Genetic comparison of seizure control by norepinephrine and neuropeptide Y

Epilepsy is a disease of neuronal hyperexcitability, and pharmacological an d genetic studies have identified norepinephrine (NE) and neuropeptide Y (N PY) as important endogenous regulators of neuronal excitability. Both trans mitters signal through G-protein-coupled receptors, are expressed either to gether or separately, and are, abundant in brain regions implicated in seiz ure generation. NPY knock-out (NPY KO) and dopamine g-hydroxylase. knock-ou t (DBH KO) mice that lack NE are susceptible to seizures, and agonists of N E and NPY receptors protect against seizures. Tb examine the relative contr ibutions of NE and NPY to neuronal excitability, we tested Dbh;Npy double k nock-out (DKO) mice for seizure sensitivity. In general, DBH KO mice were m uch more seizure-sensitive than NPY KO mice and had normal NPY expression, demonstrating that an NPY deficiency did not contribute to the DBH KO seizu re phenotype. DKO mice were only slightly more sensitive than DBH KO mice t o seizures induced by kainic acid, pentylenetetrazole, or flurothyl, althou gh DKO mice were uniquely prone to handling-induced seizures. NPY contribut ed to the seizure phenotype of DKO mice at high doses of convulsant agents and advanced stages of seizures. These data suggest that NE Is a more poten t endogenous anticonvulsant than NPY, and that NPY has the greatest contrib ution under conditions of extreme neuronal excitability.