Nicotine is the primary addictive component of tobacco products and its complex stimulus effects are readily discriminated by humans and non-human animals. Previous preclinical research investigating directly the nature of the nicotine stimulus has been limited to male rodents. The current study began to address this significant gap in the literature by training female and male rats to discriminate 0.4 mg/kg nicotine from saline in the discriminated goal-tracking task. In this task, access to sucrose was intermittently available on nicotine session. On saline session, intermixed with nicotine sessions on separate days, sucrose was not available. Both sexes acquired the discrimination as evidenced by increased head entries into the sucrose receptacle (goal-tracking) evoked by nicotine. The nicotine generalization curves were also similar between females and males. The pharmacological profile of the nicotine stimulus was assessed using substitution and targeted combination tests with the following compounds: sazetidine-A, PHA-543613, PNU-120596, bupropion, nornicotine, and cytisine. For both sexes, nornicotine fully substituted for the nicotine stimulus, whereas sazetidine-A, bupropion, and cytisine produced partial substitution. Female and male rats also responded similarly in interaction tests where a combination of 1 mg/kg of sazetidine-A plus nicotine or nornicotine shifted the nicotine dose-effect curve to the left; however, combinations of sazetidine-A plus bupropion or cytisine failed to produce this effect. These findings begin to fill a significant gap in our understanding of sex differences with respect to the nicotine stimulus and response to therapeutically interesting combinations using a model that includes both sexes.

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Published in Neuropharmacology, v. 113, part A, p. 354-366.

© 2016 Elsevier Ltd. All rights reserved.

This manuscript version is made available under the CC‐BY‐NC‐ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/.

The document available for download is the author's post-peer-review final draft of the article.

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This work was in part supported by NIH research grant DA018114 and DA034389.