC) recording has been used to characterize the disappearance of exogenous (locally-applied) DA in dorsal striatum and nucleus accumbens (NAc) of urethane-anesthetized rats. This measure of clearance reflects neuronal DA transporter function. In the second set of experiments, these studies will be extended to examine the clearance of endogenous DA, released in response to electrical stimulation, in the anesthetized rat.
The aim will be to compare endogenous and exogenous DA clearance rates. The third set of experiments will examine cocaine-induced changes in clearance of stimulation-evoked endogenous DA in dorsal striatum and NAc of unanesthetized, freely behaving rats. Concurrent in vivo EC and behavioral measurements will test the hypothesis that hypersensitivity of the DA transporter, particularly in NAc, is directly related to cocaine- induced behavioral sensitization. The effects of repeated, intermittent injections, which should result in behavioral sensitization, and continuous infusion, which should result in behavioral tolerance, will be compared. The final set of experiments will examine the possible role of 5-HT in cocaine sensitization. Increases in both extracellular 5-HT levels in NAc and 5-HT transporter binding sites in medial prefrontal cortex (MPFC) have been reported in cocaine-sensitized rats. Behavioral experiments will determine whether selective lesioning of 5-HT neurons with 5,7- dihydroxytryptamine alters expression of sensitization. Exogenous 5-HT clearance rate will be characterized using in vivo EC recording in NAc and MPEC of anesthetized rats. Subsequently, it will be determined whether 5- HT clearance in these two brain regions is differentially and persistently altered following repeated cocaine administration. Elucidation of the mechanism(s) underlying behavioral sensitization in animals may enhance our ability to predict and understand the long-term consequences of cocaine abuse, including drug-induced psychosis, in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA004216-06A1
Application #
2117081
Study Section
Special Emphasis Panel (SRCD (03))
Project Start
1987-04-01
Project End
1999-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Rorabaugh, J M; Stratford, J M; Zahniser, N R (2015) Differences in bingeing behavior and cocaine reward following intermittent access to sucrose, glucose or fructose solutions. Neuroscience 301:213-20
Mandt, Bruce H; Copenhagen, Leland I; Zahniser, Nancy R et al. (2015) Escalation of cocaine consumption in short and long access self-administration procedures. Drug Alcohol Depend 149:166-72
Rorabaugh, Jacki M; Stratford, Jennifer M; Zahniser, Nancy R (2014) A relationship between reduced nucleus accumbens shell and enhanced lateral hypothalamic orexin neuronal activation in long-term fructose bingeing behavior. PLoS One 9:e95019
Rao, Anjali; Sorkin, Alexander; Zahniser, Nancy R (2013) Mice expressing markedly reduced striatal dopamine transporters exhibit increased locomotor activity, dopamine uptake turnover rate, and cocaine responsiveness. Synapse 67:668-77
Yamamoto, Dorothy J; Nelson, Anna M; Mandt, Bruce H et al. (2013) Rats classified as low or high cocaine locomotor responders: a unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors. Neurosci Biobehav Rev 37:1738-53
Simmons, Diana L; Mandt, Bruce H; Ng, Christopher M C et al. (2013) Low- and high-cocaine locomotor responding rats differ in reinstatement of cocaine seeking and striatal mGluR5 protein expression. Neuropharmacology 75:347-55
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
Mandt, Bruce H; Johnston, Nickie L; Zahniser, Nancy R et al. (2012) Acquisition of cocaine self-administration in male Sprague-Dawley rats: effects of cocaine dose but not initial locomotor response to cocaine. Psychopharmacology (Berl) 219:1089-97
Mandt, Bruce H; Gomez, Emily; Johnston, Nickie L et al. (2012) Cocaine dose and self-administration history, but not initial cocaine locomotor responsiveness, affects sensitization to the motivational effects of cocaine in rats. J Pharmacol Exp Ther 342:214-21

Showing the most recent 10 out of 51 publications