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

- Valproate, unlike other mood stabilizers, improves CRF-induced PPI deficits.
- Valproate enhanced corticosterone secretion more effectively in CRFtg mice.
- Valproate may be particularly beneficial in patient subgroups with altered CRF systems.
- The effect of valproate was independent of GABAA and GABAB receptor activation.

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 GABAA-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 GABAA receptor antagonist bicuculline, the GABAB receptor antagonists phaclofen and SCH 50911 or combined administration of a GABAA and GABAB receptor antagonist. The beneficial effect of valproate on PPI was not mimicked by the GABAA 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.