Various studies demonstrated that the
neurotransmitter norepinephrine (NE) plays a relevant role in modulating
seizures; in particular, a powerful effect consists in delaying the kindling of limbic areas such as the amygdala and hippocampus. Given the rich NE innervation of limbic regions, we selected a sensitive trigger area, the anterior piriform cortex, to test whether previous loss of noradrenergic terminals modifies sporadic
seizures in rats. The damage to locus coeruleus terminals was produced by using the selective
neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (
DSP-4, 60 mg/kg i.p.). In intact rats,
bicuculline (a
GABA-A antagonist, 118 pmol) microinfused into this area produced sporadic
seizures, while in rats previously injected with
DSP-4,
bicuculline determined long-lasting self-sustaining
status epilepticus. In intact rats, sporadic
seizures were accompanied by a marked increase in
norepinephrine release in the contralateral piriform cortex, while in locus coeruleus-lesioned rats this phenomenon was attenuated. While
bicuculline-induced sporadic
seizures were prevented by the focal infusion of amino-7-phosphonoheptanoic
acid (
AP-7, a selective
NMDA antagonist), or 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-
benzo[f]quinoxaline-7-sulphonamide (
NBQX, a selective non-
NMDA antagonist),
status epilepticus obtained in
norepinephrine-lesioned rats was insensitive to
AP-7 but was still inhibited by
NBQX. By using fluorescent staining for damaged (
Fluoro-Jade B) and intact (
DAPI) neurons, as well as
cresyl violet, we found that rats undergoing
status epilepticus developed neuronal loss in various limbic regions. This study demonstrates a powerful effect of noradrenergic terminals in regulating the onset of limbic
status epilepticus and its sensitivity to specific
glutamate antagonists.