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ORIGINAL RESEARCH article
Front. Neurosci.
Sec. Neuropharmacology
Volume 18 - 2024 |
doi: 10.3389/fnins.2024.1425447
This article is part of the Research Topic Substance Use Disorder: Above and Beyond Addiction, Volume II View all 12 articles
Molecular mechanisms underlying sex and treatment-dependent differences in an animal model of cue-exposure therapy for cocaine relapse prevention
Provisionally accepted
Lucy Peterson
1
Jonathan Nguyen
2
Naveed Ghani
3
Pedro Rodriguez-Echemendia
2
Hui Qiao
3
Sun Y. Guwn
3
Heng-Ye Man
3*
Kathleen M. Kantak
2*- 1 Department of Pharmacology, Physiology, and Biophysics, Boston University, Boston, United States
- 2 Department of Psychological and Brain Sciences, Boston University, Boston, United States
- 3 Department of Biology, Boston University, Boston, United States
Environmental enrichment combined with the glycine transporter-1 inhibitor Org24598 (EE+ORG) during cocaine-cue extinction (EXT) inhibited reacquisition of 1.0 mg/kg cocaine self-administration in male but not female rats in a previous investigation. In this investigation, we determined if this treatment benefit in males required EXT training and ascertained the molecular basis for the observed sex difference in treatment efficacy. Nine groups of male rats trained to self-administer 1.0 mg/kg cocaine or receiving yoked-saline underwent EXT or NoEXT with or without EE and/or ORG. Next, they underwent reacquisition of cocaine self-administration or were sacrificed for molecular analysis of 9 protein targets indicative of neuroplasticity in four brain regions. Two groups of female rats trained to self-administer 1.0 mg/kg cocaine also underwent EXT with or without EE+ORG and were sacrificed for molecular analysis, as above. EE+ORG facilitated the rate of EXT learning in both sexes, and importantly, the therapeutic benefit of EE+ORG for inhibiting cocaine relapse required EXT training. Males were more sensitive than females to neuroplasticity-inducing effects of EE+ORG, which prevented reductions in total GluA1 and PSD95 proteins selectively in basolateral amygdala of male rats trained to self-administer cocaine and receiving EXT. Females were deficient in expression of multiple protein targets, especially after EE+ORG. These included total GluA1 and PSD95 proteins in basolateral amygdala, and total TrkB protein in basolateral amygdala, dorsal hippocampus, and ventromedial prefrontal cortex. Together, these results support the clinical view that sex-specific pharmacological and behavioral treatment approaches may be needed during cue exposure therapy to inhibit cocaine relapse.
Keywords: Cocaine-cue extinction, cocaine self-administration, environmental enrichment, Org24598, relapse, neuroplasticity, sex differences
Received: 29 Apr 2024; Accepted: 22 Jul 2024.
Copyright: © 2024 Peterson, Nguyen, Ghani, Rodriguez-Echemendia, Qiao, Guwn, Man and Kantak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Heng-Ye Man, Department of Biology, Boston University, Boston, United States
Kathleen M. Kantak, Department of Psychological and Brain Sciences, Boston University, Boston, United States
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