Neurobiology of Disease Chronic Valproic Acid Treatment Triggers Increased Neuropeptide Y Expression and Signaling in Rat Nucleus

Valproate (VPA) can suppress absence and other seizures, but its precise mechanisms of action are not completely understood. We investigated whether VPA influences the expression of neuropeptide Y (NPY), an endogenous anticonvulsant. Chronic VPA administra-tion to young rats (300–600 mg kg1 d1 in divided doses over 4 d) resulted in a 30–50 % increase in NPY mRNA and protein expression in the nucleus reticularis thalami (nRt) and hippocampus, but not in the neocortex, as shown by real-time PCR, radioimmu-noassay, and immunohistochemistry. No increased expressionwas observed after a single acute dose ofVPA. Chronic treatmentwith the pharmacologically inactive VPA analog octanoic acid did not elicit changes in NPY expression. No significant expression changes could be shown for themRNAsof theY1 receptororof theneuropeptides somatostatin, vasoactive intestinal polypeptide, andcholeocystokinin. Fewer synchronous spontaneous epileptiform oscillations were recorded in thalamic slices from VPA-treated animals, and oscillation duration as well as the period of spontaneous and evoked oscillations were decreased. Application of the Y1 receptor inhibitor N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-amide (BIBP3226) enhanced thalamic oscillations, indicating that NPY is released during those oscillations and acts to downregulate oscillatory strength. Chronic VPA treatment significantly potentiated the effect of BIBP3226 on oscillation duration but not on oscillation period. These results demonstrate a novel mechanism for the antiepi-leptic actions of chronic VPA therapy. Key words: epilepsy; absence seizures; spike-wave discharges; nRt; hippocampus; thalamu