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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (SRCD (03))
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University of Colorado Denver
Schools of Medicine
United States
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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
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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
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