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Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As D3R regulates the activity of the Akt\/mTOR and MEK\/ERK1\/2 pathways, we assessed the effects of SB-277011-A, a D3R antagonist, on the activity of these kinases during the reinstatement of cocaine-induced conditioned place preference (CPP) induced by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated an extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Cocaine-seeking behavior reactivation was correlated with decreased p-Akt, p-mTOR, and p-ERK1\/2 activation in both nuclei of restrained animals. While a D3R blockade prevented stress-induced CPP reinstatement and plasma corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR, and ERK1\/2 activation depending on the stressor and the dose used. Our data support the involvement of corticosterone in the SB-277011-A effects in restrained animals. Additionally, the ratios p-mTOR\/mTOR and\/or p-ERK1\/2 \/ERK1\/2 in the BLA during stress-induced relapse seem to be related to the locomotor activity of animals receiving 48 mg\/kg of the antagonist. Hence, our study indicates the D3R antagonist\u2019s efficacy to prevent stress-induced relapses in drug use through distinct modulation of Akt\/mTOR and MEK\/ERK1\/2 pathways in memory-processing nuclei.<\/jats:p>","DOI":"10.3390\/ijms241311214","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T00:35:21Z","timestamp":1688949321000},"page":"11214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Dopamine D3 Receptor Modulates Akt\/mTOR and ERK1\/2 Pathways Differently during the Reinstatement of Cocaine-Seeking Behavior Induced by Psychological versus Physiological Stress"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6141-2303","authenticated-orcid":false,"given":"Aurelio","family":"Franco-Garc\u00eda","sequence":"first","affiliation":[{"name":"Group of Cellular and Molecular Pharmacology, Department of Pharmacology, CEIR Campus Mare Nostrum, University of Murcia, 30120 Murcia, Spain"},{"name":"Instituto Murciano de Investigaci\u00f3n Biosanitaria (IMIB) Pascual Parrilla, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"Guerrero-Bautista","sequence":"additional","affiliation":[{"name":"Group of Cellular and Molecular Pharmacology, Department of Pharmacology, CEIR Campus Mare Nostrum, University of Murcia, 30120 Murcia, Spain"},{"name":"Instituto Murciano de Investigaci\u00f3n Biosanitaria (IMIB) Pascual Parrilla, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juana Mar\u00eda","family":"Hidalgo","sequence":"additional","affiliation":[{"name":"Group of Cellular and Molecular Pharmacology, Department of Pharmacology, CEIR Campus Mare Nostrum, University of Murcia, 30120 Murcia, Spain"},{"name":"Instituto Murciano de Investigaci\u00f3n Biosanitaria (IMIB) Pascual Parrilla, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4626-2674","authenticated-orcid":false,"given":"Victoria","family":"G\u00f3mez-Murcia","sequence":"additional","affiliation":[{"name":"Group of Cellular and Molecular Pharmacology, Department of Pharmacology, CEIR Campus Mare Nostrum, University of Murcia, 30120 Murcia, Spain"},{"name":"Instituto Murciano de Investigaci\u00f3n Biosanitaria (IMIB) Pascual Parrilla, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Victoria","family":"Milan\u00e9s","sequence":"additional","affiliation":[{"name":"Group of Cellular and Molecular Pharmacology, Department of Pharmacology, CEIR Campus Mare Nostrum, University of Murcia, 30120 Murcia, Spain"},{"name":"Instituto Murciano de Investigaci\u00f3n Biosanitaria (IMIB) Pascual Parrilla, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0773-4950","authenticated-orcid":false,"given":"Cristina","family":"N\u00fa\u00f1ez","sequence":"additional","affiliation":[{"name":"Group of Cellular and Molecular Pharmacology, Department of Pharmacology, CEIR Campus Mare Nostrum, University of Murcia, 30120 Murcia, Spain"},{"name":"Instituto Murciano de Investigaci\u00f3n Biosanitaria (IMIB) Pascual Parrilla, 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,7]]},"reference":[{"key":"ref_1","unstructured":"United Nations Office on Drugs and Crime (2021). 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