We next examined the effects of reversible inactivation of the habenulo-interpeduncular tract on nicotine self-administration behavior in rats, accomplished by direct microinjection of lidocaine into targeted brain sites. Lidocaine-induced inactivation of the IPN increased responding for nicotine (0.03 mg kg−1 per infusion) (Fig. 5a; Supplementary Fig. 14), further supporting a role for nicotine-induced activation of the IPN in restricting nicotine intake. Conversely, inactivation of the VTA profoundly decreased nicotine intake (0.03 mg kg−1 per infusion) (Supplementary Fig. 15, 16). Inactivation of the MHb increased nicotine intake similar to IPN inactivation (Fig. 5b), but this effect was only detected when rats self-administered a higher (0.12 mg kg−1 per infusion) unit dose of nicotine (Supplementary Figs. 17, 18). This effect is consistent with habenular-mediated activation of the IPN preferentially occurring when higher nicotine doses are consumed. Next, we investigated the role of 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
