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The transition to nicotine addiction occurs through an allostatic cycle involving the stages of binging\/intoxication, withdrawal\/negative affective states, and preoccupation\/anticipation. This review focuses on the psychological, neurobiological, and molecular mechanisms contributing to the negative affective state during withdrawal from nicotine with an emphasis on stress and how social defeat stress can affect these mechanisms. Psychologically, negative affect during withdrawal is thought to contribute to the transition from positive reinforcement of drug-taking to negative reinforcement of nicotine use. Nicotine binding to nicotinic acetylcholine receptors elicits a variety of neuronal signaling throughout the brain, over time producing within- and between-systems neuroadaptations across brain regions that govern reward, anxiety, pain, and stress responses. Continued nicotine use additionally dysregulates myriad molecular signaling pathways that directly affect nicotine intake\/aversion and withdrawal-like symptoms. Throughout all of these mechanisms, non-pharmacological stress also plays an important role in mediating much of the negative affect associated with addiction. Social defeat stress increases a variety of neuropeptide signaling that consequently exacerbates drug taking and negative affective states. Understanding the mechanisms through which these stages manifest can better our understanding of addiction disease biology and provide novel avenues for therapeutic targets.<\/jats:p>","DOI":"10.1007\/s00213-025-06852-5","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T23:51:27Z","timestamp":1753487487000},"page":"2373-2389","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The influence of stress and social defeat on neurobiological reinforcement mechanisms across reward to withdrawal in nicotine addiction"],"prefix":"10.1007","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8269-8390","authenticated-orcid":false,"given":"Kokila","family":"Shankar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8151-4850","authenticated-orcid":false,"given":"S\u00e9l\u00e8ne","family":"Zahedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3700-5003","authenticated-orcid":false,"given":"Olivier","family":"George","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,26]]},"reference":[{"issue":"1","key":"6852_CR1","doi-asserted-by":"crossref","first-page":"70","DOI":"10.48091\/SUVN5250","volume":"1","author":"D Adams","year":"2021","unstructured":"Adams D, Kaliss N, Missner A, Valentine MM (2021) The interplay of nicotine and social stress mediate dopaminergic neuron firing in the ventral tegmental area-nucleus accumbens pathway, contributing to stress and depressive mood disorders. 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