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The Journal of Neuroscience, December 15, 1999, 19(24):10985-10992

Norepinephrine-Deficient Mice Have Increased Susceptibility to Seizure-Inducing Stimuli

Patricia Szot^{1, 6}, David Weinshenker^{2, 5}, Sylvia S. White¹, Carol A. Robbins³, Nicole C. Rust^{2, 5}, Philip A. Schwartzkroin^{3, 4}, and Richard D. Palmiter^{2, 5}

Departments of ¹ Psychiatry and Behavioral Science, ² Biochemistry, ³ Neurological Surgery, and ⁴ Physiology/Biophysics and ⁵ Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, and ⁶ GRECC, Puget Sound Health Care System, Seattle, Washington 98108

Several lines of evidence suggest that norepinephrine (NE) can modulate seizure activity. However, the experimental methods used in the past cannot exclude the possible role of other neurotransmitters coreleased with NE from noradrenergic terminals. We have assessed the seizure susceptibility of genetically engineered mice that lack NE. Seizure susceptibility was determined in the dopamine -hydroxylase null mutant (Dbh /) mouse using four different convulsant stimuli: 2,2,2-trifluroethyl ether (flurothyl), pentylenetetrazol (PTZ), kainic acid, and high-decibel sound. Dbh / mice demonstrated enhanced susceptibility (i.e., lower threshold) compared with littermate heterozygous (Dbh +/) controls to flurothyl, PTZ, kainic acid, and audiogenic seizures and enhanced sensitivity (i.e., seizure severity and mortality) to flurothyl, PTZ, and kainic acid. c-Fos mRNA expression in the cortex, hippocampus (CA1 and CA3), and amygdala was increased in Dbh / mice in association with flurothyl-induced seizures. Enhanced seizure susceptibility to flurothyl and increased seizure-induced c-fos mRNA expression were reversed by pretreatment with L-threo-3,4-dihydroxyphenylserine, which partially restores the NE content in Dbh / mice. These genetically engineered mice confirm unambiguously the potent effects of the noradrenergic system in modulating epileptogenicity and illustrate the unique opportunity offered by Dbh / mice for elucidating the pathways through which NE can regulate seizure activity.

Key words: dopamine -hydroxylase; c-fos mRNA; norepinephrine; flurothyl; epilepsy; seizure; kainic acid

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Copyright © 1999 Society for Neuroscience  0270-6474/99/192410985-08$05.00/0

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