Featured article of EJN issue 36-3: Insulin in the ventral tegmental area reduces hedonic feeding and suppresses dopamine concentration via increased reuptake
Dmitry. M. Mebel, Jovi. C. Y. Wong, Yifei. J. Dong, Stephanie. L. Borgland
Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, BC, Canada.
Mesolimbic dopamine (DA) signaling has been implicated in the incentive, reinforcing and motivational aspects of food intake. Insulin receptors are expressed on dopaminergic neurons of the ventral tegmental area (VTA), and insulin may act in the VTA to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA are poorly understood. Here, we measured the effects of insulin on evoked DA concentration in the VTA using fast-scan cyclic voltammetry. Insulin concentration-dependently reduced evoked somatodendritic DA in the VTA, requiring activation of phosphoinositol 3-kinase and mTOR signaling. Insulin depression of somatodendritic DA was abolished in the presence of a selective DA transporter (DAT) inhibitor, GBR 12909, as well as in VTA slices of DAT knockout mice, suggesting that insulin upregulated the number or function of DAT to reduce DA concentration. Finally, insulin administered to the VTA depressed sated feeding of sweetened high-fat food. Taken together, these results indicate that insulin depresses DA concentration in the VTA via increased reuptake of DA through DAT. Insulin-mediated decrease of DA in the VTA may suppress salience of food once satiety is reached.
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Commentary:
Read the corresponding commentary by Garret Stuber on this article: Food for thought: attenuation of dopamine signaling by insulin.
EJN Blog Supplemental Figure (not peer-reviewed)
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Insulin suppresses somatodendritic dopamine in the VTA. Fast scan cyclic voltammetry (FSCV) is a method used to electrochemically detect dopamine in situ at the surface of a carbon-fibre microelectrode. A potential is applied to the electrode; the triangle waveform typically used for electrochemical detection of extracellular dopamine ramps from −0.4 to + 1.0 V and back, applied at 400 V/s and repeated at 10 Hz. A current is detected at the electrode due to redox reactions on the electrode surface. (A) Illustrates electrically evoked dopamine release in VTA using FSCV. Current detected at the electrode across time is depicted in a color plot to visualize changes in current at the range of applied potentials (potential is on the y-axis, time is on the x-axis and current is in color). (B) This color plot shows evoked dopamine current after application of insulin to VTA slices. The size of the current detected has significantly decreased, suggesting that after insulin application to the VTA, there is reduced somatodendritic dopamine. |
Biographical notes
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Stephanie Borgland is an assistant professor in the Department of Anesthesiology, Pharmacology and Therapeutics and a member of the Brain Research Centre at the University of British Columbia in Vancouver, Canada. Her focus of interest centers on the mesolimbic dopamine system and how circulating hormones and peptides involved in feeding modulate synaptic transmission of dopamine neurons as well as their output. Her research aims to understand the neurobiological mechanisms responsible for the homeostatic regulation of brain reward circuits and how drugs of abuse can hijack normal appetitive behavior. Lab website: http://www.borglandlab.com |
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Dmitry Mebel is currently an MD/PhD student in the laboratory of Dr. Stephanie Borgland. He started this project as an undergraduate thesis student and continued it during his graduate studies in Dr. Borgland’s laboratory. His research interests include neurophysiological mechanisms of addiction, specifically, synaptic plasticity induced by neuropeptides in brain regions relevant to addiction and their behavioral consequences. |
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Jeff Dong started working on this project as an undergraduate co-op student in Dr. Borgland’s Lab. Jeff investigated the mechanism of insulin- induced dopamine reuptake proposed in this study. Jeff is now pursuing a graduate degree at UBC in the Department of Immunology. |
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Jovi Wong received her Bachelor of Science (Hons.) degree in Integrated Sciences (Pharmacology, Pathophysiology) at the University of British Columbia in 2010, where she worked on the feeding behaviour experiments in this study as her Honours thesis project under the supervision of Dr. Stephanie Borgland. She recently received her MSc in Neuroscience from the University of Geneva and is currently pursuing her DPhil degree in Clinical Neurosciences in the Nuffield Laboratory of Ophthalmology at the University of Oxford. |