Abstract
Background:
Dopamine (DA) signalling in the brain is necessary for feeding behaviour, and alterations in the DA system have been linked to obesity. However, the precise role of DA in the control of food intake remains debated. On the one hand, food reward and motivation are associated with enhanced DA activity. On the other hand, psychostimulant drugs that increase DA signalling suppress food intake. This poses the questions of how endogenous DA neuronal activity regulates feeding, and whether enhancing DA neuronal activity would either promote or reduce food intake.
Methods:
Here, we used designer receptors exclusively activated by designer drugs (DREADD) technology to determine the effects of enhancing DA neuronal activity on feeding behaviour. We chemogenetically activated selective midbrain DA neuronal subpopulations and assessed the effects on feeding microstructure in rats.
Results:
Treatment with the psychostimulant drug amphetamine or the selective DA reuptake inhibitor GBR 12909 significantly suppressed food intake. Selective chemogenetic activation of DA neurons in the ventral tegmental area (VTA) was found to reduce meal size, but had less impact on total food intake. Targeting distinct VTA neuronal pathways revealed that specific activation of the mesolimbic pathway towards nucleus accumbens (NAc) resulted in smaller and shorter meals. In addition, the meal frequency was increased, rendering total food intake unaffected. The disrupted feeding patterns following activation of VTA DA neurons or VTA to NAc projection neurons were accompanied by locomotor hyperactivity. Activation of VTA neurons projecting towards prefrontal cortex or amygdala, or of DA neurons in the substantia nigra, did not affect feeding behaviour.
Conclusions:
Chemogenetic activation of VTA DA neurons or VTA to NAc pathway disrupts feeding patterns. Increased activity of mesolimbic DA neurons appears to both promote and reduce food intake, by facilitating both the initiation and cessation of feeding behaviour.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Zhou QY, Palmiter RD . Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 1995; 83: 1197–1209.
Wang G-J, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W et al. Brain dopamine and obesity. Lancet 2001; 357: 354–357.
Nielsen MØ, Rostrup E, Wulff S, Glenthøj B, Ebdrup BH . Striatal reward activity and antipsychotic-associated weight change in patients with schizophrenia undergoing initial treatment. JAMA Psychiatry 2016; 73: 1–8.
American Diabetes Association, American Psychiatric Assocation, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry 2004; 65: 267–272.
Wise RA . Role of brain dopamine in food reward and reinforcement. Philos Trans R B Soc R B Soc 2006; 361: 1149–1158.
Small DM, Jones-Gotman M, Dagher A . Feeding-induced dopamine release in dorsal striatum correlates with meal pleasantness ratings in healthy human volunteers. Neuroimage 2003; 19: 1709–1715.
Brown HD, McCutcheon JE, Cone JJ, Ragozzino ME, Roitman MF . Primary food reward and reward-predictive stimuli evoke different patterns of phasic dopamine signaling throughout the striatum. Eur J Neurosci 2011; 34: 1997–2006.
Verhagen LAW, Luijendijk MCM, Korte-Bouws GAH, Korte SM, Adan RAH . Dopamine and serotonin release in the nucleus accumbens during starvation-induced hyperactivity. Eur Neuropsychopharmacol 2009; 19: 309–316.
Salamone JD, Correa M . The mysterious motivational functions of mesolimbic dopamine. Neuron 2012; 76: 470–485.
Wise RA . Dopamine, learning and motivation. Nat Rev Neurosci 2004; 5: 483–494.
Berridge KC . The debate over dopamine’s role in reward: The case for incentive salience. Psychopharmacology 2007; 191: 391–431.
Davis C, Fattore L, Kaplan AS, Carter JC, Levitan RD, Kennedy JL . The suppression of appetite and food consumption by methylphenidate: The moderating effects of gender and weight status in healthy adults. Int J Neuropsychopharmacol 2012; 15: 181–187.
Leibowitz SF, Shor-Posner G, Maclow C, Grinker JA . Amphetamine: effects on meal patterns and macronutrient selection. Brain Res Bull 1986; 17: 681–689.
Foltin RW, Fischman MW . Food intake in baboons: effects of d-Amphetamine and Fenfluramine. Pharmacol Biochem Behav 1989; 31: 585–592.
Janhunen SK, la Fleur SE, Adan RAH . Blocking alpha2A adrenoceptors, but not dopamine receptors, augments bupropion-induced hypophagia in rats. Obesity 2013; 21: E700–E708.
Palmiter RD . Is dopamine a physiologically relevant mediator of feeding behavior? Trends Neurosci 2007; 30: 375–381.
van Zessen R, van der Plasse G, Adan RAH . Contribution of the mesolimbic dopamine system in mediating the effects of leptin and ghrelin on feeding. Proc Nutr Soc 2012; 71: 435–445.
Narayanan NS, Guarnieri DJ, DiLeone RJ . Metabolic hormones, dopamine circuits, and feeding. Front Neuroendocrinol 2010; 31: 104–112.
Meye FJ, Adan RAH . Feelings about food: The ventral tegmental area in food reward and emotional eating. Trends Pharmacol Sci 2014; 35: 31–40.
Berridge KC . ‘Liking’ and ‘wanting’ food rewards: brain substrates and roles in eating disorders. Physiol Behav 2009; 97: 537–550.
McCutcheon JE . The role of dopamine in the pursuit of nutritional value. Physiol Behav 2015; 152: 408–415.
Figlewicz DP, Evans SB, Murphy J, Hoen M, Baskin DG . Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res 2003; 964: 107–115.
Rossi MA, Fan D, Barter JW, Yin HH . Bidirectional modulation of substantia Nigra activity by motivational state. PLoS One 2013; 8: 1–15.
van der Plasse G, van Zessen R, Luijendijk MCM, Erkan H, Stuber GD, Ramakers GMJ et al. Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin. Int J Obes 2015; 39: 1742–1749.
Szczypka MS, Kwok K, Brot MD, Marck BT, Matsumoto AM, Donahue BA et al. Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice. Neuron 2001; 30: 819–828.
Hnasko TS, Perez FA, Scouras AD, Stoll EA, Gale SD, Luquet S et al. Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia. Proc Natl Acad Sci USA 2006; 103: 8858–8863.
Palmiter RD . Dopamine signaling in the dorsal striatum is essential for motivated behaviors: Lessons from dopamine-deficient mice. Ann N Y Acad Sci 2008; 1129: 35–46.
Boekhoudt L, Omrani A, Luijendijk MCM, Wolterink-Donselaar IG, Wijbrans EC, van der Plasse G et al. Chemogenetic activation of dopamine neurons in the ventral tegmental area, but not substantia nigra, induces hyperactivity in rats. Eur Neuropsychopharmacol 2016; 26: 1784–1793.
Wang S, Tan Y, Zhang J-E, Luo M . Pharmacogenetic activation of midbrain dopaminergic neurons induces hyperactivity. Neurosci Bull 2013; 29: 517–524.
Boender AJ, de Jong JW, Boekhoudt L, Luijendijk MCM, van der Plasse G, Adan RAH . Combined use of the canine adenovirus-2 and DREADD-technology to activate specific neural pathways in vivo. PLoS One 2014; 9: e95392.
Witten IB, Steinberg EE, Lee SY, Davidson TJ, Zalocusky KA, Brodsky M et al. Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 2011; 72: 721–733.
Tiesjema B, Adan RAH, Luijendijk MCM, Kalsbeek A, la Fleur SE . Differential effects of recombinant adeno-associated virus-mediated neuropeptide Y overexpression in the hypothalamic paraventricular nucleus and lateral hypothalamus on feeding behavior. J Neurosci 2007; 27: 14139–14146.
Janhunen SK, van der Zwaal EM, la Fleur SE, Adan RAH . Inverse agonism at α2A adrenoceptors augments the hypophagic effect of sibutramine in rats. Obesity 2011; 19: 1979–1986.
Bjorklund A, Dunnett SB . Dopamine neuron systems in the brain: an update. Trends Neurosci 2007; 30: 194–202.
Baldo BA, Sadeghian K, Basso AM, Kelley AE . Effects of selective dopamine D1 or D2 receptor blockade within nucleus accumbens subregions on ingestive behavior and associated motor activity. Behav Brain Res 2002; 137: 165–177.
Adan RAH, Vanderschuren LJMJ, la Fleur SE . Anti-obesity drugs and neural circuits of feeding. Trends Pharmacol Sci 2008; 29: 208–217.
Salamone JD, Zigmond MJ, Stricker EM . Characterization of the impaired feeding behavior in rats given haloperidol or dopamine-depleting brain lesions. Neuroscience 1990; 39: 17–24.
Koob GF, Riley SJ, Smith SC, Robbins TW . Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi and olfactory tubercle on feeding, locomotor activity, and amphetamine anorexia in the rat. J Comp Physiol Psychol 1978; 92: 917–927.
Delfs JM, Schreiber L, Kelley AE . Microinjection of cocaine into the nucleus accumbens elicits locomotor activation in the rat. J Neurosci 1990; 10: 303–310.
Creese I, Iversen SD . The role of forebrain dopamine systems in amphetamine induced stereotyped behavior in the rat. Psychopharmacologia 1974; 39: 345–357.
Ikemoto S . Ventral striatal anatomy of locomotor activity induced by cocaine, D-amphetamine, dopamine and D1/D2 agonists. Neuroscience 2002; 113: 939–955.
Lee MD, Clifton PG . Meal patterns of free feeding rats treated with clozapine, olanzapine, or haloperidol. Pharmacol Biochem Behav 2002; 71: 147–154.
Davoodi N, Kalinichev M, Korneev SA, Clifton PG . Hyperphagia and increased meal size are responsible for weight gain in rats treated sub-chronically with olanzapine. Psychopharmacology 2009; 203: 693–702.
van der Zwaal EM, Luijendijk MCM, Evers SS, la Fleur SE, Adan RAH . Olanzapine affects locomotor activity and meal size in male rats. Pharmacol Biochem Behav 2010; 97: 130–137.
Friend DM, Kravitz AV . Working together: basal ganglia pathways in action selection. Trends Neurosci 2014; 37: 301–303.
Nicola SM . The nucleus accumbens as part of a basal ganglia action selection circuit. Psychopharmacology 2007; 191: 521–550.
Robbins TW, Everitt BJ . A role for mesencephalic dopamine in activation: commentary on Berridge (2006). Psychopharmacology 2007; 191: 433–437.
Grinker JA, Drewnowski A, Enns M, Kissileff H . Effects of d-Amphetamine and Fenfluramine on feeding patterns and activity of obese and lean Zucker Rats. Pharmacol Biochem Behav 1980; 12: 265–275.
van der Hoek GA, Cooper SJ . The selective dopamine uptake inhibitor GBR 12909: its effects on the microstructure of feeding in rats. Pharmacol Biochem Behav 1994; 48: 135–140.
Skibicka KP, Shirazi RH, Rabasa-Papio C, Alvarez-Crespo M, Neuber C, Vogel H et al. Divergent circuitry underlying food reward and intake effects of ghrelin: dopaminergic VTA-accumbens projection mediates ghrelin’s effect on food reward but not food intake. Neuropharmacology 2013; 73: 274–283.
Acknowledgements
This work was funded by NeuroBasic, Full4Health (FP7-KBBE-2010-4-266408), NeuroFast (FP7/2007–2013), Nudge-IT (FP7-KBBE.2013.2.2-01), and Netherlands Organisation for Scientific Research (NWO/ALW) Veni grant. We kindly thank Bryan Roth (University of North Carolina, Chapel Hill NC, USA) and the NIMH Chemical Synthesis and Drug Supply Program for supply of CNO. We would also like to thank Ellen C Wijbrans, Anouk HA Verboven, and Jodie HK Man for assistance during experimental procedures.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Boekhoudt, L., Roelofs, T., de Jong, J. et al. Does activation of midbrain dopamine neurons promote or reduce feeding?. Int J Obes 41, 1131–1140 (2017). https://doi.org/10.1038/ijo.2017.74
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ijo.2017.74
This article is cited by
-
A D2 to D1 shift in dopaminergic inputs to midbrain 5-HT neurons causes anorexia in mice
Nature Neuroscience (2022)
-
Increased elasticity of sucrose demand during hyperdopaminergic states in rats
Psychopharmacology (2022)
-
Oxytocin activation of paraventricular thalamic neurons promotes feeding motivation to attenuate stress-induced hypophagia
Neuropsychopharmacology (2021)
-
Cocaine- and amphetamine-regulated transcript peptide- and dopamine-containing systems interact in the ventral tegmental area of the zebra finch, Taeniopygia guttata, during dynamic changes in energy status
Brain Structure and Function (2021)
-
A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia
Molecular Psychiatry (2020)