Onset Of Maximal Dentate Activation Research Articles

Ethosuximide specifically antagonizes the effect of pentylenetetrazol in the rat entorhinal cortex.

This study tested two related hypotheses. The first is that the entorhinal cortex has an important role in synchronization and spread of epileptiform activity into the dentate gyrus. The second is that ethosuximide acts by antagonizing the action of pentylenetetrazol (PTZ) in the entorhinal cortex. Experiments were carried out in urethane anesthetized rats. Recording electrodes were placed in the dentate gyrus and stimulating electrodes were placed in the angular bundle. Administration of PTZ reduced the time to onset of maximal dentate activation, which is a marker for synchronized reverberatory seizure activity in the hippocampal-parahippocampal circuits. Since PTZ facilitates the spread of epileptiform activity in, or through, the entorhinal cortex, these results support the hypothesis that the entorhinal cortex can influence the spread of seizure activity from the entorhinal cortex into the hippocampus. Ethosuximide specifically, and dose-dependently, reduced the polysynaptic response in the dentate gyrus that is initiated by PTZ, while having no effect on the response in the dentate gyrus to ipsilateral angular bundle stimulation. These results support the hypotheses that ethosuximide can antagonize this effect of PTZ.

Valproic acid and ethosuximide slow the onset of maximal dentate activation in the rat hippocampus

Valproic acid and ethosuximide are commonly used to treat absence seizures, but their mechanisms of action have not been clearly defined. This is partly due to testing in different experimental models and different species. We re-examined the effect of valproic acid and ethosuximide in an experimental model of reverberatory seizures in the hippocampus of the urethane-anesthetized rat, maximal dentate activation. Valproic acid, at 450 and 600 mg/kg i.p., caused an increase in the time to onset of seizure discharges, but only the changes with 600 mg/kg reached statistical significance. Both doses of valproic acid shortened the seizure duration. Serum levels of valproic acid were determined and it appears that in this system at least 200–400 μg/ml are needed to produce an effect on seizure onset and duration. Ethosuximide, at 600 mg/kg i.p., delayed the onset of the seizure discharge and blocked the increase in seizure duration. Both ethosuximide and valproic acid delayed the onset of the seizure discharge in this model suggesting that these drugs may help to determine the mechanisms behind seizure initiation in the hippocampal-parahippocampal circuits.

Pharmacological characterization of the afterdischarge that precedes the onset of maximal dentate activation in the rat

Two types of afterdischarges have been recorded in the dentate gyrus after trains of electrical stimulation. The first afterdischarge contains predominantly broad positive potentials. The second afterdischarge contains bursts of large amplitude population spikes and has been termed maximal dentate activation. It has been proposed that the first afterdischarge is a precursor to maximal dentate activation and, therefore, it is termed a pre-MDA afterdischarge. The effects of several drugs on these afterdischarges were compared in adult male rats anesthetized with urethane. Stimulus trains (50 Hz) designed to elicit the pre-MDA afterdischarge were administered to the left CA3 region while recording in the ipsilateral dentate gyrus and contralateral CA1 cell layer. Phenytoin (80 mg kg ), phenobarbital (60 mg kg ), ethosuximide (300 mg kg ) and sodium valproate (300 mg kg ) had no effect on the duration or characteristics of the discharge. Carbamazepine (50–60 mg/kg) and ketamine (30 mg kg ) reversibly blocked the discharge. Diazepam (3 mg kg ) reduced the duration of the discharge and also reduced the amplitude of population spikes recorded in CA1. Baclofen (10 mg kg ) and bicuculline (0.5 mg kg ) increased the duration of the discharge. The effects of dizocilpine (MK-801, 2 mg kg ) were inconsistent. These results were compared to the effects of the same drugs on the time-to-onset and duration of maximal dentate activation. The pharmacological sensitivities of maximal dentate activation and pre-MDA discharges were found to be qualitatively different.

Amygdala stimulation produces two types of hippocampal aftercharges in the urethane-anesthetized rat

How seizures spread during epileptiform events has been the subject of intensive investigations over the years. The present study explored the relationship between the amygdala and the hippocampus during afterdischarges. Stimulating electrodes were placed in the amygdala and CA3 regions of the left side in urethane-anesthetized rats. Recording microelectrodes were placed in the dentate gyrus on the left and the CA1 cell layer on the right. Afterdischarges were elicited by stimulus trains between 10 and 50 Hz to the amygdala. Most of the afterdischarges consisted of broad positive potentials in dentate gyrus and no shift of the DC potential. When the stimulus trains were repeated, the afterdischarge evolved, first by spreading to the contralateral side and then by the appearance of maximal dentate activation. The onset of maximal dentate activation was indicated by the appearance of bursts of large amplitude population spikes and a negative shift of the DC potential. These data demonstrate that two types of afterdischarges can be produced in the hippocampus of the anesthetized rat after amygdala stimulation. The observations support the hypothesis that maximal dentate activation represents synchronized reverberatory activity throughout the hippocampal-parahippocampal circuit and indicate that amygdala stimulation can access this circuit in the anesthetized animal.

Bilateral maximal dentate activation is critical for the appearance of an afterdischarge in the dentate gyrus

Recently, a phenomenon has been described in the dentate gyrus termed maximal dentate activation, which is defined by the appearance of bursts of large amplitude population spikes associated with a negative shift of the d.c. potential and a secondary rise of the extracellular potassium level. Previous work has linked maximal dentate activation to kindling of afterdischarges, either when they are elicited in the hippocampus or outside of the hippocampus in the amygdala. Recording bilaterally in the dentate gyrus, it was found that maximal dentate activation occurred on both sides, with the side ipsilateral to the stimulus (either CA3 or angular bundle) being activated first. An afterdischarge did not appear unless bilateral maximal dentate activation had occurred. With repeated stimulation, the time to onset of maximal dentate activation on the two sides of the brain became nearly equal. This was associated with the appearance of afterdischarges. However, complete synchronization of the onset of maximal dentate activation was not necessary for afterdischarge production. Maximal dentate activation and afterdischarges could be readily elicited in rats in which the hippocampal commissures had been cut. It appears that, in the intact brain, the lack of maximal dentate activation on one side of the brain can function as a “brake” for epileptic activity, preventing afterdischarges. Once this brake is removed, by cutting the hippocampal commissures or by initiating maximal dentate activation, the dentate gyrus readily expresses afterdischarges.

Cholinergic and adrenergic agents modify the initiation and termination of epileptic discharges in the dentate gyrus

A unique type of limbic seizures, maximal dentate activation, was used to examine the effects of cholinergic and adrenergic agents on the processes involved in epileptogenesis. The time to onset of maximal dentate activation was used to monitor the initiation of seizures while the duration of maximal dentate activation monitored termination of seizures. The cholinergic agonist pilocarpine shortened maximal dentate activation at 20 mg/kg and lengthened maximal dentate activation at 50 mg/kg, while both doses delayed the onset of maximal dentate activation. Atropine, a cholinergic antagonist, at 50 mg/kg, slowed the rate of lengthening of maximal dentate activation that occurred with repeated stimulation. The β-adrenergic antagonist propranolol also slowed the rate of lengthening of maximal dentate activation at 3 mg/kg and shortened maximal dentate activation at 10 mg/kg. The α 2-agonist clonidine, at 0.5 mg/kg, shortened maximal dentate activation and increased the time to onset; at 0.1 mg/kg, clonidine did not affect maximal dentate activation. Pretreatment with reserpine had no effect on either the time to onset or duration of maximal dentate activation. These results indicate that both cholinergic and adrenergic mechanisms play important roles in the initiation and termination of limbic seizures.

Pharmacological evidence indicating a role of GABAergic systems in termination of limbic seizures

The role of inhibitory systems in the initiation and termination of seizures in limbic circuits of the rat was tested by measuring the time to onset and duration of maximal dentate activation before and after the administration of GABAergic agents. Both 0.1 and 0.3 mg/kg of the GABA A receptor antagonist bicuculline lengthened maximal dentate activation while 0.3 mg/kg was needed to reversibly decrease the time to onset. Picrotoxin, an antagonist at the GABA A receptor/channel complex, lengthened maximal dentate activation, but did not alter the time to onset. Muscimol, a GABA A receptor agonist, shortened maxiaml dentate activation, but did not lengthen the time to onset. Baclofen, a GABA B receptor agonist (3 and 10 mg/kg), had no effect on the time to onset of maximal dentate activation, while 10 mg/kg baclofen shortened maximal dentate activation. These results demonstrate that agents that have selective action at both GABA A and GABA B synapses alter the duration of maximal dentate activation more than they influence the time to onset of maximal dentate activation and suggest that GABAergic mechanisms are critical in the termination of seizures.

Maximal dentate activation: a tool to screen compounds for activity against limbic seizures

A model of partial complex (limbic) seizures in the anesthetized rat based on the phenomenon of maximal dentate activation was used to study the effect of various known antiepileptic drugs. maximal dentate activation consists of a distinct triad of large amplitude population spikes, associated with a rise in [K +] 0 to 10 mM and a negative shift of the DC potential. Repeated stimulation produces lengthening of the duration of maximal dentate activation (mimicking the lengthening of afterdischarges that occurs during kindling) and a decrease in the time to onset of maximal dentate activation. Diazepam (3 mg/kg), carbamazepine (50 mg/kg) and phenobarbital (60 mg/kg) caused a reversible reduction in the duration of maximal dentate activation. Carbamazepine (30 mg/kg) and phenobarbital (20 mg/kg) prevented the lengthening of maximal dentate activation that occurs with repeated elicitation while phenytoin (80 mg/kg), ethosuximide (300 mg/kg) and valproic acid (300 mg/kg) had no effect. The doses of these known antiepileptic drugs agree with the doses efficacious against limbic seizures in awake rats. This suggests that the ability to shorten the duration of maximal dentate activation provides a useful means to screen compounds for activity against partial complex seizures.

Maximal dentate gyrus activation: characteristics and alterations after repeated seizures.

1. The dentate gyrus was activated by trains of stimulation to either the contralateral CA3 region or the ipsilateral angular bundle. Responses were monitored with recordings of extracellular field potentials and extracellular potassium ([K+]o. Maximal dentate activation was identified by the appearance of bursts of large-amplitude (20-40 mV) population spikes associated with a secondary rise in [K+]o and an abrupt negative shift of the DC potential. 2. Several parameters were defined to characterize features of maximal dentate activation. These included 1) time to onset of maximal dentate activation, 2) duration of maximal dentate activation, 3) stimulus threshold for maximal dentate activation, 4) threshold for afterdischarge production, and 5) afterdischarge durations. The time to onset of maximal dentate activation and the duration of maximal dentate activation depended on the stimulus intensity until, above a certain stimulus intensity, both parameters reached constant values. The total period of maximal dentate activation (during both stimulation and afterdischarge) was constant. 3. The characteristics of maximal dentate activation were then determined in kindled animals and compared with age-matched controls. Kindled animals had a significant increase in the total duration of maximal dentate activation and a decrease in the ratio of afterdischarge threshold to the threshold for maximal dentate activation to 1 from a ratio in control animals of 6. 4. In a set of urethan-anesthetized animals, the characteristics of maximal dentate activation before and after 36 stimuli were determined. One hour after the last of 36 stimulus-evoked seizures, there was a trend towards a decrease in the threshold for maximal dentate activation and in the time to its onset.(ABSTRACT TRUNCATED AT 250 WORDS)