Douma T N, Millan M J, Verdouw P M, Oosting R S, Olivier B, Groenink L
Dept of Pharmacology, Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Brain Center Rudolf Magnus, Universiteitsweg 99, 3584CG Utrecht, Netherlands.
Dept of Psychopharmacology, Institut de Recherches SERVIER, Croissy-sur-Seine, France.
Neuropharmacology. 2014 Apr;79:66-74. doi: 10.1016/j.neuropharm.2013.10.032. Epub 2013 Nov 7.
Corticotropin-releasing factor (CRF) is implicated in the pathogenesis of bipolar disorder, an illness associated with deficits in prepulse inhibition (PPI) of the acoustic startle response. Valproate is used in the treatment of bipolar disorder and may alter CRF activity via a GABA(A)-ergic mechanism. This study determined the effect of valproate on CRF-disrupted PPI and examined the role of the hypothalamic-pituitary-adrenal axis and GABA-ergic signaling in the effect of valproate. Valproate (60-240 mg/kg) dose-dependently reversed PPI deficits displayed by transgenic mice overexpressing CRF (CRFtg), and normalized PPI deficits induced by CRF i.c.v. infusion in 129Sv mice. Valproate enhanced corticosterone secretion more effectively in CRFtg than in wild-type mice. The effect of valproate on PPI was not blocked by the GABA(A) receptor antagonist bicuculline, the GABA(B) receptor antagonists phaclofen and SCH 50911 or combined administration of a GABA(A) and GABA(B) receptor antagonist. The beneficial effect of valproate on PPI was not mimicked by the GABA(A) receptor agonist muscimol, the GABA transaminase inhibitor vigabatrin, the histone deacetylase (HDAC) inhibitor sodium butyrate or by the mood stabilizers lithium, carbamazepine, lamotrigine or topiramate. Thus, we showed that valproate improves CRF-induced PPI deficits, albeit via a so far unknown mechanism. These marked beneficial effects of valproate on CRF-induced sensorimotor gating deficits suggest that valproate may be of particular value in specific subgroups of bipolar patients that are characterized by alterations in the CRF system.
促肾上腺皮质激素释放因子（CRF）与双相情感障碍的发病机制有关，双相情感障碍是一种与听觉惊吓反应的前脉冲抑制（PPI）缺陷相关的疾病。丙戊酸盐用于治疗双相情感障碍，可能通过GABA（A）能机制改变CRF活性。本研究确定了丙戊酸盐对CRF破坏的PPI的影响，并研究了下丘脑-垂体-肾上腺轴和GABA能信号在丙戊酸盐作用中的作用。丙戊酸盐（60 - 240mg/kg）剂量依赖性地逆转了过表达CRF的转基因小鼠（CRFtg）表现出的PPI缺陷，并使129Sv小鼠中CRF脑室内注射诱导的PPI缺陷恢复正常。丙戊酸盐在CRFtg小鼠中比在野生型小鼠中更有效地增强了皮质酮分泌。丙戊酸盐对PPI的作用未被GABA（A）受体拮抗剂荷包牡丹碱、GABA（B）受体拮抗剂巴氯芬和SCH 50911或GABA（A）和GABA（B）受体拮抗剂联合给药所阻断。丙戊酸盐对PPI的有益作用未被GABA（A）受体激动剂蝇蕈醇、GABA转氨酶抑制剂氨己烯酸、组蛋白脱乙酰酶（HDAC）抑制剂丁酸钠或情绪稳定剂锂、卡马西平、拉莫三嗪或托吡酯所模拟。因此，我们表明丙戊酸盐改善了CRF诱导的PPI缺陷，尽管其机制迄今尚不清楚。丙戊酸盐对CRF诱导的感觉运动门控缺陷的这些显著有益作用表明，丙戊酸盐在以CRF系统改变为特征的双相情感障碍患者的特定亚组中可能具有特殊价值。
