NMDA channels control meal size via central vagal afferent terminals

Abstract

The N-methyl-D-aspartate (NMDA) ion channel blocker MK-801 administered systemically or as a nanoliter injection into the nucleus of the solitary tract (NTS), increases meal size. Furthermore, we have observed that ablation of the NTS abolishes increased meal size following systemic injection of dizocilpine (MK-801) and that MK-801-induced increases in intake are attenuated in rats pretreated with capsaicin to destroy small, unmyelinated, primary afferent neurons. These findings led us to hypothesize that NMDA receptors on central vagal afferent terminals or on higher-order NTS neurons innervated by these vagal afferents might mediate increased food intake. To evaluate this hypothesis, we examined 15% sucrose intake after 50-nl MK-801 injections ipsilateral or contralateral to unilateral nodose ganglion removal (ganglionectomy). On the side contralateral to ganglionectomy, vagal afferent terminals would be intact and functional, whereas ipsilateral to ganglionectomy vagal afferent terminals would be absent. Three additional control preparations also were included: 1) sham ganglionectomy and 2) subnodose vagotomy either contralateral or ipsilateral to NTS cannula placement. We found that rats with subnodose vagotomies increased their sucrose intake after injections of MK-801 compared with saline, regardless of whether injections were made contralateral (12.6 +/- 0.2 vs. 9.6 +/- 0.3 ml) or ipsilateral (14.2 +/- 0.6 vs. 9.7 +/- 0.4 ml) to vagotomy. Rats with NTS cannula placements contralateral to nodose ganglionectomy also increased their intake after MK-801 (12.2 +/- 0.9 and 9.2 +/- 1.1 ml for MK-801 and saline, respectively). However, rats with placements ipsilateral to ganglionectomy did not respond to MK-801 (8.0 +/- 0.5 ml) compared with saline (8.3 +/- 0.4 ml). We conclude that central vagal afferent terminals are necessary for increased food intake in response to NMDA ion channel blockade. The function of central vagal afferent processes or the activity of higher-order NTS neurons driven by vagal afferents may be modulated by NMDA receptors to control meal size.

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

“…In support of this hypothesis, we have previously reported that administration of NMDA receptor antagonists into the NTS increases food intake (18,23,46). Most interesting, however, is the fact that after degeneration of central vagal afferent terminals, NTS injection of the antagonist does not increase food intake (17). These results are consistent with the working hypothesis that at least some hindbrain NMDA receptors participating in reduction of food intake by vagal signals, including CCK, are located presynaptically on vagal afferent processes in the NTS.…”

A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine

“…A large series of studies demonstrated a role for glutamate in meal size using localized microinfusions in brain areas associated with feeding or reinforcement (e.g., Zeni et al 2000). Infusions of glutamate in the Nucleus Accumbens decreased food intake, while infusions of glutamate antagonists in the Nucleus Accumbens increased food intake by increasing meal size rodents (Maldonado-Irizarry et al 1995;Stratford et al 1998;Zeni et al 2000), and central infusions of glutamate agonists and antagonists in the pigeon produced a similar pattern of results (Da Silva et al 2006;Gillespie et al 2005). Several studies have also shown that peripheral administration of the NMDA non-competitive antagonist (+)MK-801 (dizocilpine) also increased meal size in the rat (Treece et al 2000;Jahng and Houpt 2001), perhaps due to an increase in the rate of gastric emptying (Covasa et al 2000).…”

Effect of a proton pump inhibitor on postprandial gastric volume, emptying and symptoms in healthy human subjects: a pilot study

“…Protons are known to activate the release of bioactive mediators, such as serotonin and cholecystokinin, from the upper small intestine, which activate sensory mechanisms including vagal afferents. 23,24 In fact, several groups have reported increased sensitivity of the duodenum to infused acid. 25,26 However, the precise mechanism for the acid-induced postprandial symptoms is unclear.…”