Abstract
Rationale
In rodents, environmental enrichment (EE) produces both preventive and curative effects on drug addiction, and this effect is believed to depend at least in part on EE’s actions on the stress system.
Objectives
This study investigated whether exposure to EE during abstinence reduces methamphetamine seeking after extended self-administration. In addition, we investigated whether these effects are associated with alterations in the levels of glucocorticoid receptors (GR) in the brain and whether administration of GR antagonists blocks methamphetamine relapse.
Methods
We allowed rats to self-administer methamphetamine for twenty 14-h sessions. After 3 weeks of abstinence either in standard (SE) or EE conditions, we measured methamphetamine seeking in a single 3-h session. Then, we used western blot techniques to measure GR levels in several brain areas. Finally, in an independent group of rats, after methamphetamine self-administration and abstinence in SE, we administered the GR antagonist mifepristone, and we investigated methamphetamine seeking.
Results
Exposure to EE reduced methamphetamine seeking and reversed methamphetamine-induced increases in GR levels in the ventral and dorsal hippocampus. In addition, EE decreased GR levels in the amygdala in drug-naive animals, but this effect was prevented by previous exposure to methamphetamine. Administration of mifepristone significantly decreased methamphetamine seeking.
Conclusions
The anti-craving effects of EE are paralleled by restoration of methamphetamine-induced dysregulation of GR in the hippocampus. These results provide support for the hypothesis that the effect of EE on methamphetamine relapse is at least in part mediated by EE’s action on the brain stress system.
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Acknowledgments
We thank NIDA-IRP and Research Triangle Park for the kind donation of methamphetamine. This study has benefited from the facilities and expertise of PREBIOS platform (Université de Poitiers).
Funding
This work was supported by the Centre National pour la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Université de Poitiers, the Nouvelle Aquitaine CPER 2015-2020/FEDER 2014-2020 program “Habisan” and the Fondation pour la Recherche Médicale (FRM, Grant DPA20140629806 to MS).
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Nicolas, C., Hofford, R.S., Dugast, E. et al. Prevention of relapse to methamphetamine self-administration by environmental enrichment: involvement of glucocorticoid receptors. Psychopharmacology 239, 1009–1018 (2022). https://doi.org/10.1007/s00213-021-05770-6
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DOI: https://doi.org/10.1007/s00213-021-05770-6