Chronic food restriction (FR) increases the rewarding and locomotor-activating effects of drugs of abuse. By contrast, high fat, obesity-promoting diets (OB) decrease sensitivity to psychostimulants compared to ad libitum feeding (AL) of standard rodent chow. These findings suggest a role for endocrine adiposity hormones such as insulin in regulating brain reward pathways. Indeed, there is evidence for such a role of insulin, but mechanisms Novel preliminary data obtained using in vitro voltammetry show that nM levels of insulin increase evoked extracellular dopamine (DA) concentration ([DA]o) in caudate/putamen (CPu) and nucleus accumbens (NAc). Notably, this response is enhanced in FR rats, but blunted in OB rats. The goal of this multi-PI project is to test the hypothesis that insulin-dependent changes in DA neurotransmission contribute significantly to the influence of diet on brain reward circuitry. Pilot data suggest that insulin-enhanced evoked [DA]o is mediated by insulin receptors (InsRs), not on DA axons, but on cholinergic interneurons, and show a pivotal role for DA release regulation by nicotinic acetylcholine (ACh) receptors (nAChRs) located on DA axons. Previous studies of effects of insulin on feeding behavior and reward have emphasized the anorexigenic effect of insulin in the medial hypothalamus, implying a role in satiety. However, our data provide evidence for a novel role of acute insulin elevation in reward by enhancing DA release. Consistent with this hypothesis, other pilot data indicate lower evoked [DA]o in CPu in slices from FR rats, which is restored by exogenous insulin. Interestingly, evoked [DA]o is also lower in OB CPu. Mechanistic experiments in Aim 1 will evaluate signaling pathways and circuitry underlying the effects of insulin on DA release using voltammetry in brain slices and test the hypotheses that hypoinsulinemia contributes to low evoked [DA]o in FR rats, whereas decreased InsR sensitivity may underlie low evoked [DA]o in OB.
Aim 2 will combine quantitation of DA release and uptake dynamics with assessment of the effect of physiologically relevant (low nM) levels of insulin on dopamine transporter (DAT) expression and activity in axon terminal regions and in DA cell bodies in the ventral tegmental area (VTA) in synapto(neuro)somes. To translate the effects of insulin from these in vitro studies to in vivo behavior, experiments in Aim 3 will determine the effect of intrastriatal insulin and insulin receptor (InsR) antagonist injections on behavioral responses to rewarding brain stimulation and food- and drug-paired environments. The increasing prevalence of insulin resistance and obesity and the high comorbidity of disordered eating and substance abuse indicate that understanding the connections among diet, insulin, DA and reward will have important implications for prevention and treatment of addictive disorders. Our preliminary finding that insulin promotes transmitter release, including that of DA and ACh, indicates a completely new role for insulin in brain function. The marriage of mechanistic in vitro studies and in vivo behavioral assays in this multi-PI, multi-disciplinary project has high potential to help decompartmentalize pathological eating and drug addiction and to drive the development of crossover therapies are poorly understood.

Public Health Relevance

Eating disorders and substance abuse are significant health risks. The pathology of both involves brain reward circuitry, but whether the same pathways are affected is unclear, in part because of segregation of research on diet vs. drugs. This multi-PI, multi-disciplinary project is built around our preliminary evidence that insulin, a recognized regulator of satiety and metabolism, is also a reward signal in the brain. This project has the potential to change the way that insulin is viewed, and thereby lead to novel crossover therapies to treat both obesity and addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA033811-02
Application #
8540408
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (02))
Program Officer
Pilotte, Nancy S
Project Start
2012-09-15
Project End
2017-08-31
Budget Start
2013-06-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$504,830
Indirect Cost
$206,114
Name
New York University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Rice, Margaret E (2017) Monitoring Molecules in Neuroscience Then and Now. ACS Chem Neurosci 8:215-217
Ouyang, Jiangyong; Carcea, Ioana; Schiavo, Jennifer K et al. (2017) Food restriction induces synaptic incorporation of calcium-permeable AMPA receptors in nucleus accumbens. Eur J Neurosci 45:826-836
Ludwig, Mike; Apps, David; Menzies, John et al. (2016) Dendritic Release of Neurotransmitters. Compr Physiol 7:235-252
Asri, R; O'Neill, B; Patel, J C et al. (2016) Detection of evoked acetylcholine release in mouse brain slices. Analyst 141:6416-6421
Woods, C A; Guttman, Z R; Huang, D et al. (2016) Insulin receptor activation in the nucleus accumbens reflects nutritive value of a recently ingested meal. Physiol Behav 159:52-63
Carr, Kenneth D (2016) Nucleus Accumbens AMPA Receptor Trafficking Upregulated by Food Restriction: An Unintended Target for Drugs of Abuse and Forbidden Foods. Curr Opin Behav Sci 9:32-39
Sulzer, David; Cragg, Stephanie J; Rice, Margaret E (2016) Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia 6:123-148
O'Neill, Brian; Lauterstein, Dana; Patel, Jyoti C et al. (2015) Striatal dopamine release regulation by the cholinergic properties of the smokeless tobacco, gutkha. ACS Chem Neurosci 6:832-7
Stouffer, Melissa A; Woods, Catherine A; Patel, Jyoti C et al. (2015) Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward. Nat Commun 6:8543

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