Nicolas Céline, Hofford Rebecca S, Dugast Emilie, Lardeux Virginie, Belujon Pauline, Solinas Marcello, Bardo Michael T, Thiriet Nathalie
Université de Poitiers, INSERM, U-1084, Laboratoire des Neurosciences Expérimentales et Cliniques, Poitiers, France.
Department of Psychology, University of Kentucky, Lexington, KY, 40536-0509, USA.
Psychopharmacology (Berl). 2022 Apr;239(4):1009-1018. doi: 10.1007/s00213-021-05770-6. Epub 2021 Mar 25.
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.
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.
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.
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.
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.
在啮齿动物中，环境富集（EE）对药物成瘾具有预防和治疗作用，且这种作用被认为至少部分取决于EE对压力系统的影响。
本研究调查了禁欲期间暴露于EE是否会减少长期自我给药后对甲基苯丙胺的觅药行为。此外，我们还研究了这些效应是否与大脑中糖皮质激素受体（GR）水平的改变有关，以及给予GR拮抗剂是否会阻断甲基苯丙胺复吸。
我们让大鼠进行20次为期14小时的甲基苯丙胺自我给药。在标准（SE）或EE条件下禁欲3周后，我们在单次3小时的实验中测量甲基苯丙胺觅药行为。然后，我们使用蛋白质印迹技术测量几个脑区的GR水平。最后，在另一组独立的大鼠中，在甲基苯丙胺自我给药和SE条件下禁欲后，我们给予GR拮抗剂米非司酮，并研究甲基苯丙胺觅药行为。
暴露于EE减少了甲基苯丙胺觅药行为，并逆转了甲基苯丙胺引起的腹侧和背侧海马体中GR水平的升高。此外，EE降低了未接触过药物的动物杏仁核中的GR水平，但先前接触甲基苯丙胺可防止这种效应。给予米非司酮显著降低了甲基苯丙胺觅药行为。
EE的抗渴望作用与甲基苯丙胺引起的海马体中GR失调的恢复同时出现。这些结果为以下假设提供了支持，即EE对甲基苯丙胺复吸的影响至少部分是由EE对大脑压力系统的作用介导的。
