Serotonergic Modulation of Absence-Like Seizures in Groggy Rats: a Novel Rat Model of Absence Epilepsy

Abstract

Abstract.To explore the role of the serotonergic system in modulating absence seizures, we examined the effects of 5-HT 1A and 5-HT 2 agonists on the incidence of spike-and-wave discharges (SWD) in Groogy (GRY) rats, a novel rat model of absence-like epilepsy. GRY rats exhibited spontaneous absence-like seizures characterized by the incidence of sudden immobile posture and synchronously-associated SWD. The total duration of SWD in GRY rats was about 300 -400 s/15-min observation period under the control conditions. However, the incidence of SWD was markedly reduced either by the 5-HT 1A agonist (±)-8-hydroxy-2-(di-n-propylamino)-tetralin [(±)8-OH-DPAT] or the 5-HT 2 agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI]. The 5-HT reuptake inhibitors, fluoxetine and clomipramine, also inhibited the SWD generation. In addition, the inhibitory effects of (±)8-OH-DPAT and (±)DOI were reversed by WAY-100135 (5-HT 1A antagonist) and ritanserin (5-HT 2 antagonist), respectively. The present results suggest that the serotonergic system negatively regulates the incidence of absence seizures by stimulation of 5-HT 1A and 5-HT 2 receptors.

Expressional Analysis of Inwardly Rectifying Kir4.1 Channels in Groggy Rats, a Rat Model of Absence Seizures

“…ethosuximide and sodium valproate), but not by phenytoin, which lacks anti-absence activity (24). In the present study, we confirmed the incidence of absence-like seizures in Groggy rats, of which the frequency and duration for absence-like seizures were similar to those reported previously (23,25). Since Groggy rats frequently exhibited absence-like seizures, expression analysis in the present study seems to reflect the Kir levels under an ictal state.…”

“…Therefore, in the present study, we performed Western blot analysis for Kir4.1 and Kir5.1 subunit expression using the Groggy rat, a newly developed animal model of absence seizures (23)(24)(25), to clarify the pathophysiological alterations of astrocytic Kir channels in absence seizures. The expressional level of the Kir2.1 subunit was evaluated since Kir2.1 channels are also known to be expressed in astrocytes even at low density (26,27).…”

“…Surgical procedures for the electrode implantation and EEG recordings were performed as described previously (23,28). Groggy rats (n = 4) were anesthetized with pentobarbital (40 mg/kg, i.p.)…”

Unbalanced Peptidergic Inhibition in Superficial Neocortex Underlies Spike and Wave Seizure Activity

“…The location and immunocytochemical profile of the two interneuron subtypes linked to SpW here indicate neurons that receive both serotoninergic and nicotinergic excitation (Porter et al, 1999;Férézou et al, 2002), suggesting that the pharmacological models of SpW were selectively targeting these cells. The connection to nicotinic receptors links these cells to a great deal of prior work on specific epilepsy syndromes (Fonck et al, 2005), and a less well precedented link between SpW epilepsies and serotonin neuromodulation (Ohno et al, 2010). However, the seemingly differential role of the two interneuron subtypes studies does not begin to make sense unless their different peptidergic components are taken into account.…”

Pharmacokinetic/pharmacodynamic considerations for epilepsy – depression comorbidities

“…However, another experiment showed that acute, but not chronic fluoxetine at higher doses (15-25 mg/kg) increased this threshold in mice [13,14]. Fluoxetine also suppressed tonic hindlimb extension in the rat MES model and inhibited spike-and-wave discharges (SWD) in Groogy rats, a model of absence-like epilepsy [86,87]. Dietary fluoxetine (10 mg/kg for 7 days) reduced seizures in the El mouse model of genetically predisposed/handling-triggered epilepsy [88].…”