Cocaine addiction is characterized by excessive demand for drug and high propensity to relapse to drug seeking after quitting. Although many people experiment with drugs, individuals differ substantially in the degree to which addiction-related behaviors occur after drug exposure. Extensive research over the last 10 years has shown that the hypothalamic orexin neuropeptide system contributes importantly to reward processing, including cocaine demand and seeking. However, the role of orexins in either individual differences in cocaine demand and seeking ('trait'factors associated with increased risk of cocaine abuse), or in the excessive demand and seeking that occurs after extensive drug exposure ('state'factors associated with cocaine addiction), is unknown. Here, we will use a novel behavioral economics approach, combined with antisense knockdown, optogenetics, pharmacology and Fos staining, to measure the role of orexin signaling as a 'trait'factor that contributes to individual differences in cocaine demand and seeking. We will use similar methods in a model of cocaine addiction (long-access cocaine self-administration) to determine the role of orexin in 'state'factors that lead to addiction. In addition, we will examine trait-stte interactions, and determine what role orexin plays in the propensity for some individuals to readily transition to excessive drug seeking after extensive cocaine self-administration. Our preliminary studies indicate that high cocaine demand is a reliable predictor of high propensity to relapse to cocaine seeking;we will determine the role of orexin in this relationship. We will also determine which subpopulations of orexin neurons mediate cocaine demand and relapse in non-addicted subjects, as well as in the long access model of cocaine addiction. These studies will delineate the role of orexins in motivational differences that occur naturally within a population, and that may put certain individuals at risk for drug abuse. They will also provide the first test of orexin's role in the excessive demand and drug seeking in addiction, produced by prolonged experience with cocaine. We predict that spontaneous individual variability in cocaine demand and seeking involves the level of engagement of specific orexin neuronal subpopulations, and that the excessive demand and inflexible seeking characteristic of addiction corresponds to excessive orexin signaling. We also will examine the possibility that this excessive signaling in addiction may involve interactions between subpopulations of reward-related and stress-related orexin neurons. This research also has translational potential for individualized treatment: Addicts that exhibit high demand for cocaine may particularly benefit from treatments to attenuate signaling in an overly active orexin system.

Public Health Relevance

Cocaine addiction is a chronic condition that remains clinically difficult to treat. The proposed studies will reveal the role of a key brain neuropeptid system in individual differences in propensity for cocaine abuse, and in the excessive demand and relapse propensity that characterizes cocaine addiction. These findings will increase our knowledge of brain mechanisms involved in addiction, and include a test to identify addicts that may particularly benefit from orexin-based therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA006214-25S1
Application #
8740581
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
1992-08-01
Project End
2019-02-28
Budget Start
2014-04-01
Budget End
2015-02-28
Support Year
25
Fiscal Year
2014
Total Cost
$137,042
Indirect Cost
$45,375
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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McGlinchey, Ellen M; Aston-Jones, Gary (2018) Dorsal Hippocampus Drives Context-Induced Cocaine Seeking via Inputs to Lateral Septum. Neuropsychopharmacology 43:987-1000
James, Morgan H; McGlinchey, Ellen M; Vattikonda, Asrita et al. (2018) Cued Reinstatement of Cocaine but Not Sucrose Seeking Is Dependent on Dopamine Signaling in Prelimbic Cortex and Is Associated with Recruitment of Prelimbic Neurons That Project to Contralateral Nucleus Accumbens Core. Int J Neuropsychopharmacol 21:89-94
Freeman, Linnea R; Aston-Jones, Gary (2018) Activation of medial hypothalamic orexin neurons during a Go/No-Go task. Brain Res :
Porter-Stransky, Kirsten A; Bentzley, Brandon S; Aston-Jones, Gary (2017) Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil. Addict Biol 22:303-317
Bentzley, Brandon S; Aston-Jones, Gary (2017) Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential. Addict Biol 22:946-957
Bowrey, Hannah E; James, Morgan H; Aston-Jones, Gary (2017) New directions for the treatment of depression: Targeting the photic regulation of arousal and mood (PRAM) pathway. Depress Anxiety 34:588-595
Buchta, William C; Mahler, Stephen V; Harlan, Benjamin et al. (2017) Dopamine terminals from the ventral tegmental area gate intrinsic inhibition in the prefrontal cortex. Physiol Rep 5:
James, Morgan H; Aston-Jones, Gary (2017) Orexin/Hypocretin, Central Amygdala, and Escalation of Cocaine Intake. Biol Psychiatry 81:552-553
Moorman, David E; James, Morgan H; Kilroy, Elisabeth A et al. (2017) Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats. Brain Res 1654:34-42

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