Valproate improves prepulse inhibition deficits induced by corticotropin-releasing factor independent of GABA_A and GABA_B receptor activation

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• 作者：Douma TN^a ; Millan MJ^b ; Verdouw PM^a ; Oosting RS^a ; Olivier B^a ; ^c ; Groenink L^a ; ^{l.groenink@uu.nl" class="auth_mail}
• 关键词：CRH ; Corticosterone ; Sensorimotor gating ; HDAC inhibitor ; GABA ; Mood stabilizer
• 刊名：Neuropharmacology
• 出版年：April, 2014
• 年：2014
• 卷：79
• 期：Complete
• 页码：66-74
• 全文大小：707 K

文摘

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聽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.