Department of Psychology, Tufts University, 530 Boston Ave. (Bacon Hall), Medford, MA, 02155, USA.
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
Psychopharmacology (Berl). 2017 Sep;234(18):2813-2821. doi: 10.1007/s00213-017-4676-8. Epub 2017 Jul 11.
A history of brief intermittent social defeat stress can escalate cocaine self-administration and induce long-term adaptations in the mesolimbic dopamine system. Extra-hypothalamic corticotrophin releasing factor (CRF) has been shown to be closely associated with stress-induced escalation of drug use. How repeated stress modulates CRF release in the ventral tegmental area (VTA) and the roles of CRF receptors during different phases of stress-induced cocaine self-administration remain to be defined.
The current study examines the roles of CRF and CRF receptor 1 (CRFR1) in escalated intravenous cocaine self-administration after exposure to social defeat stress in mice.
First, CRFR1 antagonist (CP 376,395, 15 mg/kg, i.p.) given 30 min prior to each social defeat episode prevented later escalated cocaine self-administration. When CP 376,395 (5 and 15 mg/kg, i.p.) was administered 10 days after the last episode of social stress, the escalation of cocaine intake was dose-dependently reversed. Moreover, socially defeated mice showed increased CRF release in the VTA compared to controls. To further explore the role of CRFR1, CP 376,395 (0.5 and 1 μg/0.2 μl) was infused directly into the VTA before the cocaine self-administration session. Intra-VTA antagonism of CRFR1 was sufficient to reverse social defeat stress-escalated cocaine self-administration.
These findings suggest that CRF and CRFR1 exert multiple roles in the response to social stress that are relevant to escalated cocaine self-administration.
短暂的间歇性社交挫败应激可加重可卡因的自我给药，并诱导中脑边缘多巴胺系统的长期适应。已证实，下丘脑外促肾上腺皮质释放因子（CRF）与应激诱导的药物使用增加密切相关。反复应激如何调节腹侧被盖区（VTA）中的 CRF 释放，以及 CRF 受体在应激诱导的可卡因自我给药的不同阶段所起的作用仍有待确定。
本研究旨在探讨 CRF 和 CRF 受体 1（CRFR1）在社交挫败应激后小鼠静脉内可卡因自我给药增加中的作用。
首先，在每次社交挫败发作前 30min 给予 CRFR1 拮抗剂（CP 376,395，15mg/kg，腹腔注射），可防止随后可卡因自我给药的增加。当 CP 376,395（5 和 15mg/kg，腹腔注射）在社交应激的最后一次发作后 10 天给予时，可卡因摄入的增加呈剂量依赖性逆转。此外，与对照组相比，社交挫败的小鼠 VTA 中的 CRF 释放增加。为了进一步探讨 CRFR1 的作用，在可卡因自我给药前将 CP 376,395（0.5 和 1μg/0.2μl）直接注入 VTA。VTA 内 CRFR1 的拮抗作用足以逆转社交挫败应激引起的可卡因自我给药增加。
这些发现表明，CRF 和 CRFR1 在应对社交应激方面发挥多种作用，与可卡因自我给药增加有关。
