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The Journal of Neuroscience, October 1, 2001, 21(19):7764-7769

Genetic Comparison of Seizure Control by Norepinephrine and Neuropeptide Y

David Weinshenker^{1, 2}, Patricia Szot^{3, 4}, Nicole S. Miller^{1, 2}, Nicole C. Rust^{1, 2}, John G. Hohmann⁵, Ujwal Pyati², Sylvia S. White^{3, 4}, and Richard D. Palmiter^{1, 2}

Departments of ¹ Howard Hughes Medical Institute, ² Biochemistry, ³ Psychiatry and Behavioral Science, ⁴ Geriatric Research, Education, and Clinical Center, and ⁵ Program for Neurobiology and Behavior, University of Washington, Seattle, Washington 98195

Epilepsy is a disease of neuronal hyperexcitability, and pharmacological and genetic studies have identified norepinephrine (NE) and neuropeptide Y (NPY) as important endogenous regulators of neuronal excitability. Both transmitters signal through G-protein-coupled receptors, are expressed either together or separately, and are abundant in brain regions implicated in seizure generation. NPY knock-out (NPY KO) and dopamine -hydroxylase knock-out (DBH KO) mice that lack NE are susceptible to seizures, and agonists of NE and NPY receptors protect against seizures. To examine the relative contributions of NE and NPY to neuronal excitability, we tested Dbh;Npy double knock-out (DKO) mice for seizure sensitivity. In general, DBH KO mice were much more seizure-sensitive than NPY KO mice and had normal NPY expression, demonstrating that an NPY deficiency did not contribute to the DBH KO seizure phenotype. DKO mice were only slightly more sensitive than DBH KO mice to seizures induced by kainic acid, pentylenetetrazole, or flurothyl, although DKO mice were uniquely prone to handling-induced seizures. NPY contributed 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 potent endogenous anticonvulsant than NPY, and that NPY has the greatest contribution under conditions of extreme neuronal excitability.

Key words: norepinephrine; NPY; dopamine -hydroxylase; mice; epilepsy; seizure; pentylenetetrazole; flurothyl; kainic acid; mice; knock-out; in situ hybridization; neurotransmitter

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21197764-06$05.00/0

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