NMDA NR2 receptors participate in CCK-induced reduction of food intake and hindbrain neuronal activation.
Previous work has shown that blockade of NMDAR by non-competitive (MK-801) and competitive (AP5) antagonists increase food intake by acting in the dorsal hindbrain. NMDAR are heteromeric complexes composed of NR1, NR2 and NR3 subunits. Competitive NR2B antagonists potently increase feeding when injected into the hindbrain. NR2 immunoreactivity is present in the hindbrain, vagal afferents and enteric neurons. NMDA receptors expressed on peripheral vagal afferent processes in the GI tract modulate responsiveness to GI stimuli. Therefore, it is possible that peripheral as well as central vagal NMDA receptors participate in control of food intake. To examine this possibility, we recorded intake of rodent chow, a palatable liquid food (15% sucrose), and non-nutrient (0.2% saccharin) solutions following intraperitoneal (i.p.) administration of D-CPPene, a competitive NMDA receptor antagonist that is selective for binding to the NR2B/A channel subunit. To assess participation of peripheral NMDA receptors in postoral satiation signals, we examined the ability of D-CPPene to attenuate reduction of feeding and hindbrain Fos expression following IP CCK administration. IP D-CPPene (2, 3 mg/kg) produced a significant increase in sucrose and chow intake but not saccharin. Pretreatment with D-CPPene (2 mg/kg) reversed CCK (2 microg/kg)-induced inhibition of sucrose intake, and attenuated CCK-induced Fos-Li in the dorsal hindbrain. These results confirm that antagonism of hindbrain NMDA receptors increases food intake. In addition our results suggest that NMDA receptors outside the hindbrain, perhaps in the periphery, participate in vagally mediated, CCK-induced reduction of food intake and NTS neuron activation.
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Physiology IDGP, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
Swartz
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Ritter
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Burns
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Covasa
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D000704:Analysis of Variance; D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000494:pharmacology; D001069:Appetite Regulation / Q000187:drug effects / Q000502:physiology*; D004435:Eating; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D008297:Male; D009474:Neurons / Q000502:physiology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012249:Rhombencephalon / Q000502:physiology*; D012439:Saccharin; D012527:Satiation / Q000502:physiology; D012844:Sincalide / Q000008:administration & dosage / Q000494:pharmacology*; D013395:Sucrose
D001067:Appetite Depressants; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; C065286:SDZ EAA 494; D013395:Sucrose; D012439:Saccharin; D012844:Sincalide