Evidence for a norepinephrine-dependent brain-stem substrate in the development of kindling antagonism

Abstract

Kindling antagonism' is a modification of the standard kindling paradigm in which two limbic system structures are stimulated on alternate trials. The consistent outcome of this procedure is that one site ('dominant site') develops typical generalized seizures, while kindled seizure development from the other site ('suppressed site') is arrested at an intermediate stage. Our recent research suggests that kindling antagonism is dependent on hindbrain norepinephrine (NE) systems. The present study explores this relationship further. Neonatal rats were treated with intracerebral injections of 6-hydroxydopamine (6-OHDA). At adulthood, these animals received either (1) a low dose of 6-OHDA (75 micrograms), (2) a high dose of 6-OHDA (200 micrograms), or (3) vehicle. Regional NE concentrations were determined by high pressure liquid chromatography. Neonatal 6-OHDA followed by vehicle resulted in decreases in forebrain and increases in hindbrain NE concentrations. Low dose 6-OHDA at adulthood depleted cerebellar, but not pontine-medullary NE. High dose 6-OHDA resulted in depletions of both cerebellar and pontine-medullary NE. Only high dose 6-OHDA significantly interfered with the development of antagonism. Neonatal 6-OHDA facilitated the rate of dominant site kindling independently of subsequent adult treatment regimens. Results suggest that the influence of NE on kindling antagonism is mediated through a brain-stem substrate and that the influence of NE on kindling rate is mediated through a forebrain substrate.