Michael E. Corcoran

Role of forebrain catecholamines in amygdaloid kindling

The rate and pattern of seizure development provoked by repeated electrical stimulation of the amygdala (kindling) was assessed in rats that had been pretreated with intracerebral injections of the selective catecholaminergic neurotoxin 6-hydroxy-dopamine. Rats with selective depletion of forebrain noradrenaline displayed a highly significant facilitation of both primary-site and secondary-site kindling, whereas no such effect occurred in rats with selective depletion of forebrain dopamine. The facilitative effects of noradrenaline depletion were apparently related to disinhibition of the spread of seizure discharge from the stimulated site rather than to increased epileptogenicity in the stimulated site itself. These results are consistent with previous evidence that noradrenaline reduces the susceptibility of the central nervous system to epileptiform activity, and they suggest that a lessening of seizure-suppressant noradrenergic function in the forebrain might be part of the mechanism underlying kindling.

Epileptiform effects of met-enkephalin, β-endorphin and morphine: Kindling of generalized seizures and potentiation of epileptiform effects by handling

Repeated spaced injection of small amounts of beta-endorphin or Met-enkephalin into the hippocampus or posterior amygdala of the rat led to the development of kindled generalized convulsions. Similar injection of morphine into the hippocampus or anterior amygdala resulted in epileptiform spiking followed by tolerance. The epileptiform spiking and convulsive behavior varied in a dose-related manner. Naloxone blocked or greatly attenuated the electrographic seizure and convulsive behavior. Prior kindling with beta-endorphin or Met-enkephalin significantly facilitated electrical kindling of the amygdala. Handling or conspecific threat potentiated the epileptiform spiking and convulsive behavior in some cases. The results indicate that the epileptogenic response to intracerebrally applied opioid peptides is site-specific within the rat brain, and they support the idea that endogenous opioid mechanisms may play a role in convulsive seizures. They also suggest a possible opiate-based mechanism for the stress-induced exacerbation of seizures.

Depletion of noradrenaline fails to affect kindled seizures

Convulsive seizures were kindled in rats by repeated stimulation of the amygdala, and the subjects then received intracerebral injections of 6-hydroxydopamine into the dorsal noradrenergic bundle. Although this treatment severely depleted noradrenaline, there was no effect on the intensity or duration of seizures, suggesting that noradrenaline does not regulate kindled seizures when they have developed.

Antagonism of central but not peripheral cholinergic receptors retards amygdala kindling in rats.

The effects of antagonism of muscarinic cholinergic receptors on the development of seizures produced by electrical stimulation of the amygdala (kindling) were assessed in three experiments. Rats pretreated with the muscarinic antagonist scopolamine developed seizures more slowly than did untreated rats. Whereas scopolamine retarded the development of seizures in a dose-dependent manner, it did not affect the intensity or duration of seizures when administered to kindled control rats. Pretreatment with methylscopolamine, a quaternary derivative of scopolamine that does not readily cross the blood-brain barrier, did not affect the rate of development of seizures, nor did it affect established seizures. Thus the prophylactic effects of scopolamine are produced in the central nervous system and not in the periphery. The results from these experiments are consistent with the idea that central cholinergic or cholinoceptive neurons are critically involved in amygdala kindling.

Antikindling effects of locus coeruleus stimulation: Mediation by ascending noradrenergic projections

Electrical stimulation of the noradrenergic locus coeruleus (LC) delays the generalization of partial seizures during amygdaloid kindling by increasing the time spent in the earliest stages of seizure development. To determine whether noradrenergic axons projecting to the midbrain and forebrain are involved in this antikindling effect, we examined the effects of lesions of the dorsal noradrenergic bundle, induced by intracerebral infusions of 6-hydroxydopamine (6-OHDA), on kindling and the antikindling action of stimulation of the LC. Stimulation of the LC during amygdaloid kindling increased the number of afterdischarges (ADs) spent in the early stages of partial seizure and decreased the number of ADs spent in later stages of generalized seizure, as has been described previously. LC-stimulated rats also displayed longer durations of AD during early stages of kindling. The antikindling effect of LC stimulation was blocked by lesions of the dorsal bundle, whereas the facilitatory effects of LC stimulation on generalization and on the duration of AD were unaffected by the lesions. These results suggest that the antikindling action of LC stimulation is mediated by the ascending projections of noradrenergic neurons, presumably through enhanced release of noradrenaline. On the other hand, the facilitatory effects of LC stimulation on the development of later stages of seizure and on the duration of AD appear to be independent of the ascending dorsal bundle.

Naloxone and the kindling of seizures.

Abstract In view of evidence indicating that endogenous opiate-like peptides have epileptiform effects, we examined the effect of the opiate antagonist naloxone on the kindling of seizures produced by repeated electrical stimulation of the amygdala or the caudate nucleus in rats. Naloxone had no effect on the threshold for local after-discharge in the two areas and failed to retard the rate of kindling of clinical seizures. These results suggest that an interaction of opiate-like peptides with central opiate receptors does not play any critical role in the kindling of seizures.

Kindling of hippocampal field CA1 impairs spatial learning and retention in the Morris water maze

We used two procedures to assess the spatial learning and memory of rats in the Morris water maze task subsequent to kindling of hippocampal field CA1: (1) seizures were kindled with stimulation of CA1 prior to training in the water maze (acquisition); and (2) maze training was imposed until performance stabilized, seizures were kindled with stimulation of CA1, and then performance in the maze was reassessed (retention). In both conditions, behavioral testing occurred 24 h after the last kindled seizure. When the effects of CA1 kindling on acquisition were tested, we found that kindling of generalized seizures with stimulation of field CA1 (kindling), but not kindling of non-convulsive or partial seizures (partial kindling), produced deficits in the water maze. When the effects of CA1 kindling on retention were tested, however, we found that kindling of either partial or generalized seizures produced deficits in the water maze. The results suggest that the processing of spatial information is vulnerable to the long-lasting changes in neural excitability associated with kindling.

Limbic seizures, but not kindling, reversibly impair place learning in the Morris water maze

We investigated the effects of kindling and kindled seizures in different limbic structures on place and cue learning in the Morris water maze. The triggering of seizures by stimulation of the perforant path, septum, or amygdala prior to daily training impaired place learning, but had little effect on visible platform training or swim speed. Seizures triggered by stimulation of the medial perforant path after daily training also impaired place learning. Conversely, place learning proceeded normally in rats tested 24 h after kindling triggered by stimulation of the perforant path, septum, or amygdala, indicating that kindling per se does not affect place learning. Each group was able to learn the location of a reversed platform when pretraining seizures were discontinued; and perforant path and septal kindled rats, but not amygdaloid kindled rats, were impaired at learning the location of a reversed platform when seizures were triggered before training. The results confirm previous reports that limbic seizures produce amnesia, but they contradict the finding that hippocampal kindling impairs learning on tasks sensitive to hippocampal lesions.

Relations between amygdaloid and anterior neocortical kindling

Primary kindling of generalized seizures with amygdaloid stimulation facilitated the subsequent kindling of generalized seizures with neocortical stimulation. Similarly, initial kindling of generalized seizures with anterior neocortical stimulation facilitated the kindling of generalized amygdaloid seizures. Unexpectedly, there were striking differences in the reliability with which seizures could be triggered by amygdaloid and neocortical stimulation. The results support the idea that there is a single mechanism that is responsible for seizure generalization.

Kindling of seizures with low-frequency electrical stimulation

Repeated application of electrical stimulation to the amygdala at a frequency of 3 Hz resulted in the development of afterdischarge and behavioral seizures. The rate of low-frequency kindling was faster than that of kindling with conventional 60 Hz stimulation, but the form of the seizures kindled with the two frequencies of stimulation was identical. Low-frequency kindling was obtained only when pulses of sufficient duration and intensity were administered.