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The cysteine pro\u2010drug, N\u2010acetyl\u2010cysteine (NAC), is a promising glutamatergic agent that has shown some clinical efficacy in reducing nicotine use in humans. The purpose of this study was to examine NAC in two rodent models of nicotine dependence. NAC (0, 5, 20, 50 and 100\u2009mg\/kg) was examined on locomotor activity in groups of rats previously exposed to nicotine or saline. In the second experiment, NAC (0, 50 and 100\u2009mg\/kg\u2009i.p.) was evaluated against the discriminative stimulus effects of nicotine (0.2\u2009mg\/kg) using a two\u2010lever procedure under a tandem schedule (VI10\u201d\u2010FR10) of food reinforcement. Pre\u2010treatment with NAC in doses greater than 20\u2009mg\/kg attenuated the expression of conditioned hyperactivity when rats were placed in locomotor boxes previously paired with chronic nicotine administration. The same doses of NAC had modest effects in attenuating nicotine\u2010stimulated hyperactivity in nicotine\u2010treated or saline\u2010treated rats tested in the same locomotor boxes. In the discrimination task, NAC did not generalise to the nicotine stimulus and nor did it modify the dose\u2013response curve to nicotine, suggesting that NAC may not modify the subjective effects of nicotine. These results suggest NAC selectively attenuates conditioned responses to nicotine\u2010paired stimuli without modifying nicotine\u2010induced hyperactivity or the discriminative stimulus effects of nicotine. Thus, the study proposes that if NAC was to act in a similar selective manner in humans, the specific action of NAC to attenuate conditioned responses may limit its potential as a treatment to manage nicotine dependence.<\/jats:p>","DOI":"10.1111\/adb.70051","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T13:39:28Z","timestamp":1756474768000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective Effects of Acutely Administered N\u2010Acetyl\u2010Cysteine in Rodent Models of Nicotine\u2010Conditioned Behaviours"],"prefix":"10.1111","volume":"30","author":[{"given":"Kelsey","family":"Stoddart","sequence":"first","affiliation":[{"name":"Institute of Neuroscience Newcastle University  Newcastle UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Davies","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience Newcastle 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