This application requests renewal of a NIDA-sponsored MERIT Award as a R01. The overall goal is to under- stand why individuals differ in cocaine-induced activation and, specifically, i) how the dopamine (DA) trans- porter (DAT) contributes to this differential responsiveness and ii) how this individual variability is predictive of cocaine abuse liability. Adult outbred male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their differential open-field locomotor activity following a low dose cocaine injection. These initial differences in cocaine activation are explained, in part, by how effectively cocaine inhibits the DAT in dorsal striatum (dSTR) and nucleus accumbens (NAc). This classification also predicts repeated cocaine-induced behaviors associated with reward and reinforcement, in that LCRs, more than HCRs, exhibit locomotor sensitization, conditioned place preference and motivation to self- administer cocaine. Differential LCR/HCR DAT inhibition would be expected to result in differences in extra- cellular DA levels and DA receptor (R) stimulation.
Aim 1 will use i) in vivo microdialysis to define the overall relationship between endogenous extracellular DA in dSTR and NAc core and acute and repeated cocaine- induced locomotor activation in LCRs and HCRs and ii) new state-of-the-art in vivo electrochemical recording technology to assess real-time changes in cocaine-induced endogenous extracellular DA levels in dSTR and subregions of NAc (core and shell) in freely-behaving LCRs and HCRs.
Aim 2 will explore potential differences between LCRs and HCRs in cocaine-induced i) rapid DAT regulation (trafficking) in dSTR and NAc and ii) longer-term DAT and DA R regulation that could help to explain the behavioral differences. These experiments will measure open-field activity, cell surface DAT levels, [3H]DA uptake kinetics, and levels of the orphan G- protein-coupled receptor GPR37. Quantitative autoradiographic analysis of in vitro radioligand binding will be used to assess regulation of DATs, D1Rs, D2Rs and agonist-stimulated G-protein coupling.
Aim 3 will deter- mine how LCR/HCR classification predicts addiction-related effects of cocaine by measuring i) sensitization during acquisition of cocaine self-administration and cocaine pre-exposure, ii) sensitization to motivational effects of cocaine measured under a progressive ratio schedule of reinforcement, and iii) incentive sensiti- zation in the context of cue-elicited reinstatement of responding for cocaine and responding under a second- order schedule of reinforcement. Concurrent in vivo electrochemical recording will be used to address particular questions in the self-administration experiments. Together, the results will provide novel insights as to why initial insensitivity to cocaine locomotor activation is associated with the more "addiction prone" pheno- type, how both rapid and longer-term DAT adaptations and their consequences contribute to this individual variability, and how sensitization impacts cocaine self-administration. Understanding the biological bases for individual differences in cocaine abuse/addiction is of fundamental importance for treating this disease. Individuals vary markedly in their vulnerability to cocaine abuse and addiction. This project will use an animal model to explore how individual differences in normal brain chemistry can contribute to variability in cocaine-induced activation and addiction-like behaviors. Understanding the biological bases for individual differences in cocaine abuse/addiction is of fundamental importance for developing new ways to treat, and ultimately prevent, this devastating brain disease and public health problem.
Individuals vary markedly in their vulnerability to cocaine abuse and addiction. This project will use an animal model to explore how individual differences in normal brain chemistry can contribute to variability in cocaine-induced activation and addiction-like behaviors. Understanding the biological bases for individual differences in cocaine abuse/addiction is of fundamental importance for developing new ways to treat, and ultimately prevent, this devastating brain disease and public health problem.
|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, 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|
|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|
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