The gustatory nerves of mice lacking P2X2 and P2X3 purinergic receptor subunits (P2X-dblKO) are unresponsive to taste stimulation (Finger et al., 2005). Surprisingly, P2X-dblKO mice show residual behavioral responses to concentrated tastants, presumably via post-ingestive detection. Therefore, the current study tested whether post-ingestive signaling is functional in P2X-dblKO mice and if so, whether it activates the primary viscerosensory nucleus of the medulla, the nucleus of the solitary tract (nTS). Like WT animals, P2X-dblKO mice learned to prefer a flavor paired with 150 mM monosodium glutamate (MSG) over a flavor paired with water. This preference shows that, even in the absence of taste sensory input, post-ingestive cues are detected and associated with a flavor in P2X-dblKO mice. MSG-evoked neuronal activation in the nTS was measured by expression of the immediate early gene c-Fos (c-Fos-like immunoreactivity; Fos-LI). In rostral, gustatory nTS, P2X-dblKO animals, unlike WT animals, showed no taste quality-specific labeling of neurons. Further, MSG-evoked Fos-LI was significantly less in P2X-dblKO mice compared to WT animals. In contrast, in more posterior, viscerosensory nTS, MSG-induced Fos-LI was similar in WT and P2X-dblKO mice. Together, these results suggest that P2X-dblKO mice can form preferences based on post-ingestive cues and that post-ingestive detection of MSG does not rely on the same purinergic signaling that is crucial for taste.