title: A damage to locus coeruleus neurons converts sporadic seizures into self-sustaining limbic status epilepticus.
abstract: 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.
authors.affiliation: Department of Neurosciences, Section of Neurology, University of Pisa, Italy.
authors.forename: Filippo S
authors.initials: FS
authors.lastname: Giorgi
authors.forename: Michela
authors.initials: M
authors.lastname: Ferrucci
authors.forename: Gloria
authors.initials: G
authors.lastname: Lazzeri
authors.forename: Chiara
authors.initials: C
authors.lastname: Pizzanelli
authors.forename: Paola
authors.initials: P
authors.lastname: Lenzi
authors.forename: Maria G
authors.initials: MG
authors.lastname: Alessandrl
authors.forename: Luigi
authors.initials: L
authors.lastname: Murri
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000633:toxicity; D001640:Bicuculline / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000032:analysis; D002531:Cerebellum / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D004347:Drug Interactions; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D018756:GABA Antagonists; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007696:Kindling, Neurologic / Q000378:metabolism*; D008125:Locus Coeruleus / Q000293:injuries* / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism; D009833:Olfactory Pathways / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D013194:Staining and Labeling; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D001596:Benzylamines; D015306:Biogenic Monoamines; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009498:Neurotoxins; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D004299:Dopamine beta-Hydroxylase; C012102:DSP 4; D009638:Norepinephrine; D001640:Bicuculline