Generalized Tonic Seizures Induced by a Unilateral Microinjection of Kainic Acid into the Pontine Reticular Formation in Rats

Purpose : Following Penfield and Jasper's proposal of the centrencephalic theory, the brainstem reticular formation was believed to be involved in the expression of generalized seizures and the generalization of partial seizures. In our study, an experimental animal model of generalized tonic seizures was produced by the unilateral microinjection of kainic acid (KA) into the pontine reticular formation (PRF) of Wistar rats. In addition, local cerebral glucose utilization (LCGU) was measured during the acute phase of the seizure by autoradiography by using [ 14 C]2‐deoxyglucose to determine the extent of the hypermetabolic area in the brain induced by the seizure. Methods : Under general anesthesia with sodium pentobarbital, adult male Wistar rats weighing 280–320 g were implanted stereotaxially with a chemitrode in the left PRF and a monopolar electrode in the central medial thalamic nucleus. Stainless‐steel screw electrodes for recording the electrocorticogram were placed bilaterally on the dura over the sensorimotor cortex. After ≥1 week after surgery, 0.8 kg of KA was injected into the left PRF via the chemitrode. After the injection, the electroencephalographic and behavioral consequences were observed over a period of 7 days. For the LCGU study, the rats were unrestrained for 7 days after recovery from stereotaxic surgery. They were anesthetized with 1.5% halothane, and catheters were inserted into the femoral artery and vein. They were immobilized from the waist down by means of a loosefitting plaster cast and allowed to recover from anesthesia for ≥2 h. Then KA or a phosphate buffer solution was administered into the PRF via an implanted cannula. The LCGU study described by Sokoloff et al. was started 75 min later. Results : At an average of 16.9 min after the injection, the rats began to run and jump intermittently in the recording chamber (wild running). At an average of 22.5 min after the injection, they began to assume a tonic posture in which the upper body was strongly contorted to the left or backward and the four limbs were fully extended. About 2 h after the injection, wild running ceased, but the tonic seizure status persisted. Occasionally, clonic seizures were detected in the face or limbs during tonic seizures. The tonic seizures peaked at 3–4 h after the injection and then gradually recovered, completely disappearing within 24 h. On the EEG, at an average of 50.9 min after the KA injection, a high‐amplitude spike discharge appeared in the PRF and simultaneously spread bilaterally to the sensorimotor cortex. Synchronous interictal discharges persisted for 24 h after the injection but disappeared 3 days after the KA injection. LCGU was significantly augmented bilaterally in the PRF, mesencephalic reticular formation, periaqueductal gray, superior colliculus, raphe nucleus, locus ceruleus, zona incerta, medial forebrain bundle, CA1 and CA3 fields of the hippocampus, and amygdala. LCGU was also markedly increased in the lateral and medial geniculate nuclei, lateral septa1 nucleus, ventromedial nucleus of the hypothalamus, and lateral preoptic area on the side of the KA injection. The degree of LCGU in the entorhinal cortex and piriform cortex varied greatly. Conclusions : These results suggest that the PRF plays an important role in the primary and secondary generalization of tonic seizure. The epileptic discharge passed through the medial forebrain bundle from the PRF, entered the hypothalamus and basal forebrain, and affected the limbic system. When the epileptic discharge reaches the cerebral cortex from the PRF through this route, clonic seizures may occur.