Adolescent cocaine differentially impacts psychomotor sensitization and epigenetic profiles in adult male rats with divergent affective phenotypes.
Adolescent cocaine differentially impacts psychomotor sensitization and epigenetic profiles in adult male rats with divergent affective phenotypes.
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DOI：
10.3389/fpsyt.2022.1024617
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发表时间：
2022
影响因子：
4.7
通讯作者：
Akil, Huda
中科院分区：
文献类型：
--
作者：
Parsegian, Aram;Garcia-Fuster, M. Julia;Hebda-Bauer, Elaine;Watson, Stanley. J. J.;Flagel, Shelly. B. B.;Akil, Huda
青少年吸毒确实预示着成年后成瘾倾向的增加，但并不是所有人都受到同样的影响。为了探索这种对早期吸毒经历的差异反应的生物学基础，我们使用了一种遗传大鼠气质模型，并评估了青少年可卡因暴露对成年精神运动致敏的影响。与成年低反应大鼠（bLR）相比，高反应大鼠（bHR）对可卡因的精神运动激活效应更敏感，并且在长期可卡因暴露和/或戒断后更容易恢复药物寻求行为。我们发现，在青春期或成年期，7天的可卡因致敏方案（15 mg/kg/天）只会在bhr中产生精神运动性致敏，而双重可卡因暴露会阻止进一步的致敏，这表明神经可塑性是有限的。相比之下，blr青少年时期的可卡因改变了他们的弹性表型，使他们在成年后对可卡因的反应更灵敏。为了开始探索这些行为表型的神经相关性，我们评估了涉及成瘾倾向的两种功能相反的表观遗传染色质修饰，即四个纹状体亚区组蛋白3赖氨酸9 （H3K9）上的允许乙酰化（ac）和抑制性三甲基化（me3）。在bHRs中，与可卡因致敏相关的伏隔核（NAc）核心H3K9me3降低和acH3K9升高。在blr中，青春期和成年期可卡因暴露的组合导致对可卡因挑战的反应增加，也增加了核心的acH3K9。因此，青少年可卡因经历与遗传背景相互作用，引发与成年期成瘾相关的不同行为特征，并同时改变与可卡因致敏和元可塑性相关的NAc表观遗传组蛋白特征。
Adolescent drug use reliably predicts increased addiction liability in adulthood, but not all individuals are equally impacted. To explore the biological bases of this differential reactivity to early life drug experience, we used a genetic rat model of temperament and evaluated the impact of adolescent cocaine exposure on adult psychomotor sensitization. Relative to adult bred low-responder (bLR) rats, bred high-responders (bHR) are more sensitive to the psychomotor-activating effects of cocaine and reinstate drug-seeking behavior more readily following prolonged cocaine exposure and/or abstinence. We found that a 7-day sensitizing cocaine regimen (15 mg/kg/day) during either adolescence or adulthood produced psychomotor sensitization in bHRs only, while a dual cocaine exposure prevented further sensitization, suggesting limits on neuroplasticity. By contrast, adolescent cocaine in bLRs shifted their resilient phenotype, rendering them more responsive to cocaine in adulthood following adolescent cocaine. To begin to explore the neural correlates of these behavioral phenotypes, we assessed two functionally opposite epigenetic chromatin modifications implicated in addiction liability, permissive acetylation (ac) and repressive tri-methylation (me3) on Histone 3 Lysine 9 (H3K9), in four striatal sub-regions. In bHRs, decreased H3K9me3 and increased acH3K9 in the nucleus accumbens (NAc) core associated with cocaine sensitization. In bLRs, the combination of cocaine exposure in adolescence and adulthood, which lead to an increased response to a cocaine challenge, also increased acH3K9 in the core. Thus, adolescent cocaine experience interacts with genetic background to elicit different behavioral profiles relevant to addiction in adulthood, with concurrent modifications in the epigenetic histone profiles in the NAc that associate with cocaine sensitization and with metaplasticity.
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影响因子：
5.3
作者：
Lud Cadet J
通讯作者：
Lud Cadet J
影响因子：
6
作者：
Degenhardt, Louisa;Coffey, Carolyn;Patton, George C.
通讯作者：
Patton, George C.
影响因子：
2
作者：
Gundersen, HJG;Jensen, EBV;Nielsen, J
通讯作者：
Nielsen, J
影响因子：
5.7
作者：
Feng J;Nestler EJ
通讯作者：
Nestler EJ
影响因子：
3.4
作者：
García-Fuster MJ;Parsegian A;Watson SJ;Akil H;Flagel SB
通讯作者：
Flagel SB