ABSTRACT
Convulsive seizures triggered by maximal electroshock (MES) induce profound abnormalities in neural regulation of cardiac rhythm that are manifested by a period of marked cardiac arrhythmia in the immediate postictal state. It is not known whether seizure severity or seizure experience may influence the duration of cardiac arrhythmia in the postictal state. We varied the duration of MES administered to rats to vary seizure severity, as measured by the extensor to flexion (E/F) ratio. In separate experiments, rats were subjected to daily MES. Finally, we pretreated rats with ketamine prior to MES to block seizures hindlimb extension. In all animals, the R-R interval was plotted on the tachogram, and the duration of the arrhythmia was measured. Increases in MES duration increased significantly the E/F ratio and prolonged significantly the postictal cardiac arrhythmia. Repetition of MES caused a kindling effect with respect to seizure severity resulting in a significant increase of the E/F ratio and significant increases in the duration of postictal arrhythmia. Blocking of the hindlimb extension by ketamine abolished arrhythmia suggesting that the arrhythmia is not caused directly by MES. Severity of tonic convulsive seizures is a determinant of disordered cardiac autonomic regulation and directly influences the duration of cardiac arrhythmia during the immediate postictal state following MES. Seizure repetition also increases abnormalities of postictal neural regulation of the heart, but further studies are needed to determine whether this effect is independent of seizure severity increases.
Subject(s)
Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/physiopathology , Electroshock/adverse effects , Seizures/physiopathology , Animals , Disease Progression , Electrocardiography , Electrodes, Implanted , Electroencephalography , Hindlimb/physiopathology , Ketamine/pharmacology , Kindling, Neurologic , Male , Rats , Rats, Sprague-Dawley , Seizures/etiology , Severity of Illness IndexABSTRACT
Recent studies suggest that the deep layers of superior colliculus (DLSC) play a role in the network for audiogenic seizures (AGS) in genetically epilepsy-prone rats (GEPR-9s). The present study examined the role of glutamatergic and noradrenergic receptors in DLSC in modulation of AGS susceptibility. The study examined effects of a competitive NMDA receptor antagonist [dl-2-amino-7-phosphonoheptanoic acid (AP7)] or an alpha1 noradrenergic agonist (phenylephrine) focally microinjected into DLSC as compared to effects in the inferior colliculus (IC) and pontine reticular formation (PRF), which are major established components of the AGS network. The results demonstrated that blockade of NMDA receptors in DLSC suppressed AGS susceptibility. AP7 microinjection was effective at relatively low doses in IC, but required higher doses in DLSC and PRF. The DLSC was relatively more sensitive to seizure reduction by the alpha1 noradrenergic agonist as compared to the IC and PRF. The anticonvulsant effect of AP7 was longer-lasting than phenylephrine in the DLSC and IC but not in the PRF. These data suggest that neurons in the DLSC are a requisite component for the neuronal network for AGS in GEPR-9s and that NMDA and alpha1 adrenoreceptors in this site may play important roles in the modulation of AGS propagation. The relatively greater sensitivity of DLSC to phenylephrine as compared to IC and PRF indicates that norepinephrine may be more important in the modulation of AGS in DLSC, which contrasts to the role of glutamate modulation. These data support recent neuronal recording data, which indicate that DLSC neurons play a critical role in AGS.
Subject(s)
Epilepsy/physiopathology , Receptors, Adrenergic/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Superior Colliculi/chemistry , Superior Colliculi/physiopathology , 2-Amino-5-phosphonovalerate/analogs & derivatives , 2-Amino-5-phosphonovalerate/pharmacology , Acoustic Stimulation , Adrenergic alpha-Agonists/pharmacology , Animals , Excitatory Amino Acid Antagonists/pharmacology , Female , Glutamic Acid/physiology , Inferior Colliculi/chemistry , Inferior Colliculi/physiopathology , Male , Microinjections , Norepinephrine/physiology , Phenylephrine/pharmacology , Rats , Rats, Mutant Strains , Reticular Formation/chemistry , Reticular Formation/physiopathologyABSTRACT
Previous studies have implicated a decreased efficacy of GABA as an important defect subserving the audiogenic seizures of the genetically epilepsy-prone rat (GEPR-9). The inferior colliculus (IC) is a critical site for audiogenic seizure (AGS) initiation, and the pontine reticular formation (PRF) is implicated in the propagation of AGS and in other generalized seizure models. The present study observed that microinjection of baclofen, a GABA-B receptor agonist, into IC protects against AGS, and blockade of the breakdown of endogenous GABA by gabaculine, a GABA transaminase inhibitor, increased GABA levels and blocked AGS susceptibility in the GEPR-9. Microinjection of baclofen or gabaculine into the PRF reduced AGS severity, but the doses required were considerably greater and the degree of anticonvulsant effect was less. Uptake of [3H]GABA into GEPR-9 synaptosomes from the IC is significantly increased as compared to normal, which could contribute to the diminished effectiveness of GABA in the GEPR-9. Previous studies indicate that GABA-A receptor agonists block AGS with IC microinjection, and recent data indicate that blockade of GABA uptake in this nucleus significantly reduced AGS severity. These data taken together strongly support the critical importance of the defect in GABA function in the IC in modulating susceptibility to audiogenic seizure initiation in the GEPR-9.
