Obesity and drug addiction are diseases that affect a disturbingly large percentage of the population, cost billions of dollars to treat, and represent a increasing drain on our health care system. One factor that contributes to the onset of these diseases is reward seeking behavior. As individuals become obese, they seek and consume food well beyond caloric need. As individuals become addicted, they seek and consume non-nutritive drugs. The mesolimbic system, comprising the ventral tegmental area dopamine neurons and the nucleus accumbens, critically participates in normal reward seeking behavior as well as maladaptive behaviors including the overconsumption of food and drug taking. It has been known for decades that physiological state (hunger, satiety) can modulate reward seeking behavior. However, the mechanisms by which this occurs remain unknown. Here, this gap in knowledge will be addressed by monitoring mesolimbic signaling in real-time during reward seeking behavior towards nutritive (food) and non-nutritive (cocaine, intracranial self-stimulation rewards. The parent grant of this competitive renewal contributed to the establishment of phasic fluctuations in mesolimbic signaling as critical for goal-directed behavior. Indeed, phasic fluctuations in mesolimbic signaling, which occur within hundreds of milliseconds of reward seeking and reward consumption, appear to be especially important for reward-directed behaviors and reinforcement. These fluctuations will be recorded using fast-scan cyclic voltammetry to assay dopamine levels and electrophysiology to assay the firing rates of individual nucleus accumbens neurons. Both techniques allow phasic signals to be correlated with discrete behavioral events in awake, behaving rats.
The aims of this proposal are: i) to determine how accumulation of nutrients alters reward-evoked phasic mesolimbic activity during operant responding for food, cocaine or intracranial self-stimulation, and whether metabolism of carbohydrates is necessary for nutrient feedback on phasic mesolimbic signaling and reward seeking; ii) to determine whether central and intra-ventral tegmental area glucagon-like peptide 1 (GLP-1), a centrally active satiety signal, provides negative feedback for phasic mesolimbic signaling and reward seeking; and iii) to determine whether central and intra-ventral tegmental area ghrelin, a centrally active hunger signal, provides positive feedback for phasic mesolimbic signaling and reward seeking. The significance of this work is in the discovery of novel mechanisms underlying normal and maladaptive reward seeking. This will provide therapeutic targets, in both the periphery and within mesolimbic circuitry, for treating disorders of motivatio, including obesity and drug addiction.

Public Health Relevance

Inappropriate reward seeking behavior contributes to the development of both obesity and drug addiction - disorders that are profound threats to public health. This proposal aims to understand how metabolic signals alter the function of neural circuitry classically thought to underlie reward seeking behavior. The studies will elucidate novel mechanisms underlying normal and maladaptive reward seeking and provide therapeutic targets for treating reward seeking disorders, including obesity and drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA025634-09
Application #
9412138
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Grant, Steven J
Project Start
2009-07-15
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
McCutcheon, James E; Roitman, Mitchell F (2018) Mode of Sucrose Delivery Alters Reward-Related Phasic Dopamine Signals in Nucleus Accumbens. ACS Chem Neurosci :
Hsu, Ted M; McCutcheon, James E; Roitman, Mitchell F (2018) Parallels and Overlap: The Integration of Homeostatic Signals by Mesolimbic Dopamine Neurons. Front Psychiatry 9:410
Fortin, Samantha M; Roitman, Mitchell F (2018) Challenges to body fluid homeostasis differentially recruit phasic dopamine signaling in a taste-selective manner. J Neurosci :
Gerth, Ashlynn I; Alhadeff, Amber L; Grill, Harvey J et al. (2017) Regional influence of cocaine on evoked dopamine release in the nucleus accumbens core: A role for the caudal brainstem. Brain Res 1655:252-260
McMurray, Matthew S; Conway, Sineadh M; Roitman, Jamie D (2017) Brain Stimulation Reward Supports More Consistent and Accurate Rodent Decision-Making than Food Reward. eNeuro 4:
Fortin, Samantha M; Roitman, Mitchell F (2017) Physiological state tunes mesolimbic signaling: Lessons from sodium appetite and inspiration from Randall R. Sakai. Physiol Behav 178:21-27
Whiting, Lynda; McCutcheon, James E; Boyle, Christina N et al. (2017) The area postrema (AP) and the parabrachial nucleus (PBN) are important sites for salmon calcitonin (sCT) to decrease evoked phasic dopamine release in the nucleus accumbens (NAc). Physiol Behav 176:9-16
Fortin, Samantha M; Roitman, Mitchell F (2017) Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core. Physiol Behav 176:17-25
Fortin, Samantha M; Chartoff, Elena H; Roitman, Mitchell F (2016) The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors. Neuropsychopharmacology 41:906-15
Chartoff, Elena H; Ebner, Shayla R; Sparrow, Angela et al. (2016) Relative Timing Between Kappa Opioid Receptor Activation and Cocaine Determines the Impact on Reward and Dopamine Release. Neuropsychopharmacology 41:989-1002

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