HHS Public Access Author manuscript Author Manuscript
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Curr Opin Behav Sci. 2016 June ; 9: 66–70. doi:10.1016/j.cobeha.2016.02.005.
GLP-1 influences food and drug reward Matthew R. Hayes1 and Heath D. Schmidt2 1Translational 2Department
Neuroscience Program, Department of Psychiatry, Perelman School of Medicine
of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania
Abstract Author Manuscript Author Manuscript
Natural rewards, including food, water, sleep and social interactions, are required to sustain life. The neural substrates that regulate the reinforcing effects of these behaviors are also the same neurobiological mechanisms mediating mood, motivation and the rewarding effects of pharmacological stimuli. That the neuropeptide glucagon-like peptide-1 (GLP-1) is under investigation for both the homeostatic and hedonic controls of feeding is not surprising or novel. However, if the neural substrates that underline food reward are shared with other reward-related behaviors generally, then future research should investigate and embrace the likelihood that endogenous and exogenous GLP-1 receptor activation may influence multiple reward-related behaviors. Indeed, studies of the neurobiological mechanisms underlying motivated feeding behavior have informed much of the basic research investigating neural substrates of drug addiction. An emerging literature demonstrates a role for the GLP-1 system in modulating maladaptive reward behaviors, including drug and alcohol consumption. Thus, if GLP-1-based pharmacotherapies are to be used to treat drug addiction and other diseases associated with maladaptive reward behaviors (e.g. obesity and eating disorders), the neuroscience field must conduct systematic, mechanistic neuropharmacological and behavioral studies of each GLP-1 receptor-expressing nucleus within the brain. It is possible that behavioral selectivity may result from these studies, which could inform future approaches to targeting GLP-1R signaling in discrete brain nuclei to treat motivated behaviors. Equally as likely, non-selective effects on natural reward and maladaptive reward behaviors may be observed for GLP-1-based pharmacotherapies. In this case, a better understanding of the effects of increased central GLP-1R activation on motivated behaviors will aid in clinical approaches toward treating aberrant feeding behaviors and/or drug dependence.
Author Manuscript
Address correspondence to: Matthew R. Hayes, Ph.D., [email protected], Address: TRL building, Office 2209, 125 South 31st Street, Philadelphia, PA 19104, Phone: 215-573-6070, Fax: 215-898-9439, Heath D. Schmidt, Ph.D., [email protected], TRL building, Office 2213, 125 South 31st Street, Philadelphia, PA 19104, 215-573-8291, 215-573-7605. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The authors Matthew R. Hayes and Heath D. Schmidt report no conflicts of interest for the work reviewed here.
Hayes and Schmidt
Page 2
Author Manuscript
Introduction
Author Manuscript
Given the remarkable number of neuropeptide and neurotransmitter systems that exist in the body to regulate energy balance, it seems initially paradoxical that obesity rates continue to rise worldwide [1]. More broadly stated, the staggering number of overweight/obese individuals in Western cultures argues that humans lack homeostatic energy balance equilibrium in the modern food environment. Many theories have been proposed, discussed, heavily reviewed and cited on this topic [2,3]. Among the leading theories, Rosenbaum and colleagues[4] have put forward the notion that humans evolved not to defend a lean phenotype, but rather to defend adiposity and the surplus of energy storage. Indeed, while the brain initiates autonomic, behavioral, and endocrine responses to the presence of a multitude of energy balance relevant neuropeptide/neurotransmitter signals, the brain also initiates many autonomic, behavioral, and endocrine responses to the absence of these neuropeptide/neurotransmitter signals[5-7]. Couple this evolutionary view of energy balance regulation with the known reduced levels of physical activity among modern humans[8], along with today’s obesogenic food environment[9] and you have the necessary framework to promote for overweight and obesity.
Author Manuscript
We view the concept of food reward as an evolutionary adaptation that enabled mammalian species to seek out, procure, select and when possible, ingest large quantities of the most highly energy dense foods in an energy-restricted environment. Unfortunately, in the modern obesogenic food environment, the neural circuitry underlying the processing of food reward is now a major contributing factor to the etiology of the chronic hyperphagia that contributes to obesity. To this end, it is our opinion that pharmaceutical targeting of CNS nuclei that modulate food reward represents a viable treatment strategy for not only obesity and eating disorders, but also other maladaptive reward behaviors (e.g. drug / alcohol addiction). This brief opinionated review therefore focuses on the general concept of food reward and how glucagon-like peptide-1 (GLP-1) acts within the brain to affect food reward and other reward-related behaviors not associated with food. Where appropriate, areas for future GLP-1 research needs are also discussed.
Defining the neural mechanisms underlying reward-based feeding versus hunger-based feeding
Author Manuscript
When sated, laboratory animals and humans are less inclined to derive “reward” from food[10-12]. When in energy deficit, laboratory animals and humans will display increased motivational behaviors and subjective ratings of food, respectively[10-13]. It is likely that feeding behavior in sated versus non-sated animals and humans are mediated by a combination of overlapping and distinct homeostatic / reward-based neural substrates. Neuropeptides, along with other feeding-related hormones, affect information processing in nuclei distributed throughout the neuraxis[5-7]. If different mechanisms underlying rewardbased feeding from those that underlie hunger-based feeding, then characterizing the relevant nuclei mediating the effects of these neuropeptides in these behavior paradigms under different energy states is critically important. Further, such analyses must also be conducted in the obesogenic state, where a surplus of stored energy is readily available in the adipose tissue, yet the brain’s perception of that energy stores is impaired[9]. Exactly Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 3
Author Manuscript
how neuropeptides modulate each of these distributed CNS sites under various energy states to encode and integrate feeding-related information pertaining to pleasure, reward, and incentive salience for specific foods will be important to define as this information may inform future strategies targeting select circuits to treat obesity. Similarly, given that energy state can also affect motivation for drug reward [14-17] and that drug taking can also impact energy state[18,19], it is important to consider what role a neuropeptide system like GLP-1 may have on both food and drug reward driven behaviors under various energy balance states.
Central actions of GLP-1 on food and drug rewards
Author Manuscript
With an ever-increasing availability of highly palatable / energy dense foods, increasing emphasis has been placed on hedonic reward nuclei in the brain and their relative contributions to chronic hyperphagia. Moreover, strategies toward developing novel pharmacotherapies for obesity center on identifying novel neural substrates altered by palatable food in these nuclei. Once such neural substrate that affects both homeostatic and hedonic reward-related feeding behavior is the neuropeptide GLP-1. To this end, pharmacotherapies targeting the GLP-1 system have emerged as leading treatment options for obesity and are now receiving an increased level of attention for their potential role in treating maladaptive reward behaviors.
Author Manuscript
Under normal physiological circumstances peripheral GLP-1 functions in a paracrine-like manner to activate GLP-1 receptors (GLP-1R) expressed on the dendritic terminals of vagal afferents innervating the gastrointestinal (GI) tract [see [20] for review]. However, GLP-1 is also synthesized in the brain by preproglucagon neurons located in the nucleus tractus solitarius (NTS) of the caudal brainstem. These NTS GLP-1-producing neurons project to a multitude of energy balance-relevant nuclei that express the GLP-1R in the hindbrain, midbrain, and forebrain [see [20] for review]. Like vagal-GLP-1R activation, direct intraparenchymal activation of GLP-1R in a multitude of CNS nuclei will result in a suppression of food intake[21-24]. Thus, it becomes difficult to determine the mechanisms mediating the food intake suppressive effects of GLP-1R agonists when these compounds are administered systemically. For example, the GLP-1R agonists liraglutide and exendin-4 are both capable of penetrating the blood-brain barrier and gaining access to multiple CNS nuclei in the brain in amounts sufficient to drive physiological and behavioral responses[25,26]. Therefore, one of the current challenges of the obesity field is to characterize the energy balance responses mediated by individual GLP-1R-expressing nuclei and the physiological and behavioral mechanisms mediating these responses.
Author Manuscript
To date, studies have shown a physiological and/or pharmacological role for food intake control by GLP-1R activation in a variety of CNS nuclei, including the NTS, paraventricular, dorso-medial, ventral-medial and lateral hypothalamus, as well as the ventral hippocampus, ventral tegmental area (VTA), parabrachial nucleus, and nucleus accumbens subregions [see [20] for review]. While research pursuant to the exploration of GLP-1-mediated effects in all of these nuclei is certainly warranted, of particular interest is research aimed at identifying GLP-1-modulation of food reward-related processing. Indeed, with the growing appreciation that the excessive food intake that contributes to human obesity is not driven by metabolic
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 4
Author Manuscript Author Manuscript
need, a number of laboratories have made major advances in our understanding of the role that GLP-1 signaling in the mesolimbic reward system has on energy balance control[27-29]. Perhaps most attractive from an obesity treatment perspective is the finding that GLP-1R activation in the VTA and nucleus accumbens core has been shown to selectively reduce intake of highly palatable, energy dense food without producing a significant suppression of intake of a standard bland diet in rats presented with both diets simultaneously[27,30,31]. However, others have reported that GLP-1R activation in the VTA and accumbens can suppress intake of a standard rodent diet in animals not provided with a dietary choice (i.e., only given access to standard chow)[28,29]. Thus, it may be that GLP-1R activation in these mesolimbic nuclei reduces the motivational incentive of the most rewarding stimuli/food available. Further, at least in the case of the VTA, systemic administration of GLP-1R agonists are able to directly activate VTA-expressing GLP-1R to suppress food intake and body weight gain in rats[31]. These provocative findings indicate that GLP-1 signaling in the mesoaccumbens system may function selectively to mediate the hedonic, rewarding value of palatable food.
Author Manuscript
Recent evidence has shown that GLP-1R activation in nuclei like the NTS, historically a nucleus believed to solely regulate homeostatic or non-reward related feeding, can also suppress motivation to eat and the rewarding value of food (as measured by progressive ratio operant responding and conditioned place preference, respectively)[32,33]. The mechanisms for this reward-suppression are still unclear. However, as the NTS communicates with mesolimbic nuclei through mono- and polysynaptic circuits, one possibility is that GLP-1R signaling in the NTS is affecting food reward through modulation of messocortical structures. Additionally, the NTS is a critical nucleus involved in autonomic processing and outputs associated with core body temperature, brown adipose tissue temperature, heart rate, and gastrointestinal motility [see [6,34,35] for review]. Thus, GLP-1R activation in the NTS may reduce motivated behaviors as a secondary consequence to dysregulation of autonomic function and/or malaise-like effects. Thus, further studies are certainly warranted to elucidate the mechanisms mediating reduced food-reward by NTS GLP-1R signaling. This need is underscored by the recent FDA-approval of the GLP-1R agonist liraglutide for the treatment of obesity[36].
Author Manuscript
An emerging literature now suggests that GLP-1Rs play an important role in drug addiction. For example, systemic administration of a GLP-1R agonist reduces the rewarding effects of drugs of abuse[37,38]. Since GLP-1Rs are expressed centrally, it is important to evaluate the individual contributions of various GLP-1R-expressing nuclei in the brain to drug-taking and –seeking behaviors. It will also be important to consider whether the benefits of GLP-1Rmediated reductions in drug taking and seeking are achievable with current GLP-1-based pharmacotherapies at doses that also affect normal feeding behaviors. Given that under certain experimental conditions, activation of mesolimbic GLP-1Rs can selectively attenuate intake of palatable foods preferentially over intake of bland food[27], it may be possible to reduce drug taking without affecting consumption of normal chow. Full dose-response curves for the effects of GLP-1R ligands on food intake, drug taking and sucrose selfadministration are therefore needed to identify possible dosing windows in which activation of GLP-1Rs may selectively influence responding for hedonic rewards (i.e. palatable food and drugs of abuse) versus more general effects (i.e. intake of normal bland food). Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 5
Author Manuscript
A recent study showed that activation of VTA GLP-1Rs reduces the reinforcing efficacy of cocaine [39]. Further, this VTA GLP-1R-mediated affect on voluntary cocaine taking was shown to be physiologically relevant. While the mechanism underlying these effects is not entirely clear, there is some evidence that cocaine-mediated elevation in plasma corticosterone is associated with increased activation of GLP-1-producing neurons in the hindbrain (i.e., NTS). GLP-1-producing NTS neurons project monosynaptically to the VTA[27] and activation of this pathway may represent a homeostatic response to reduce the reinforcing efficacy of cocaine. Thus, pharmacologically exploiting this novel neural circuit may prove useful as a potential future treatment strategy to reduce cocaine use in humans.
Does GLP-1 really affect reward?
Author Manuscript Author Manuscript
Too often, animal studies designed to assess food reward/motivation will be analyzed when the animal is in a chronic food deprivation state or done in ad libitum fed animals where the postprandial time is not controlled (which will affect the concentration of endogenous mealderived GLP-1 levels in the periphery and CNS). Another common limitation in studies designed to address food reward is an absence of experiments controlling for the effects of stress, fear, anxiety, nausea, malaise, and anhedonia on reward-related behaviors. Additionally, prior associative learning with a specific food, the environment, and postingestive consequences with those foods can bias the coding and behaviors associated with motivation and reward in ways that drawing firm conclusions difficult[25,40,41]. Deriving conclusions about food reward without taking into consideration all of the aforementioned limitations is therefore difficult at best. Thus, such conclusions should be made only after careful triangulation of various behavioral physiological paradigms designed to address reward have been conducted (e.g. operant conditioning, CPP, cue-potentiated feeding, timepaired measurement of the electrophysiological and electrochemical read-out of the behavior, etc) – and – after numerous control experiments have been conducted to conclude that an alternative explanation(s) is not contributing to changes in motivated/reinforced behaviors. These multi-level analyses are costly both in time and resources and are unfortunately not often conducted.
Author Manuscript
Given that GLP-1Rs are expressed in so many nuclei throughout the neuraxis and that current GLP-1R agonists are injected systemically in humans, there are a wealth of studies that are needed to determine the cellular, molecular, physiological and behavioral mechanisms by which GLP-1R signaling is or is not selectively affecting food and non-food rewards. For the GLP-1 system as a whole, our opinion is that a critical mass of studies have been conducted (some reviewed here) with congruent findings to suggest that GLP-1R signaling affects food reward and drug taking. We point out however, that unequivocal data has been reported showing that the GLP-1 system is also involved in stress, visceral malaise, nausea and emetic events[7,22,25,42-45]. We also believe that current GLP-1-based pharmacotherapies at select doses can be a useful tool to treat obesity, eating disorders, and drug/alcohol addiction; however, further basic and clinical trials are still needed to evaluate these hypotheses. What is clear from the literature is that the magnitude of effects and ubiquitous utilization of current GLP-1-based pharmacotherapies on all maladaptive reward behaviors may be limited due to the additional side effects of these compounds mentioned above. Thus, it is our hope that as the field continues to define the neuroanatomical, cellular,
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 6
Author Manuscript
and molecular substrates mediating each physiological and behavioral effect produced by central GLP-1Rs, these studies will inform the development of future GLP-1 pharmacological agents with more selective site(s) of action and reduced incidence of adverse events.
Acknowledgments The authors are partially supported by the following grants from the National Institutes of Health: R01-DA037897 (H.D.S.) and R01-DK096139 (M.R.H.).
References
Author Manuscript Author Manuscript Author Manuscript
1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: A systematic analysis for the global burden of disease study 2013. Lancet. 2014; 384(9945):766–781. [PubMed: 24880830] 2. McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J, Baskin M, Benca RM, Biggio J, Boggiano MM, Eisenmann JC, Elobeid M. Ten putative contributors to the obesity epidemic. et al. Crit Rev Food Sci Nutr. 2009; 49(10):868–913. 3. Thomas DM, Bouchard C, Church T, Slentz C, Kraus WE, Redman LM, Martin CK, Silva AM, Vossen M, Westerterp K, Heymsfield SB. Why do individuals not lose more weight from an exercise intervention at a defined dose? An energy balance analysis. Obes Rev. 2012; 13(10):835– 847. [PubMed: 22681398] *4. Rosenbaum M, Kissileff HR, Mayer LE, Hirsch J, Leibel RL. Energy intake in weight-reduced humans. Brain Res. 2010; 1350:95–102. This review discusses neuroendocrine changes that occur with reduced body weight loss that promote for weight regain. New theories are put forward regarding evolutionary selection to defend adiposity rather than to defend a lean physiology. [PubMed: 20595050] 5. Grill HJ. Distributed neural control of energy balance: Contributions from hindbrain and hypothalamus. Obesity (Silver Spring). 2006; 14(Suppl 5):216S–221S. [PubMed: 17021370] 6. Grill HJ, Hayes MR. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 2012; 16(3):296–309. [PubMed: 22902836] 7. Hayes MR, Mietlicki-Baase EG, Kanoski SE, De Jonghe BC. Incretins and amylin: Neuroendocrine communication between the gut, pancreas, and brain in control of food intake and blood glucose. Annu Rev Nutr. 2014; 34:237–260. [PubMed: 24819325] 8. Hayes M, Chustek M, Heshka S, Wang Z, Pietrobelli A, Heymsfield SB. Low physical activity levels of modern homo sapiens among free-ranging mammals. Int J Obes (Lond). 2005; 29(1):151– 156. [PubMed: 15534614] *9. Berthoud HR. The neurobiology of food intake in an obesogenic environment. Proc Nutr Soc. 2012:1–10. This review offers a refreshing all inclusive view of how distributed nuclei of the brain cross communicate to maintain energy balance and the pertebations that exist to these circuitries during obesity. A top down consideration of energy inbalance is considered and shifts attention away from the hypothalamic view that pervails the literature with regard to obesity etiology and treatment. 10. Mai B, Sommer S, Hauber W. Motivational states influence effort-based decision making in rats: The role of dopamine in the nucleus accumbens. Cognitive, affective & behavioral neuroscience. 2012; 12(1):74–84. 11. Haase L, Green E, Murphy C. Males and females show differential brain activation to taste when hungry and sated in gustatory and reward areas. Appetite. 2011; 57(2):421–434. [PubMed: 21718731] 12. Nader K, Bechara A, van der Kooy D. Neurobiological constraints on behavioral models of motivation. Annual review of psychology. 1997; 48:85–114.
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 7
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
13. Arana FS, Parkinson JA, Hinton E, Holland AJ, Owen AM, Roberts AC. Dissociable contributions of the human amygdala and orbitofrontal cortex to incentive motivation and goal selection. J Neurosci. 2003; 23(29):9632–9638. [PubMed: 14573543] 14. Corrigall WA, Coen KM. Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl). 1989; 99(4):473–478. [PubMed: 2594913] 15. Corrigall WA, Herling S, Coen KM. Evidence for a behavioral deficit during withdrawal from chronic nicotine treatment. Pharmacol Biochem Behav. 1989; 33(3):559–562. [PubMed: 2587598] 16. Hopkins TJ, Rupprecht LE, Hayes MR, Blendy JA, Schmidt HD. Galantamine, an acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, attenuates nicotine taking and seeking in rats. Neuropsychopharmacology. 2012; 37(10): 2310–2321. [PubMed: 22669169] 17. Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ. Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature. 2011; 471(7340):597–601. [PubMed: 21278726] 18. Zoli M, Picciotto MR. Nicotinic regulation of energy homeostasis. Nicotine Tob Res. 2012; 14(11): 1270–1290. [PubMed: 22990212] 19. Grebenstein PE, Thompson IE, Rowland NE. The effects of extended intravenous nicotine administration on body weight and meal patterns in male sprague-dawley rats. Psychopharmacology (Berl). 2013; 228(3):359–366. [PubMed: 23494231] 20. Hayes MR, Mietlicki-Baase EG, Kanoski SE, De Jonghe BC. Incretins and amylin: Neuroendocrine communication between the gut, pancreas, and brain in control of food intake and blood glucose. Annu Rev Nutr. 2014; 34:237–260. [PubMed: 24819325] 21. Hayes MR, Skibicka KP, Grill HJ. Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-likepeptide-1 receptor stimulation. Endocrinology. 2008; 149(8):4059–4068. [PubMed: 18420740] 22. Kinzig KP, D'Alessio DA, Seeley RJ. The diverse roles of specific glp-1 receptors in the control of food intake and the response to visceral illness. J Neurosci. 2002; 22(23):10470–10476. [PubMed: 12451146] 23. Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F, Gremeaux T, Drucker DJ, Kahn CR, Girard J, et al. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest. 2005; 115(12): 3554–3563. [PubMed: 16322793] 24. Schick RR, Zimmermann JP, vorm Walde T, Schusdziarra V. Peptides that regulate food intake: Glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. Am J Physiol Regul Integr Comp Physiol. 2003; 284(6):R1427–1435. [PubMed: 12776726] **25. Kanoski SE, Rupprecht LE, Fortin SM, De Jonghe BC, Hayes MR. The role of nausea in food intake and body weight suppression by peripheral glp-1 receptor agonists, exendin-4 and liraglutide. Neuropharmacology. 2012; 62(5-6):1916–1927. The most common side effect of GLP-1-based pharmaceuticals is nausea and emesis. Yet, despite this knowledge, no study had been conducted to systematically evaluate whether or not food intake and body weight could be achieved in the absence of malaise. Further, this manuscript begins to address the neuroanatomical and behavioral mechanisms mediating GLP-1-induced nausea/malaise. Importantly, this manuscript combined with future research has now demonstrated that select CNS GLP-1R-expressing nuclei can reduce food intake and motivated behaivors without producing illness-like behaviors, while activation of other CNS GLP-1R-expressing nuclei will elicit a suppression of feeding that is accompanied by illness-like behaviors. [PubMed: 22227019] **26. Kanoski SE, Fortin SM, Arnold M, Grill HJ, Hayes MR. Peripheral and central glp-1 receptor populations mediate the anorectic effects of peripherally administered glp-1 receptor agonists, liraglutide and exendin-4. Endocrinology. 2011; 152(8):3103–3112. Now embraced by the GLP-1 field, this manuscript was controversial when first published as it showed that peripherally injected GLP-1 receptor agonists were penetrating into the brain in sufficient quantities to elicit suppression of food intake and body weight. This topic was originally controversial, as such a finding opened the possibility of GLP-1R analogs producing off-target behavioral effects. Future studies have now gone on to identically replicate this original report. [PubMed: 21693680]
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 8
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
**27. Alhadeff AL, Rupprecht LE, Hayes MR. Glp-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology. 2012; 153(2):647–658. [PubMed: 22128031] **28. Dickson SL, Shirazi RH, Hansson C, Bergquist F, Nissbrandt H, Skibicka KP. The glucagon-like peptide 1 (glp-1) analogue, exendin-4, decreases the rewarding value of food: A new role for mesolimbic glp-1 receptors. J Neurosci. 2012; 32(14) **29. Dossat AM, Lilly N, Kay K, Williams DL. Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake. J Neurosci. 2011; 31(41):14453–14457. The three aforementioned annotated reports should all be discussed together. Each of these manuscripts were published within just a few months of one another and showed very similar effects. Specifically, these manuscripts demonstrated a role for both endogenous and exogenous GLP-1 receptor signaling in the nucleus accumbens and ventral tegmental area to the control of food intake and palatable feeding behavior. The consistant findings between these three original studies jumpstarted the GLP-1-reward-based literature for food intake, eating disorders, and other maladaptive motivated behaviors (e.g. drug addiction). [PubMed: 21994361] 30. Mietlicki-Baase EG, Ortinski PI, Reiner DJ, Sinon CG, McCutcheon JE, Pierce RC, Roitman MF, Hayes MR. Glucagon-like peptide-1 receptor activation in the nucleus accumbens core suppresses feeding by increasing glutamatergic ampa/kainate signaling. J Neurosci. 2014; 34(20):6985–6992. [PubMed: 24828651] 31. Mietlicki-Baase EG, Ortinski PI, Rupprecht LE, Olivos DR, Alhadeff AL, Pierce RC, Hayes MR. The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by ampa/kainate receptors. Am J Physiol Endocrinol Metab. 2013 32. Alhadeff AL, Grill HJ. Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding. Am J Physiol Regul Integr Comp Physiol. 2014; 307(4):R465–470. [PubMed: 24944243] 33. Richard JE, Anderberg RH, Goteson A, Gribble FM, Reimann F, Skibicka KP. Activation of the glp-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system. PLoS One. 2015; 10(3):e0119034. [PubMed: 25793511] 34. Moran TH. Gut peptide signaling in the controls of food intake. Obesity (Silver Spring). 2006; 14(Suppl 5):250S–253S. [PubMed: 17021376] 35. Bartness TJ, Vaughan CH, Song CK. Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond). 2010; 34(Suppl 1):S36–42. [PubMed: 20935665] 36. Mordes JP, Liu C, Xu S. Medications for weight loss. Curr Opin Endocrinol Diabetes Obes. 2015; 22(2):91–97. [PubMed: 25692921] 37. Engel JA, Jerlhag E. Role of appetite-regulating peptides in the pathophysiology of addiction: Implications for pharmacotherapy. CNS drugs. 2014; 28(10):875–886. [PubMed: 24958205] 38. Skibicka KP. The central glp-1: Implications for food and drug reward. Frontiers in neuroscience. 2013; 7:181. [PubMed: 24133407] 39. Schmidt HD, Mietlicki-Baase EG, Ige KY, Maurer JJ, Reiner DJ, Zimmer DJ, Van Nest DS, Guercio LA, Wimmer ME, Olivos DR, De Jonghe BC, et al. Glucagon-like peptide-1 receptor activation in the ventral tegmental area decreases the reinforcing efficacy of cocaine. Neuropsychopharmacology. 2015 40. Sclafani A. Oral and postoral determinants of food reward. Physiol Behav. 2004; 81(5):773–779. [PubMed: 15234183] 41. Kanoski SE, Davidson TL. Western diet consumption and cognitive impairment: Links to hippocampal dysfunction and obesity. Physiol Behav. 2011; 103(1):59–68. [PubMed: 21167850] 42. Maniscalco JW, Zheng H, Gordon PJ, Rinaman L. Negative energy balance blocks neural and behavioral responses to acute stress by "silencing" central glucagon-like peptide 1 signaling in rats. J Neurosci. 2015; 35(30):10701–10714. [PubMed: 26224855] 43. Maniscalco JW, Kreisler AD, Rinaman L. Satiation and stress-induced hypophagia: Examining the role of hindbrain neurons expressing prolactin-releasing peptide or glucagon-like peptide 1. Front Neurosci. 2012; 6:199. [PubMed: 23346044] 44. Rinaman L. Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus. Am J Physiol. 1999; 277(2 Pt 2):R582–590. [PubMed: 10444567]
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 9
Author Manuscript
45. Chan SW, Lin G, Yew DT, Yeung CK, Rudd JA. Separation of emetic and anorexic responses of exendin-4, a glp-1 receptor agonist in suncus murinus (house musk shrew). Neuropharmacology. 2013; 70:141–147. [PubMed: 23357334]
Author Manuscript Author Manuscript Author Manuscript Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 10
Author Manuscript
Highlights •
GLP-1 receptor activation will influence multiple reward-related behaviors
•
Obesity and maladaptive reward behaviors can be treated by targeting reward nuclei
•
Current GLP-1 analogs can be used to treat obesity and drug/alcohol addiction
•
Current GLP-1 analogs are limited in effect size due to side effects
Author Manuscript Author Manuscript Author Manuscript Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01. Published in final edited form as: Curr Opin Behav Sci. 2016 June ; 9: 66–70. doi:10.1016/j.cobeha.2016.02.005.
GLP-1 influences food and drug reward Matthew R. Hayes1 and Heath D. Schmidt2 1Translational 2Department
Neuroscience Program, Department of Psychiatry, Perelman School of Medicine
of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania
Abstract Author Manuscript Author Manuscript
Natural rewards, including food, water, sleep and social interactions, are required to sustain life. The neural substrates that regulate the reinforcing effects of these behaviors are also the same neurobiological mechanisms mediating mood, motivation and the rewarding effects of pharmacological stimuli. That the neuropeptide glucagon-like peptide-1 (GLP-1) is under investigation for both the homeostatic and hedonic controls of feeding is not surprising or novel. However, if the neural substrates that underline food reward are shared with other reward-related behaviors generally, then future research should investigate and embrace the likelihood that endogenous and exogenous GLP-1 receptor activation may influence multiple reward-related behaviors. Indeed, studies of the neurobiological mechanisms underlying motivated feeding behavior have informed much of the basic research investigating neural substrates of drug addiction. An emerging literature demonstrates a role for the GLP-1 system in modulating maladaptive reward behaviors, including drug and alcohol consumption. Thus, if GLP-1-based pharmacotherapies are to be used to treat drug addiction and other diseases associated with maladaptive reward behaviors (e.g. obesity and eating disorders), the neuroscience field must conduct systematic, mechanistic neuropharmacological and behavioral studies of each GLP-1 receptor-expressing nucleus within the brain. It is possible that behavioral selectivity may result from these studies, which could inform future approaches to targeting GLP-1R signaling in discrete brain nuclei to treat motivated behaviors. Equally as likely, non-selective effects on natural reward and maladaptive reward behaviors may be observed for GLP-1-based pharmacotherapies. In this case, a better understanding of the effects of increased central GLP-1R activation on motivated behaviors will aid in clinical approaches toward treating aberrant feeding behaviors and/or drug dependence.
Author Manuscript
Address correspondence to: Matthew R. Hayes, Ph.D., [email protected], Address: TRL building, Office 2209, 125 South 31st Street, Philadelphia, PA 19104, Phone: 215-573-6070, Fax: 215-898-9439, Heath D. Schmidt, Ph.D., [email protected], TRL building, Office 2213, 125 South 31st Street, Philadelphia, PA 19104, 215-573-8291, 215-573-7605. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The authors Matthew R. Hayes and Heath D. Schmidt report no conflicts of interest for the work reviewed here.
Hayes and Schmidt
Page 2
Author Manuscript
Introduction
Author Manuscript
Given the remarkable number of neuropeptide and neurotransmitter systems that exist in the body to regulate energy balance, it seems initially paradoxical that obesity rates continue to rise worldwide [1]. More broadly stated, the staggering number of overweight/obese individuals in Western cultures argues that humans lack homeostatic energy balance equilibrium in the modern food environment. Many theories have been proposed, discussed, heavily reviewed and cited on this topic [2,3]. Among the leading theories, Rosenbaum and colleagues[4] have put forward the notion that humans evolved not to defend a lean phenotype, but rather to defend adiposity and the surplus of energy storage. Indeed, while the brain initiates autonomic, behavioral, and endocrine responses to the presence of a multitude of energy balance relevant neuropeptide/neurotransmitter signals, the brain also initiates many autonomic, behavioral, and endocrine responses to the absence of these neuropeptide/neurotransmitter signals[5-7]. Couple this evolutionary view of energy balance regulation with the known reduced levels of physical activity among modern humans[8], along with today’s obesogenic food environment[9] and you have the necessary framework to promote for overweight and obesity.
Author Manuscript
We view the concept of food reward as an evolutionary adaptation that enabled mammalian species to seek out, procure, select and when possible, ingest large quantities of the most highly energy dense foods in an energy-restricted environment. Unfortunately, in the modern obesogenic food environment, the neural circuitry underlying the processing of food reward is now a major contributing factor to the etiology of the chronic hyperphagia that contributes to obesity. To this end, it is our opinion that pharmaceutical targeting of CNS nuclei that modulate food reward represents a viable treatment strategy for not only obesity and eating disorders, but also other maladaptive reward behaviors (e.g. drug / alcohol addiction). This brief opinionated review therefore focuses on the general concept of food reward and how glucagon-like peptide-1 (GLP-1) acts within the brain to affect food reward and other reward-related behaviors not associated with food. Where appropriate, areas for future GLP-1 research needs are also discussed.
Defining the neural mechanisms underlying reward-based feeding versus hunger-based feeding
Author Manuscript
When sated, laboratory animals and humans are less inclined to derive “reward” from food[10-12]. When in energy deficit, laboratory animals and humans will display increased motivational behaviors and subjective ratings of food, respectively[10-13]. It is likely that feeding behavior in sated versus non-sated animals and humans are mediated by a combination of overlapping and distinct homeostatic / reward-based neural substrates. Neuropeptides, along with other feeding-related hormones, affect information processing in nuclei distributed throughout the neuraxis[5-7]. If different mechanisms underlying rewardbased feeding from those that underlie hunger-based feeding, then characterizing the relevant nuclei mediating the effects of these neuropeptides in these behavior paradigms under different energy states is critically important. Further, such analyses must also be conducted in the obesogenic state, where a surplus of stored energy is readily available in the adipose tissue, yet the brain’s perception of that energy stores is impaired[9]. Exactly Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 3
Author Manuscript
how neuropeptides modulate each of these distributed CNS sites under various energy states to encode and integrate feeding-related information pertaining to pleasure, reward, and incentive salience for specific foods will be important to define as this information may inform future strategies targeting select circuits to treat obesity. Similarly, given that energy state can also affect motivation for drug reward [14-17] and that drug taking can also impact energy state[18,19], it is important to consider what role a neuropeptide system like GLP-1 may have on both food and drug reward driven behaviors under various energy balance states.
Central actions of GLP-1 on food and drug rewards
Author Manuscript
With an ever-increasing availability of highly palatable / energy dense foods, increasing emphasis has been placed on hedonic reward nuclei in the brain and their relative contributions to chronic hyperphagia. Moreover, strategies toward developing novel pharmacotherapies for obesity center on identifying novel neural substrates altered by palatable food in these nuclei. Once such neural substrate that affects both homeostatic and hedonic reward-related feeding behavior is the neuropeptide GLP-1. To this end, pharmacotherapies targeting the GLP-1 system have emerged as leading treatment options for obesity and are now receiving an increased level of attention for their potential role in treating maladaptive reward behaviors.
Author Manuscript
Under normal physiological circumstances peripheral GLP-1 functions in a paracrine-like manner to activate GLP-1 receptors (GLP-1R) expressed on the dendritic terminals of vagal afferents innervating the gastrointestinal (GI) tract [see [20] for review]. However, GLP-1 is also synthesized in the brain by preproglucagon neurons located in the nucleus tractus solitarius (NTS) of the caudal brainstem. These NTS GLP-1-producing neurons project to a multitude of energy balance-relevant nuclei that express the GLP-1R in the hindbrain, midbrain, and forebrain [see [20] for review]. Like vagal-GLP-1R activation, direct intraparenchymal activation of GLP-1R in a multitude of CNS nuclei will result in a suppression of food intake[21-24]. Thus, it becomes difficult to determine the mechanisms mediating the food intake suppressive effects of GLP-1R agonists when these compounds are administered systemically. For example, the GLP-1R agonists liraglutide and exendin-4 are both capable of penetrating the blood-brain barrier and gaining access to multiple CNS nuclei in the brain in amounts sufficient to drive physiological and behavioral responses[25,26]. Therefore, one of the current challenges of the obesity field is to characterize the energy balance responses mediated by individual GLP-1R-expressing nuclei and the physiological and behavioral mechanisms mediating these responses.
Author Manuscript
To date, studies have shown a physiological and/or pharmacological role for food intake control by GLP-1R activation in a variety of CNS nuclei, including the NTS, paraventricular, dorso-medial, ventral-medial and lateral hypothalamus, as well as the ventral hippocampus, ventral tegmental area (VTA), parabrachial nucleus, and nucleus accumbens subregions [see [20] for review]. While research pursuant to the exploration of GLP-1-mediated effects in all of these nuclei is certainly warranted, of particular interest is research aimed at identifying GLP-1-modulation of food reward-related processing. Indeed, with the growing appreciation that the excessive food intake that contributes to human obesity is not driven by metabolic
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 4
Author Manuscript Author Manuscript
need, a number of laboratories have made major advances in our understanding of the role that GLP-1 signaling in the mesolimbic reward system has on energy balance control[27-29]. Perhaps most attractive from an obesity treatment perspective is the finding that GLP-1R activation in the VTA and nucleus accumbens core has been shown to selectively reduce intake of highly palatable, energy dense food without producing a significant suppression of intake of a standard bland diet in rats presented with both diets simultaneously[27,30,31]. However, others have reported that GLP-1R activation in the VTA and accumbens can suppress intake of a standard rodent diet in animals not provided with a dietary choice (i.e., only given access to standard chow)[28,29]. Thus, it may be that GLP-1R activation in these mesolimbic nuclei reduces the motivational incentive of the most rewarding stimuli/food available. Further, at least in the case of the VTA, systemic administration of GLP-1R agonists are able to directly activate VTA-expressing GLP-1R to suppress food intake and body weight gain in rats[31]. These provocative findings indicate that GLP-1 signaling in the mesoaccumbens system may function selectively to mediate the hedonic, rewarding value of palatable food.
Author Manuscript
Recent evidence has shown that GLP-1R activation in nuclei like the NTS, historically a nucleus believed to solely regulate homeostatic or non-reward related feeding, can also suppress motivation to eat and the rewarding value of food (as measured by progressive ratio operant responding and conditioned place preference, respectively)[32,33]. The mechanisms for this reward-suppression are still unclear. However, as the NTS communicates with mesolimbic nuclei through mono- and polysynaptic circuits, one possibility is that GLP-1R signaling in the NTS is affecting food reward through modulation of messocortical structures. Additionally, the NTS is a critical nucleus involved in autonomic processing and outputs associated with core body temperature, brown adipose tissue temperature, heart rate, and gastrointestinal motility [see [6,34,35] for review]. Thus, GLP-1R activation in the NTS may reduce motivated behaviors as a secondary consequence to dysregulation of autonomic function and/or malaise-like effects. Thus, further studies are certainly warranted to elucidate the mechanisms mediating reduced food-reward by NTS GLP-1R signaling. This need is underscored by the recent FDA-approval of the GLP-1R agonist liraglutide for the treatment of obesity[36].
Author Manuscript
An emerging literature now suggests that GLP-1Rs play an important role in drug addiction. For example, systemic administration of a GLP-1R agonist reduces the rewarding effects of drugs of abuse[37,38]. Since GLP-1Rs are expressed centrally, it is important to evaluate the individual contributions of various GLP-1R-expressing nuclei in the brain to drug-taking and –seeking behaviors. It will also be important to consider whether the benefits of GLP-1Rmediated reductions in drug taking and seeking are achievable with current GLP-1-based pharmacotherapies at doses that also affect normal feeding behaviors. Given that under certain experimental conditions, activation of mesolimbic GLP-1Rs can selectively attenuate intake of palatable foods preferentially over intake of bland food[27], it may be possible to reduce drug taking without affecting consumption of normal chow. Full dose-response curves for the effects of GLP-1R ligands on food intake, drug taking and sucrose selfadministration are therefore needed to identify possible dosing windows in which activation of GLP-1Rs may selectively influence responding for hedonic rewards (i.e. palatable food and drugs of abuse) versus more general effects (i.e. intake of normal bland food). Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 5
Author Manuscript
A recent study showed that activation of VTA GLP-1Rs reduces the reinforcing efficacy of cocaine [39]. Further, this VTA GLP-1R-mediated affect on voluntary cocaine taking was shown to be physiologically relevant. While the mechanism underlying these effects is not entirely clear, there is some evidence that cocaine-mediated elevation in plasma corticosterone is associated with increased activation of GLP-1-producing neurons in the hindbrain (i.e., NTS). GLP-1-producing NTS neurons project monosynaptically to the VTA[27] and activation of this pathway may represent a homeostatic response to reduce the reinforcing efficacy of cocaine. Thus, pharmacologically exploiting this novel neural circuit may prove useful as a potential future treatment strategy to reduce cocaine use in humans.
Does GLP-1 really affect reward?
Author Manuscript Author Manuscript
Too often, animal studies designed to assess food reward/motivation will be analyzed when the animal is in a chronic food deprivation state or done in ad libitum fed animals where the postprandial time is not controlled (which will affect the concentration of endogenous mealderived GLP-1 levels in the periphery and CNS). Another common limitation in studies designed to address food reward is an absence of experiments controlling for the effects of stress, fear, anxiety, nausea, malaise, and anhedonia on reward-related behaviors. Additionally, prior associative learning with a specific food, the environment, and postingestive consequences with those foods can bias the coding and behaviors associated with motivation and reward in ways that drawing firm conclusions difficult[25,40,41]. Deriving conclusions about food reward without taking into consideration all of the aforementioned limitations is therefore difficult at best. Thus, such conclusions should be made only after careful triangulation of various behavioral physiological paradigms designed to address reward have been conducted (e.g. operant conditioning, CPP, cue-potentiated feeding, timepaired measurement of the electrophysiological and electrochemical read-out of the behavior, etc) – and – after numerous control experiments have been conducted to conclude that an alternative explanation(s) is not contributing to changes in motivated/reinforced behaviors. These multi-level analyses are costly both in time and resources and are unfortunately not often conducted.
Author Manuscript
Given that GLP-1Rs are expressed in so many nuclei throughout the neuraxis and that current GLP-1R agonists are injected systemically in humans, there are a wealth of studies that are needed to determine the cellular, molecular, physiological and behavioral mechanisms by which GLP-1R signaling is or is not selectively affecting food and non-food rewards. For the GLP-1 system as a whole, our opinion is that a critical mass of studies have been conducted (some reviewed here) with congruent findings to suggest that GLP-1R signaling affects food reward and drug taking. We point out however, that unequivocal data has been reported showing that the GLP-1 system is also involved in stress, visceral malaise, nausea and emetic events[7,22,25,42-45]. We also believe that current GLP-1-based pharmacotherapies at select doses can be a useful tool to treat obesity, eating disorders, and drug/alcohol addiction; however, further basic and clinical trials are still needed to evaluate these hypotheses. What is clear from the literature is that the magnitude of effects and ubiquitous utilization of current GLP-1-based pharmacotherapies on all maladaptive reward behaviors may be limited due to the additional side effects of these compounds mentioned above. Thus, it is our hope that as the field continues to define the neuroanatomical, cellular,
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 6
Author Manuscript
and molecular substrates mediating each physiological and behavioral effect produced by central GLP-1Rs, these studies will inform the development of future GLP-1 pharmacological agents with more selective site(s) of action and reduced incidence of adverse events.
Acknowledgments The authors are partially supported by the following grants from the National Institutes of Health: R01-DA037897 (H.D.S.) and R01-DK096139 (M.R.H.).
References
Author Manuscript Author Manuscript Author Manuscript
1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: A systematic analysis for the global burden of disease study 2013. Lancet. 2014; 384(9945):766–781. [PubMed: 24880830] 2. McAllister EJ, Dhurandhar NV, Keith SW, Aronne LJ, Barger J, Baskin M, Benca RM, Biggio J, Boggiano MM, Eisenmann JC, Elobeid M. Ten putative contributors to the obesity epidemic. et al. Crit Rev Food Sci Nutr. 2009; 49(10):868–913. 3. Thomas DM, Bouchard C, Church T, Slentz C, Kraus WE, Redman LM, Martin CK, Silva AM, Vossen M, Westerterp K, Heymsfield SB. Why do individuals not lose more weight from an exercise intervention at a defined dose? An energy balance analysis. Obes Rev. 2012; 13(10):835– 847. [PubMed: 22681398] *4. Rosenbaum M, Kissileff HR, Mayer LE, Hirsch J, Leibel RL. Energy intake in weight-reduced humans. Brain Res. 2010; 1350:95–102. This review discusses neuroendocrine changes that occur with reduced body weight loss that promote for weight regain. New theories are put forward regarding evolutionary selection to defend adiposity rather than to defend a lean physiology. [PubMed: 20595050] 5. Grill HJ. Distributed neural control of energy balance: Contributions from hindbrain and hypothalamus. Obesity (Silver Spring). 2006; 14(Suppl 5):216S–221S. [PubMed: 17021370] 6. Grill HJ, Hayes MR. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 2012; 16(3):296–309. [PubMed: 22902836] 7. Hayes MR, Mietlicki-Baase EG, Kanoski SE, De Jonghe BC. Incretins and amylin: Neuroendocrine communication between the gut, pancreas, and brain in control of food intake and blood glucose. Annu Rev Nutr. 2014; 34:237–260. [PubMed: 24819325] 8. Hayes M, Chustek M, Heshka S, Wang Z, Pietrobelli A, Heymsfield SB. Low physical activity levels of modern homo sapiens among free-ranging mammals. Int J Obes (Lond). 2005; 29(1):151– 156. [PubMed: 15534614] *9. Berthoud HR. The neurobiology of food intake in an obesogenic environment. Proc Nutr Soc. 2012:1–10. This review offers a refreshing all inclusive view of how distributed nuclei of the brain cross communicate to maintain energy balance and the pertebations that exist to these circuitries during obesity. A top down consideration of energy inbalance is considered and shifts attention away from the hypothalamic view that pervails the literature with regard to obesity etiology and treatment. 10. Mai B, Sommer S, Hauber W. Motivational states influence effort-based decision making in rats: The role of dopamine in the nucleus accumbens. Cognitive, affective & behavioral neuroscience. 2012; 12(1):74–84. 11. Haase L, Green E, Murphy C. Males and females show differential brain activation to taste when hungry and sated in gustatory and reward areas. Appetite. 2011; 57(2):421–434. [PubMed: 21718731] 12. Nader K, Bechara A, van der Kooy D. Neurobiological constraints on behavioral models of motivation. Annual review of psychology. 1997; 48:85–114.
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 7
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
13. Arana FS, Parkinson JA, Hinton E, Holland AJ, Owen AM, Roberts AC. Dissociable contributions of the human amygdala and orbitofrontal cortex to incentive motivation and goal selection. J Neurosci. 2003; 23(29):9632–9638. [PubMed: 14573543] 14. Corrigall WA, Coen KM. Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl). 1989; 99(4):473–478. [PubMed: 2594913] 15. Corrigall WA, Herling S, Coen KM. Evidence for a behavioral deficit during withdrawal from chronic nicotine treatment. Pharmacol Biochem Behav. 1989; 33(3):559–562. [PubMed: 2587598] 16. Hopkins TJ, Rupprecht LE, Hayes MR, Blendy JA, Schmidt HD. Galantamine, an acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, attenuates nicotine taking and seeking in rats. Neuropsychopharmacology. 2012; 37(10): 2310–2321. [PubMed: 22669169] 17. Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ. Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature. 2011; 471(7340):597–601. [PubMed: 21278726] 18. Zoli M, Picciotto MR. Nicotinic regulation of energy homeostasis. Nicotine Tob Res. 2012; 14(11): 1270–1290. [PubMed: 22990212] 19. Grebenstein PE, Thompson IE, Rowland NE. The effects of extended intravenous nicotine administration on body weight and meal patterns in male sprague-dawley rats. Psychopharmacology (Berl). 2013; 228(3):359–366. [PubMed: 23494231] 20. Hayes MR, Mietlicki-Baase EG, Kanoski SE, De Jonghe BC. Incretins and amylin: Neuroendocrine communication between the gut, pancreas, and brain in control of food intake and blood glucose. Annu Rev Nutr. 2014; 34:237–260. [PubMed: 24819325] 21. Hayes MR, Skibicka KP, Grill HJ. Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-likepeptide-1 receptor stimulation. Endocrinology. 2008; 149(8):4059–4068. [PubMed: 18420740] 22. Kinzig KP, D'Alessio DA, Seeley RJ. The diverse roles of specific glp-1 receptors in the control of food intake and the response to visceral illness. J Neurosci. 2002; 22(23):10470–10476. [PubMed: 12451146] 23. Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, Benhamed F, Gremeaux T, Drucker DJ, Kahn CR, Girard J, et al. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest. 2005; 115(12): 3554–3563. [PubMed: 16322793] 24. Schick RR, Zimmermann JP, vorm Walde T, Schusdziarra V. Peptides that regulate food intake: Glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. Am J Physiol Regul Integr Comp Physiol. 2003; 284(6):R1427–1435. [PubMed: 12776726] **25. Kanoski SE, Rupprecht LE, Fortin SM, De Jonghe BC, Hayes MR. The role of nausea in food intake and body weight suppression by peripheral glp-1 receptor agonists, exendin-4 and liraglutide. Neuropharmacology. 2012; 62(5-6):1916–1927. The most common side effect of GLP-1-based pharmaceuticals is nausea and emesis. Yet, despite this knowledge, no study had been conducted to systematically evaluate whether or not food intake and body weight could be achieved in the absence of malaise. Further, this manuscript begins to address the neuroanatomical and behavioral mechanisms mediating GLP-1-induced nausea/malaise. Importantly, this manuscript combined with future research has now demonstrated that select CNS GLP-1R-expressing nuclei can reduce food intake and motivated behaivors without producing illness-like behaviors, while activation of other CNS GLP-1R-expressing nuclei will elicit a suppression of feeding that is accompanied by illness-like behaviors. [PubMed: 22227019] **26. Kanoski SE, Fortin SM, Arnold M, Grill HJ, Hayes MR. Peripheral and central glp-1 receptor populations mediate the anorectic effects of peripherally administered glp-1 receptor agonists, liraglutide and exendin-4. Endocrinology. 2011; 152(8):3103–3112. Now embraced by the GLP-1 field, this manuscript was controversial when first published as it showed that peripherally injected GLP-1 receptor agonists were penetrating into the brain in sufficient quantities to elicit suppression of food intake and body weight. This topic was originally controversial, as such a finding opened the possibility of GLP-1R analogs producing off-target behavioral effects. Future studies have now gone on to identically replicate this original report. [PubMed: 21693680]
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 8
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
**27. Alhadeff AL, Rupprecht LE, Hayes MR. Glp-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology. 2012; 153(2):647–658. [PubMed: 22128031] **28. Dickson SL, Shirazi RH, Hansson C, Bergquist F, Nissbrandt H, Skibicka KP. The glucagon-like peptide 1 (glp-1) analogue, exendin-4, decreases the rewarding value of food: A new role for mesolimbic glp-1 receptors. J Neurosci. 2012; 32(14) **29. Dossat AM, Lilly N, Kay K, Williams DL. Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake. J Neurosci. 2011; 31(41):14453–14457. The three aforementioned annotated reports should all be discussed together. Each of these manuscripts were published within just a few months of one another and showed very similar effects. Specifically, these manuscripts demonstrated a role for both endogenous and exogenous GLP-1 receptor signaling in the nucleus accumbens and ventral tegmental area to the control of food intake and palatable feeding behavior. The consistant findings between these three original studies jumpstarted the GLP-1-reward-based literature for food intake, eating disorders, and other maladaptive motivated behaviors (e.g. drug addiction). [PubMed: 21994361] 30. Mietlicki-Baase EG, Ortinski PI, Reiner DJ, Sinon CG, McCutcheon JE, Pierce RC, Roitman MF, Hayes MR. Glucagon-like peptide-1 receptor activation in the nucleus accumbens core suppresses feeding by increasing glutamatergic ampa/kainate signaling. J Neurosci. 2014; 34(20):6985–6992. [PubMed: 24828651] 31. Mietlicki-Baase EG, Ortinski PI, Rupprecht LE, Olivos DR, Alhadeff AL, Pierce RC, Hayes MR. The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by ampa/kainate receptors. Am J Physiol Endocrinol Metab. 2013 32. Alhadeff AL, Grill HJ. Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding. Am J Physiol Regul Integr Comp Physiol. 2014; 307(4):R465–470. [PubMed: 24944243] 33. Richard JE, Anderberg RH, Goteson A, Gribble FM, Reimann F, Skibicka KP. Activation of the glp-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system. PLoS One. 2015; 10(3):e0119034. [PubMed: 25793511] 34. Moran TH. Gut peptide signaling in the controls of food intake. Obesity (Silver Spring). 2006; 14(Suppl 5):250S–253S. [PubMed: 17021376] 35. Bartness TJ, Vaughan CH, Song CK. Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond). 2010; 34(Suppl 1):S36–42. [PubMed: 20935665] 36. Mordes JP, Liu C, Xu S. Medications for weight loss. Curr Opin Endocrinol Diabetes Obes. 2015; 22(2):91–97. [PubMed: 25692921] 37. Engel JA, Jerlhag E. Role of appetite-regulating peptides in the pathophysiology of addiction: Implications for pharmacotherapy. CNS drugs. 2014; 28(10):875–886. [PubMed: 24958205] 38. Skibicka KP. The central glp-1: Implications for food and drug reward. Frontiers in neuroscience. 2013; 7:181. [PubMed: 24133407] 39. Schmidt HD, Mietlicki-Baase EG, Ige KY, Maurer JJ, Reiner DJ, Zimmer DJ, Van Nest DS, Guercio LA, Wimmer ME, Olivos DR, De Jonghe BC, et al. Glucagon-like peptide-1 receptor activation in the ventral tegmental area decreases the reinforcing efficacy of cocaine. Neuropsychopharmacology. 2015 40. Sclafani A. Oral and postoral determinants of food reward. Physiol Behav. 2004; 81(5):773–779. [PubMed: 15234183] 41. Kanoski SE, Davidson TL. Western diet consumption and cognitive impairment: Links to hippocampal dysfunction and obesity. Physiol Behav. 2011; 103(1):59–68. [PubMed: 21167850] 42. Maniscalco JW, Zheng H, Gordon PJ, Rinaman L. Negative energy balance blocks neural and behavioral responses to acute stress by "silencing" central glucagon-like peptide 1 signaling in rats. J Neurosci. 2015; 35(30):10701–10714. [PubMed: 26224855] 43. Maniscalco JW, Kreisler AD, Rinaman L. Satiation and stress-induced hypophagia: Examining the role of hindbrain neurons expressing prolactin-releasing peptide or glucagon-like peptide 1. Front Neurosci. 2012; 6:199. [PubMed: 23346044] 44. Rinaman L. Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus. Am J Physiol. 1999; 277(2 Pt 2):R582–590. [PubMed: 10444567]
Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 9
Author Manuscript
45. Chan SW, Lin G, Yew DT, Yeung CK, Rudd JA. Separation of emetic and anorexic responses of exendin-4, a glp-1 receptor agonist in suncus murinus (house musk shrew). Neuropharmacology. 2013; 70:141–147. [PubMed: 23357334]
Author Manuscript Author Manuscript Author Manuscript Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
Hayes and Schmidt
Page 10
Author Manuscript
Highlights •
GLP-1 receptor activation will influence multiple reward-related behaviors
•
Obesity and maladaptive reward behaviors can be treated by targeting reward nuclei
•
Current GLP-1 analogs can be used to treat obesity and drug/alcohol addiction
•
Current GLP-1 analogs are limited in effect size due to side effects
Author Manuscript Author Manuscript Author Manuscript Curr Opin Behav Sci. Author manuscript; available in PMC 2017 June 01.
