The NMDA ion channel blocker, MK-801, administered systemically or as a nanoliter injection into the solitary nucleus (NTS), increases meal size. Furthermore, we have observed that ablation of the NTS abolishes increased meal size following systemic injection of MK-801 and that MK-801-induced increases in intake are attenuated in rats pre-treated 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 nanoliter 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, while ipsilateral to ganglionectomy vagal afferent terminals would be absent. Three additional control preparations also were included: sham ganglionectomy and sub-nodose vagotomy either contralateral or ipsilateral to NTS cannula placement. We found that rats with sub-nodose vagotomies increased their sucrose intake following MK-801 compared to saline, regardless of whether injections were made contralateral (12.6±0.2 vs. 9.6±0.3 ml) or ipsilateral (14.2±0.6 ml vs. 9.7±0.4 ml) to vagotomy. Rats with NTS cannula placements contralateral to nodose ganglionectomy also increased their intake following MK-801 (12.2±0.9 ml 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 to 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.