Valproic acid improves prepulse inhibition deficits in mice over-expressing corticotropin-releasing factor independent of GABA-A and GABA-B receptor activation

Corticotropin-releasing factor (CRF) is implicated in the induction, exacerbation and expression of psychotic symptoms in schizophrenia and bipolar disorder. These disorders are characterized by deficits in prepulse inhibition (PPI) of the acoustic startle response (a measure of sensorimotor gating); that is, a compromised ability to filter extraneous sensory stimuli. Since mood stabilizers are therapeutically useful for treating psychotic states like bipolar disorder, we evaluated the influence of mechanisticallydistinct mood stabilizers (lithium, carbamazepine, lamotrigine, topiramate and valproate) on the sensorimotor gating deficits displayed by transgenic mice over-expressing CRF. Valproic acid (60-240mg/kg ip) was the only drug that significantly improved, and at the highest dose completely restored, disrupted PPI in CRF transgenics. The most prominent difference in mechanism of action between valproic acid and the other mood stabilizers is its enhancement of GABAergic transmission. However, in follow-up experiments, the beneficial effects of valproic acid could not be antagonized by the GABA-A receptor antagonist bicuculline (5mg/kg ip), nor by the GABA-B receptor antagonist phaclofen (15mg/kg ip), nor by combined administration of these agents. Interestingly, however, the GABA-B receptor agonist baclofen significantly improved impaired sensorimotor gating in CRF transgenic mice when given alone. In conclusion, the present findings implicate that the effects of valproic acid cannot simply be attributed to increased GABAergic transmission. Furthermore, the beneficial actions of baclofen suggest that the detrimental actions of CRF on PPI may be related to adaptive changes in GABAergic transmission.