Anticonvulsant effect of enhancement of noradrenergic transmission in the superior colliculus in genetically epilepsy-prone rats (GEPRs): a microinjection study.

An expanding body of data has indicated that the seizure prone state in genetically epilepsy-prone rats (GEPRs) is partially caused by deficits in central nervous system noradrenergic transmission. Several lines of evidence suggest that the noradrenergic terminals in the superior colliculus (SC) may act as determinants of seizure predisposition in the GEPR. In order to assess the role of the noradrenergic transmission in the SC in the regulation of seizure severity, several drugs with different mechanisms of enhancing noradrenergic transmission were bilaterally microinfused into the SC of GEPR-9s (severe seizure GEPRs). The rats were tested for audiogenic seizure intensity at 0.25, 1, 2, 3, and 4 h after treatments. Bilateral infusion of vehicle produced no reduction in the severity of the audiogenic seizure. Desipramine (2, 4, 8 micrograms/side), nisoxetine (2, 4, 8 micrograms/side), and idazoxan (0.25, 1, 4 micrograms/side) all decreased the seizure severity in a dose-dependent fashion. Significant decreases in the seizure severity were also observed after administration of methoxamine (0.15 microgram/side) or phenylephrine (0.15 microgram/side). Pretreatment with prazosin (1 microgram/side) significantly diminished the anticonvulsant effectiveness of methoxamine and nisoxetine while prazosin, by itself, had no effects on the seizure intensity. These results suggest that noradrenergic transmission in the SC may be involved in the seizure regulation in GEPR-9s, and that this regulation may be mediated, at least in part, through alpha 1 receptors.

Neurite extension of developing noradrenergic neurons is impaired in genetically epilepsy-prone rats (GEPR-3s): an in vitro study on the locus coeruleus.

A primary determinant of seizure susceptibility and severity in genetically epilepsy-prone rats (GEPRs), is a generalized deficiency in the central noradrenergic system of these animals. In particular, this deficiency includes reduced numbers of norepinephrine (NE) synaptic terminals in several brain areas and distinctly fewer NE axons within the auditory tectum. Two strains of GEPRs have been developed: GEPR-3s that have moderately severe clonic seizures and GEPR-9s that have severe tonic seizures culminating in complete hindlimb extension. Seizures in animals of each substrain are preceded by a brief episode of wild running. The developmental profile of NE axonal growth in GEPRs compared to control rats is not known, but may be causally related to NE deficiencies in this seizure model. The present study compared developmental neurite extension of fetal NE neurons in vitro between GEPR-3s and Sprague-Dawley control rats, the strain from which GEPR-3s were originally derived. Neurite arborization of individual NE neurons was assessed by quantitative morphometry following immunocytochemical identification of tyrosine hydroxylase (TH). Preliminary studies using explant and dispersed-cell cultures of control-rat tissues showed that optimal culture parameters to support neuritogenesis of LC neurons included the use of dispersed-cell cultures, Pronectin-F substrate, day-14 gestation donor-tissue, no use of cytosine-arabinofuranoside (ARA-c, a glial mitotic inhibitor) and the presence of co-cultured tectal tissue. Compared to fetal control-rat NE neurons co-cultured with fetal control-rat tectum, NE neurons derived from fetal GEPR-3 LC in co-culture with GEPR-3 tectum exhibited only 30% of the neurite extension of control-rat LC neurons and GEPR-3 LC neurons had a similarly deficient amount of branching. This study suggests, but does not prove, that deficiency in tectal NE in GEPR-3s involves a developmental deficiency in neurite extension from GEPR-3 LC neurons. Hypothetically, this deficiency may also contribute to the well described NE deficiency in other regions of the adult GEPR brain.