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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical University of South Carolina
Schools of Medicine
United States
Zip Code
Cason, Angie M; Aston-Jones, Gary (2014) Role of orexin/hypocretin in conditioned sucrose-seeking in female rats. Neuropharmacology 86:97-102
Mahler, Stephen V; Hensley-Simon, Megan; Tahsili-Fahadan, Pouya et al. (2014) Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors. Addict Biol 19:49-60
Mahler, Stephen V; Moorman, David E; Smith, Rachel J et al. (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17:1298-303
Georges, Francois; Le Moine, Catherine; Aston-Jones, Gary (2006) No effect of morphine on ventral tegmental dopamine neurons during withdrawal. J Neurosci 26:5720-6
Harris, G C; Wimmer, M; Byrne, R et al. (2004) Glutamate-associated plasticity in the ventral tegmental area is necessary for conditioning environmental stimuli with morphine. Neuroscience 129:841-7
Harris, Glenda C; Aston-Jones, Gary (2003) Critical role for ventral tegmental glutamate in preference for a cocaine-conditioned environment. Neuropsychopharmacology 28:73-6
Harris, Glenda C; Aston-Jones, Gary (2003) Altered motivation and learning following opiate withdrawal: evidence for prolonged dysregulation of reward processing. Neuropsychopharmacology 28:865-71
Harris, Glenda C; Aston-Jones, Gary (2003) Enhanced morphine preference following prolonged abstinence: association with increased Fos expression in the extended amygdala. Neuropsychopharmacology 28:292-9
Georges, Francois; Aston-Jones, Gary (2003) Prolonged activation of mesolimbic dopaminergic neurons by morphine withdrawal following clonidine: participation of imidazoline and norepinephrine receptors. Neuropsychopharmacology 28:1140-9
Georges, Francois; Aston-Jones, Gary (2002) Activation of ventral tegmental area cells by the bed nucleus of the stria terminalis: a novel excitatory amino acid input to midbrain dopamine neurons. J Neurosci 22:5173-87

Showing the most recent 10 out of 48 publications