Chronic opipramol treatment extinguishes cocaine craving through Rac1 in responders: A rat model study.

Autor: Bareli T; Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel., Ahdoot HL; Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel., Ben-Moshe H; Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel., Barnea R; Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel., Warhaftig G; Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel., Maayan R; The Laboratory of Biological Psychiatry, Felsenstein Medical Research Center and Sackler Faculty of Medicine, Tel Aviv University, Beilinson Campus, Petah Tikva, Israel., Roska P; Department for the Treatment of Substance Abuse and Mental Health Services, Israeli Ministry of Health, Jerusalem, Israel.; The Hebrew University of Jerusalem, Jerusalem, Israel., Weizman A; The Laboratory of Biological Psychiatry, Felsenstein Medical Research Center and Sackler Faculty of Medicine, Tel Aviv University, Beilinson Campus, Petah Tikva, Israel.; Research Unit, Geha Mental Health Center, Petah Tikva, Israel., Yadid G; Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Jazyk: angličtina
Zdroj: Addiction biology [Addict Biol] 2021 Sep; Vol. 26 (5), pp. e13014. Date of Electronic Publication: 2021 Jan 28.
DOI: 10.1111/adb.13014
Abstrakt: Ras-related C3 botulinum toxin substrate 1 (Rac1), of the Rho small GTPase family, is a key regulator of actin cytoskeleton rearrangement and plays an important role in dendritic morphogenesis. Cocaine produces neuronal alterations, including structural changes in dendritic number and morphology. Emerging data indicate sigma-1 receptors (σ-1Rs) as a promising candidate for the prevention of cocaine craving. Opipramol is a σ-1R agonist approved in some European countries for depression and anxiety. Here we report that opipramol, mediated by Rac1, attenuates cocaine-seeking behavior in a rat model of self-administration. The opipramol effect was shown in two phases. It decreased cocaine-seeking behavior throughout the withdrawal phase and, interestingly, showed a significant reduction of cocaine-primed reinstatement in 75% of the opipramol-treated group (termed 'responders'). All opipramol-treated rats showed a decrease in σ-1R mRNA expression levels in the nucleus accumbens (NAc) versus controls. Responders also exhibited significantly decreased NAc Rac1 mRNA expression levels, compared with non-responder rats. Hence, Rac1 differentiated responders from non-responders. Rac1 correlated positively with σ-1R mRNA levels in opipramol responders. In another experiment, Rac1 inhibitor injected directly into the NAc core decreased active lever presses on the first day of extinction, indicating the critical role of Rac1 in the opipramol effect on drug seeking. We postulate that chronic activation of σ-1R, through a dynamic interaction with Rac1, may suggest a new approach to treat substance use disorder (SUD). Rac1 inhibition is a prerequisite for decreasing drug seeking and rehabilitation, and this can be achieved by opipramol, a medication that can be given during detoxification.
(© 2021 Society for the Study of Addiction.)
Databáze: MEDLINE
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