title: Valproate improves prepulse inhibition deficits induced by corticotropin-releasing factor independent of GABA(A) and GABA(B) receptor activation.
abstract: 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.
authors.affiliation: Dept of Pharmacology, Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Brain Center Rudolf Magnus, Universiteitsweg 99, 3584CG Utrecht, Netherlands.
authors.forename: T N
authors.initials: TN
authors.lastname: Douma
authors.affiliation: Dept of Psychopharmacology, Institut de Recherches SERVIER, Croissy-sur-Seine, France.
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: Dept of Pharmacology, Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Brain Center Rudolf Magnus, Universiteitsweg 99, 3584CG Utrecht, Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: Verdouw
authors.affiliation: Dept of Pharmacology, Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Brain Center Rudolf Magnus, Universiteitsweg 99, 3584CG Utrecht, Netherlands.
authors.forename: R S
authors.initials: RS
authors.lastname: Oosting
authors.affiliation: Dept of Pharmacology, Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Brain Center Rudolf Magnus, Universiteitsweg 99, 3584CG Utrecht, Netherlands; Dept of Psychiatry, Yale University, School of Medicine, New Haven, CT, USA.
authors.forename: B
authors.initials: B
authors.lastname: Olivier
authors.affiliation: Dept of Pharmacology, Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Brain Center Rudolf Magnus, Universiteitsweg 99, 3584CG Utrecht, Netherlands. Electronic address: l.groenink@uu.nl.
authors.forename: L
authors.initials: L
authors.lastname: Groenink
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018682:GABA Agents / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011963:Receptors, GABA-A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D018682:GABA Agents; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D056572:Histone Deacetylase Inhibitors; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D014635:Valproic Acid; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone
keywords: CRH; Corticosterone; GABA; HDAC inhibitor; Mood stabilizer; Sensorimotor gating