rats. We found that low doses of nicotine (0.125–0.25 mg kg−1; free-base; SC) lowered BSR thresholds by a similar magnitude in the Lenti-Control and Lenti-α5-shRNA rats (Fig. 3b). However, as the dose of nicotine was increased (1–1.5 mg kg−1; free-base; SC), BSR thresholds were elevated above baseline in Lenti-Control rats, but continued to be lowered below baseline levels in Lenti-α5-shRNA rats (Fig. 3b). These data demonstrate that the stimulatory effects of nicotine on brain reward systems, which likely provide a crucial source of reinforcement that maintains the tobacco smoking habit38, are unaltered by deficits in α5* nAChRs in the MHb-IPN pathway. Instead, the inhibitory effects of higher nicotine doses on the activity of reward circuitries, which likely determine the amounts of nicotine that can be consumed, are greatly attenuated by knockdown of α5* nAChRs in this pathway.
