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.

Previous exposure to (±) 3,4-methylenedioxymethamphetamine produces long-lasting alteration in limbic brain excitability measured by electroencephalogram spectrum analysis, brain metabolism and seizure susceptibility

“…However, in mice, 5HT loss is milder, while a severe DA depletion occurs, as described in detail by the Colado's group (Colado et al, 2001) and shown by other studies (Stone et al, 1987;Logan et al, 1988;Ali et al, 1991;Cadet et al, 1995;Fornai et al, 2001Fornai et al, , 2004b. Both monoamines might modulate seizures (see, for instance, Pasini et al, 1996;Starr, 1996;Heisler et al, 1998;Torta and Monaco, 2002;Giorgi et al, 2003Giorgi et al, , 2004. However, this is unlikely to occur in the present study.…”

Locus Coeruleus and Neuronal Plasticity in a Model of Focal Limbic Epilepsy

“…Limbic structures are widely innervated by LC noradrenergic fibers, and among them the olfactory cortex and hippocampus are particularly rich in NE terminals (Fallon and Moore, 1978;Giorgi et al, 2003, and the present data). In models of limbic seizures the loss of NE was shown to modulate significantly seizure incidence and susceptibility (Weinshenker and Szot, 2002;Giorgi et al, 2004).…”

“…NE fibers originating from the nucleus Locus Coeruleus (LC) innervate profusely the whole cortex, and particularly the olfactory cortex (Fallon and Moore, 1978;Giorgi et al, 2003, and the present data).…”

Assessment of Brain Monoaminergic Signaling Through Mathematical Modeling of Skin Conductance Response

“…This refers to a different role of the LC activation that could lie in a feedback effect upon the higher brain structures. Indeed, it was shown that the noradrenegic projections from the LC have inhibitory influence on the kindling effect in the amygdala and the hippocampus (Giorgi et al, 2003). Beside that, the neurons in the amygdala that had been inhibited by the stimulation of the carotid sinus and baroreceptors were also inhibited by the stimulation of the LC (Schätze et al, 1987).…”