Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

Abstract

injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of D-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (D-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, DCPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.vagus; satiation; gut-brain peptides SATIATION IS THE PROCESS by which food entering the gastrointestinal tract gradually reduces food intake, eventually resulting in termination of a meal. Previous reports from our group and others indicate that systemic administration of antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAr antagonists) delays satiation and increases meal size (see, for example, Refs. 8, 9, and 25). Additionally, we demonstrated that injecting NMDAr antagonists directly into the nucleus of the solitary tract (NTS), where vagal afferents from the gastrointestinal tract synapse, increases meal size (19,23,46) and that lesions of the NTS abolish this effect (47). These observations suggest that NMDA receptors, perhaps in the NTS, participate in vagally mediated control of food intake.The hypothesis that NMDA receptors participate in the process of satiation is supported by our prior reports that peripherally administered NMDA receptor antagonists attenuate reduction of food intake induced by CCK (11, 19), a gut peptide known to reduce food intake by activating abdominal vagal a...

Glucoregulatory Relevance of Small Intestinal Nutrient Sensing in Physiology, Bariatric Surgery, and Pharmacology

“…Nevertheless, activation of this vagal gut-brain axis is vital for nutrient-triggered negative feedback, since treating the gut with anesthetics, neurotoxins, or vagotomy abolishes the effects of intestinal nutrients on food intake and glucose regulation (Schwartz, 2011). Vagal afferent fibers terminate in the nucleus tractus solitarius (NTS) of the hindbrain, and antagonism of N-methyl-D-aspartate (NMDA) receptors in the NTS reverses the effects of intestinal nutrients or CCK to lower food intake or suppress HGP (Cheung et al, 2009;Wang et al, 2008;Wright et al, 2011). Intestinal CCK-mediated activation of NTS NMDA receptors leads to MAPK-ERK1/2 signaling and phosphorylation of synapsin I in hindbrain neurons (Campos et al, 2012), and through unclear mechanisms, these neurons act as a relay for vagal gut-derived signals to control food intake or suppress HGP via the hepatic vagal efferent (Wang et al, 2008).…”

NMDA-type glutamate receptors participate in reduction of food intake following hindbrain melanocortin receptor activation

“…Our use of D-CPP-ene was based on our prior experience with the antagonist and its effectiveness in blocking CCK-induced reduction of food intake when injected into the fourth ventricle or NTS (13,61). In addition, functional electrophysiological experiments indicate that D-CPPene effectively blocks NMDAR participation in vagus-to-NTS synaptic transmission (63).…”

“…In a crossover, counterbalanced experimental design, overnight-fasted rats (16 h) received a fourth ventricle injection of saline (0.9% NaCl), MTII (50 pmol; Phoenix Pharmaceuticals, Burlingame, CA), D-4-[(2E)-3-phosphono-2-propenyl]-2-piperazinecarboxylic acid (D-CPP-ene; 40 ng; Tocris, Ellisville, MO), or a cocktail containing D-CPP-ene and MTII in the above amounts. The selection of D-CPP-ene was based on our prior experience with the antagonist and its effectiveness in being able to block CCK-induced reduction of food intake when injected into the fourth ventricle or NTS (14,61). In addition, functional electrophysiological experiments indicate that D-CPP-ene effectively blocks NMDAR-dependent contributions in vagus-to-NTS neurotransmission (63).…”

“…Consistent with glutamate's role in vagal afferent transmission and control of meal size, antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) administered into the hindbrain increase food intake by delaying satiation (32,55) and prevent reduction of food intake by CCK (14,27,61). Therefore, we hypothesized that reduction of food intake by hindbrain MC3/4R agonist injection requires NMDAR activation.…”

Putative roles of neuropeptides in vagal afferent signaling

“…MK801 has been reported to have off-target effects, interacting with other ion channels; however the NMDA receptor antagonists, AP5, and a NR2 subunit antagonist that distinguishes between different types of NMDA receptors, have also been shown to increase food intake in rats when injected into the medial NTS [49,50]. CCK-induced satiation, known to activate a vagal afferent pathway, was also found to be abolished by NTS injection of MK801 [51]. Neuro-anatomical studies demonstrated that exogenous CCK administration activated neurons in the medial NTS, and that activation of these neurons was abolished with NMDA receptor antagonists [51,53].…”