scholarly journals Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine

2015 ◽  
Vol 41 (7) ◽  
pp. 1917-1928 ◽  
Author(s):  
Heath D Schmidt ◽  
Elizabeth G Mietlicki-Baase ◽  
Kelsey Y Ige ◽  
John J Maurer ◽  
David J Reiner ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Receptor Activation ◽  
Reinforcing Efficacy ◽  
Glucagon Like Peptide ◽  
Ventral Tegmental ◽  
Glucagon Like Peptide 1

scholarly journals Glucagon-like peptide-1 receptor activation in the ventral tegmental area attenuates cocaine seeking in rats

2018 ◽  
Vol 43 (10) ◽  
pp. 2000-2008 ◽  
Author(s):  
Nicole S. Hernandez ◽  
Kelsey Y. Ige ◽  
Elizabeth G. Mietlicki-Baase ◽  
Gian Carlo Molina-Castro ◽  
Christopher A. Turner ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Receptor Activation ◽  
Cocaine Seeking ◽  
Glucagon Like Peptide ◽  
Ventral Tegmental ◽  
Glucagon Like Peptide 1

scholarly journals The food intake-suppressive effects of glucagon-like peptide-1 receptor signaling in the ventral tegmental area are mediated by AMPA/kainate receptors

2013 ◽  
Vol 305 (11) ◽  
pp. E1367-E1374 ◽  
Author(s):  
Elizabeth G. Mietlicki-Baase ◽  
Pavel I. Ortinski ◽  
Laura E. Rupprecht ◽  
Diana R. Olivos ◽  
Amber L. Alhadeff ◽  
...  
Keyword(s):  
Food Intake ◽  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Kainate Receptors ◽  
System Control ◽  
Receptor Signaling ◽  
Palatable Food ◽  
Glucagon Like Peptide ◽  
Ventral Tegmental ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 receptor (GLP-1R) activation in the ventral tegmental area (VTA) is physiologically relevant for the control of palatable food intake. Here, we tested whether the food intake-suppressive effects of VTA GLP-1R activation are mediated by glutamatergic signaling within the VTA. Intra-VTA injections of the GLP-1R agonist exendin-4 (Ex-4) reduced palatable high-fat food intake in rats primarily by reducing meal size; these effects were mediated in part via glutamatergic AMPA/kainate but not NMDA receptor signaling. Additional behavioral data indicated that GLP-1R expressed specifically within the VTA can partially mediate the intake- and body weight-suppressive effects of systemically administered Ex-4, offering the intriguing possibility that this receptor population may be clinically relevant for food intake control. Intra-VTA Ex-4 rapidly increased tyrosine hydroxylase levels within the VTA, suggesting that GLP-1R activation modulates VTA dopaminergic signaling. Further evidence for this hypothesis was provided by electrophysiological data showing that Ex-4 increased the frequency of AMPA-mediated currents and reduced the paired/pulse ratio in VTA dopamine neurons. Together, these data provide novel mechanisms by which GLP-1R agonists in the mesolimbic reward system control for palatable food intake.

scholarly journals 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 ◽  
Vol 153 (2) ◽  
pp. 647-658 ◽  
Author(s):  
Amber L. Alhadeff ◽  
Laura E. Rupprecht ◽  
Matthew R. Hayes
Keyword(s):  
Body Weight ◽  
Nucleus Accumbens ◽  
Food Intake ◽  
Ventral Tegmental Area ◽  
Nucleus Tractus Solitarius ◽  
Receptor Activation ◽  
Current Data ◽  
Solitary Tract ◽  
Ventral Tegmental ◽  
Glucagon Like Peptide 1

Central glucagon-like-peptide-1 (GLP-1) receptor activation reduces food intake; however, brain nuclei and mechanism(s) mediating this effect remain poorly understood. Although central nervous system GLP-1 is produced almost exclusively in the nucleus of the solitary tract in the hindbrain, GLP-1 receptors (GLP-1R) are expressed throughout the brain, including nuclei in the mesolimbic reward system (MRS), e.g. the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Here, we examine the MRS as a potential site of action for GLP-1-mediated control of food intake and body weight. Double immunohistochemistry for Fluorogold (monosynaptic retrograde tracer) and GLP-1 neuron immunoreactivity indicated that GLP-1-producing nucleus tractus solitarius neurons project directly to the VTA, the NAc core, and the NAc shell. Pharmacological data showed that GLP-1R activation in the VTA, NAc core, and NAc shell decreased food intake, especially of highly-palatable foods, and body weight. Moreover, blockade of endogenous GLP-1R signaling in the VTA and NAc core resulted in a significant increase in food intake, establishing a physiological relevance for GLP-1 signaling in the MRS. Current data highlight these nuclei within the MRS as novel sites for GLP-1R-mediated control of food intake and body weight.

scholarly journals Glucagon-Like Peptide-1 (GLP-1) and 5-Hydroxytryptamine 2c (5-HT2c) Receptor Agonists in the Ventral Tegmental Area (VTA) Inhibit Ghrelin-Stimulated Appetitive Reward

2019 ◽  
Vol 20 (4) ◽  
pp. 889 ◽  
Author(s):  
Erin Howell ◽  
Hannah Baumgartner ◽  
Lia Zallar ◽  
Joaquín Selva ◽  
Liv Engel ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Receptor Agonist ◽  
Food Reinforcement ◽  
Progressive Ratio ◽  
Sprague Dawley ◽  
Operant Responding ◽  
Orexigenic Peptide ◽  
Glucagon Like Peptide ◽  
Ventral Tegmental ◽  
Glucagon Like Peptide 1

Current literature indicates that the orexigenic peptide ghrelin increases appetitive motivation via signaling in the mesolimbic reward system. Another gastric peptide, glucagon-like peptide-1 (GLP-1), and the neurotransmitter 5-hydroxytryptamine (5-HT), are both known to suppress operant responding for food by acting on key mesolimbic nuclei, including the ventral tegmental area (VTA). In order to investigate the interaction effects of ghrelin, GLP-1, and 5-HT within the VTA, we measured operant responding for sucrose pellets after the administration of ghrelin, the GLP-1 receptor agonist exendin-4 (Ex-4), and the 5-HT2c receptor agonist Ro60-0175 in male Sprague-Dawley rats. Following training on a progressive ratio 3 (PR3) schedule, animals were first injected with ghrelin into the VTA at doses of 3 to 300 pmol. In subsequent testing, separate rats were administered intraperitoneal (IP) Ex-4 (0.1–1.0 µg/kg) or VTA Ex-4 (0.01–0.1 µg) paired with 300 pmol ghrelin. In a final group of rats, the 5-HT2c agonist Ro60-0175 was injected IP (0.25–1.0 mg/kg) or into the VTA (1.5–3.0 µg), and under both conditions paired with 300 pmol ghrelin delivered into the VTA. Our results indicated that ghrelin administration increased operant responding for food reward and that this effect was attenuated by IP and VTA Ex-4 pretreatment as well as pre-administration of IP or VTA Ro60-0175. These data provide compelling evidence that mesolimbic GLP-1 and serotonergic circuitry interact with the ghrelinergic system to suppress ghrelin’s effects on the mediation of food reinforcement.

Cocaine-induced increases in motivation require 2-arachidonoylglycerol mobilization and CB1 receptor activation in the ventral tegmental area

2021 ◽  
pp. 108625
Author(s):  
Sheila A. Engi ◽  
Erin J. Beebe ◽  
Victoria M. Ayvazian ◽  
Fabio C. Cruz ◽  
Joseph F. Cheer ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Ventral Tegmental

scholarly journals Residues within the Transmembrane Domain of the Glucagon-Like Peptide-1 Receptor Involved in Ligand Binding and Receptor Activation: Modelling the Ligand-Bound Receptor

2011 ◽  
Vol 25 (10) ◽  
pp. 1804-1818 ◽  
Author(s):  
K. Coopman ◽  
R. Wallis ◽  
G. Robb ◽  
A. J. H. Brown ◽  
G. F. Wilkinson ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Structural Model ◽  
Transmembrane Domain ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Agonist Affinity ◽  
Camp Generation ◽  
N Terminus ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The C-terminal regions of glucagon-like peptide-1 (GLP-1) bind to the N terminus of the GLP-1 receptor (GLP-1R), facilitating interaction of the ligand N terminus with the receptor transmembrane domain. In contrast, the agonist exendin-4 relies less on the transmembrane domain, and truncated antagonist analogs (e.g. exendin 9–39) may interact solely with the receptor N terminus. Here we used mutagenesis to explore the role of residues highly conserved in the predicted transmembrane helices of mammalian GLP-1Rs and conserved in family B G protein coupled receptors in ligand binding and GLP-1R activation. By iteration using information from the mutagenesis, along with the available crystal structure of the receptor N terminus and a model of the active opsin transmembrane domain, we developed a structural receptor model with GLP-1 bound and used this to better understand consequences of mutations. Mutation at Y152 [transmembrane helix (TM) 1], R190 (TM2), Y235 (TM3), H363 (TM6), and E364 (TM6) produced similar reductions in affinity for GLP-1 and exendin 9–39. In contrast, other mutations either preferentially [K197 (TM2), Q234 (TM3), and W284 (extracellular loop 2)] or solely [D198 (TM2) and R310 (TM5)] reduced GLP-1 affinity. Reduced agonist affinity was always associated with reduced potency. However, reductions in potency exceeded reductions in agonist affinity for K197A, W284A, and R310A, while H363A was uncoupled from cAMP generation, highlighting critical roles of these residues in translating binding to activation. Data show important roles in ligand binding and receptor activation of conserved residues within the transmembrane domain of the GLP-1R. The receptor structural model provides insight into the roles of these residues.

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