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OCD can be treated with exposure-with-response prevention (ERP) therapy in which patients are exposed to triggers but are encouraged to refrain from compulsions, to extinguish compulsive responses. The compulsions of OCD are strengthened by many repeated exposures to triggers, but little is known about the effects of extended repetition of avoidance behaviors on extinction. Here we assessed the extent to which overtraining of active avoidance affects subsequent extinction-with-response prevention (Ext-RP) as a rodent model of ERP, in which rats are extinguished to triggers, while the avoidance option is prevented. Male rats conditioned for 8d or 20d produced similar avoidance behavior to a tone paired with a shock, however, the 20d group showed a severe impairment of extinction during Ext-RP, as well as heightened anxiety. Furthermore, the majority of overtrained (20d) rats (75%) exhibited persistent avoidance following Ext-RP. In the 8d group, only a minority of rats (37%) exhibited persistent avoidance, and this was associated with elevated activity (c-Fos) in the prelimbic cortex and nucleus accumbens. In the 20d group, the minority of non-persistent rats (25%) showed elevated activity in the insular-orbital cortex and paraventricular thalamus. Lastly, extending the duration of Ext-RP prevented the deleterious effects of overtraining on extinction and avoidance. These rodent findings suggest that repeated expression of compulsion-like behaviors biases individuals toward persistent avoidance and alters avoidance circuits, thereby reducing the effectiveness of current extinction-based therapies.<\/jats:p>","DOI":"10.1038\/s41398-020-00892-5","type":"journal-article","created":{"date-parts":[[2020,7,3]],"date-time":"2020-07-03T12:12:33Z","timestamp":1593778353000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Prolonged avoidance training exacerbates OCD-like behaviors in a rodent model"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6062-2205","authenticated-orcid":false,"given":"Freddyson J.","family":"Mart\u00ednez-Rivera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos J.","family":"S\u00e1nchez-Navarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos I.","family":"Huertas-P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin D.","family":"Greenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Rasmussen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory J.","family":"Quirk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,3]]},"reference":[{"key":"892_CR1","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.jad.2018.11.006","volume":"245","author":"LA Brown","year":"2019","unstructured":"Brown, L. 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Functional neuroimaging of avoidance habits in obsessive-compulsive disorder. Am. J. Psychiatry 172, 284\u2013293 (2015).","journal-title":"Am. J. Psychiatry"},{"key":"892_CR7","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1073\/pnas.1609194114","volume":"114","author":"AM Apergis-Schoute","year":"2017","unstructured":"Apergis-Schoute, A. M. et al. Neural basis of impaired safety signaling in Obsessive Compulsive Disorder. Proc. Natl. Acad. Sci. USA 114, 3216\u20133221 (2017).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"892_CR8","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.brat.2014.08.006","volume":"62","author":"MR Milad","year":"2014","unstructured":"Milad, M. R., Rosenbaum, B. L. & Simon, N. M. Neuroscience of fear extinction: implications for assessment and treatment of fear-based and anxiety related disorders. Behav. Res Ther. 62, 17\u201323 (2014).","journal-title":"Behav. 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