Pavlovian conditioning with the internal stimulus effects of intravenous nicotine heightens later nicotine taking with variation by dose and sex.

We have previously demonstrated that the interoceptive stimulus effects of intravenous nicotine (0.03 mg/kg/inf) can acquire conditioned reinforcing value through appetitive Pavlovian conditioning. In this report, we replicate and extend that work by examining the dose- and sex-generality of this effect. 240 male and female Sprague-Dawley rats were divided into groups defined by infusion dose (0, 0.003, 0.01, or 0.03 mg/kg nicotine). These were further divided into rats who received Paired or Unpaired appetitive conditioning between infusions and sucrose presentations. Interoceptive conditioning took place over 24 daily sessions. The Paired group received 10 trials of response-independent infusions of their assigned nicotine dose followed 30 s afterwards by 4-s access to sucrose. The Unpaired group also received 10 infusions and 10 deliveries of sucrose but spaced 4-8 min apart. Thereafter, the chambers were refitted with nosepokes and all groups could self-administer infusions of their assigned solution according to a progressive ratio schedule. Paired conditioning history enhanced the later self-administration of 0.01 and 0.03 mg/kg/inf nicotine in females. Males self-administered 0.03 mg/kg/inf nicotine-regardless of conditioning history. These data demonstrate that appetitive learning involving the stimulus effects of nicotine can substantially alter the reinforcing effects of nicotine in later self-administration, which effect is both dose- and sex-dependent.