glutamate-mediated transmission in these brain sites in regulating nicotine intake. Microinjection of the competitive N-methy-D-aspartate (NMDA) glutamate receptor antagonist LY23595946 into the IPN dose-dependently increased nicotine self-administration (Fig. 5c). LY235959 infused into MHb also increased nicotine intake at the higher unit dose of nicotine, whereas infusion into VTA decreased nicotine intake (Fig, 5d; Supplementary Fig. 16). Taken together, these data support a conceptual framework in which high levels of nicotine intake stimulate the habenulo-interpeduncular tract through α5* nAChRs and thereby enhance NMDA receptor-mediated glutamatergic transmission in the IPN. This nicotine-induced enhancement of IPN activity relays an inhibitory motivational signal that limits further drug intake. Deficient α5* nAChR signaling diminishes the magnitude of this inhibitory motivational signal, permitting larger amounts of nicotine to be consumed (Supplementary Fig. 19).
