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However, the neurobiological mechanisms underlying the relationship between chronic opioid use and withdrawal and development of PTSD are poorly understood. Our previous work identified that chronic escalating heroin administration and withdrawal can produce enhanced fear learning, an animal model of hyperarousal, and is associated with an increase in dorsal hippocampal (DH) interleukin-1\u03b2 (IL-1\u03b2). However, other cytokines, such as TNF-\u03b1, work synergistically with IL-1\u03b2 and may have a role in the development of enhanced fear learning. Based on both translational rodent and clinical studies, TNF-\u03b1 has been implicated in hyperarousal states of PTSD, and has an established role in hippocampal-dependent learning and memory. The first set of experiments tested the hypothesis that chronic heroin administration followed by withdrawal is capable of inducing alterations in DH TNF-\u03b1 expression. The second set of experiments examined whether DH TNF-\u03b1 expression is functionally relevant to the development of enhanced fear learning. We identified an increase of TNF-\u03b1 immunoreactivity and positive cells at 0, 24, and 48 h into withdrawal in the dentate gyrus DH subregion. Interestingly, intra-DH infusions of etanercept (TNF-\u03b1 inhibitor) 0, 24, and 48 h into heroin withdrawal prevented the development of enhanced fear learning and mitigated withdrawal-induced weight loss. Overall, these findings provide insight into the role of TNF-\u03b1 in opioid withdrawal and the development of anxiety disorders such as PTSD.<\/jats:p>","DOI":"10.1007\/s12035-021-02322-z","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T08:37:40Z","timestamp":1613291860000},"page":"2963-2973","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Hippocampal TNF-\u03b1 Signaling Mediates Heroin Withdrawal-Enhanced Fear Learning and Withdrawal-Induced Weight Loss"],"prefix":"10.1007","volume":"58","author":[{"given":"Shveta V.","family":"Parekh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline E.","family":"Paniccia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia O.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5404-7910","authenticated-orcid":false,"given":"Donald T.","family":"Lysle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,13]]},"reference":[{"issue":"4","key":"2322_CR1","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1176\/appi.ajp.163.4.652","volume":"163","author":"KL Mills","year":"2006","unstructured":"Mills KL, Teesson M, Ross J, Peters L (2006) Trauma, PTSD, and substance use disorders: findings from the Australian National Survey of Mental Health and Well-Being. 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