Psychology Department, Tufts University, Bacon Hall, 530 Boston Avenue, Medford, MA, 02155, USA.
Department of Neuroscience, Sackler School of Graduate Biomedical Sciences, Boston, MA, 02111, USA.
Psychopharmacology (Berl). 2018 Jun;235(6):1807-1820. doi: 10.1007/s00213-018-4905-9. Epub 2018 Apr 25.
Episodic bouts of social stress can precede the initiation, escalation, or relapse to disordered alcohol intake. Social stress may engender neuroadaptations in the hypothalamic-pituitary-adrenal (HPA) axis and in extrahypothalamic stress circuitry to promote the escalation of alcohol intake.
We aimed to (1) confirm a pattern of escalated drinking in socially defeated mice and to (2) test drugs that target distinct aspects of the HPA axis and extrahypothalamic neural substrates for their effectiveness in reducing murine, stress-escalated drinking.
Male C57BL/6J (B6) mice were socially defeated by resident Swiss-derived males for ten consecutive days receiving 30 bites/day. Ten days after the final defeat, cohorts of B6 mice received continuous or intermittent access to 20% EtOH (w/v) and water. After 4 weeks of drinking, mice were injected with weekly, systemic doses of the CRF-R1 antagonist, CP376395; the glucocorticoid receptor antagonist, mifepristone; the 11-beta-hydroxylase inhibitor, metyrapone; or the 5-alpha-reductase inhibitor, finasteride.
Prior to drug treatments, defeated mice reliably consumed more EtOH than non-defeated controls, and mice given alcohol intermittently consumed more EtOH than those with continuous access. CP376395 (17-30 mg/kg) reduced continuous, but not intermittent EtOH intake (g/kg) in socially defeated mice. Mifepristone (100 mg/kg), however, increased drinking by defeated mice with intermittent access to alcohol while reducing drinking during continuous access. When administered finasteride (100 mg/kg) or metyrapone (50 mg/kg), all mice reduced their EtOH intake while increasing their water consumption.
Mice with a history of episodic social defeat stress were selectively sensitive to the effects of CRF-R1 antagonism, suggesting that CRF-R1 may be a potential target for treating alcohol use disorders in individuals who escalate their drinking after exposure to repeated bouts of psychosocial stress. Future studies will clarify how social defeat stress may alter the expression of extrahypothalamic CRF-R1 and glucocorticoid receptors.
阶段性的社交压力事件可先于紊乱性酒精摄入的开始、加重或复发。社交压力可能会引起下丘脑-垂体-肾上腺（HPA）轴和下丘脑外应激回路的神经适应性改变，从而促进酒精摄入的加重。
我们旨在（1）证实社交挫败小鼠的饮酒加重模式，以及（2）测试针对 HPA 轴和下丘脑外神经基质的不同方面的药物，以评估其降低应激诱导的小鼠饮酒的效果。
雄性 C57BL/6J（B6）小鼠连续 10 天接受 30 次/天的瑞士来源雄性的社交挫败。在最后一次挫败后 10 天，B6 小鼠接受连续或间歇性获得 20%乙醇（w/v）和水。在 4 周的饮酒后，小鼠每周接受全身给予 CRF-R1 拮抗剂 CP376395、糖皮质激素受体拮抗剂米非司酮、11-β-羟化酶抑制剂美替拉酮或 5-α-还原酶抑制剂非那雄胺。
在药物治疗之前，挫败小鼠确实比非挫败对照小鼠消耗更多的乙醇，并且间歇性给予酒精的小鼠比连续给予酒精的小鼠消耗更多的乙醇。CP376395（17-30mg/kg）降低了社交挫败小鼠的连续，但不降低间歇性乙醇摄入（g/kg）。然而，米非司酮（100mg/kg）增加了间歇性获得酒精的挫败小鼠的饮酒量，同时减少了连续获得酒精的饮酒量。当给予非那雄胺（100mg/kg）或美替拉酮（50mg/kg）时，所有小鼠都减少了乙醇摄入，同时增加了水的摄入。
有阶段性社交挫败应激史的小鼠对 CRF-R1 拮抗剂的作用具有选择性敏感性，这表明 CRF-R1 可能是治疗因反复经历心理社会压力而加重饮酒的个体的酒精使用障碍的潜在靶点。未来的研究将阐明社交挫败应激如何改变下丘脑外 CRF-R1 和糖皮质激素受体的表达。
