Motor Seizure Duration Research Articles

Lack of robust anticonvulsant effects of muscimol microinfusions in the anterior substantia nigra of kindled rats

The substantia nigra pars reticulata is thought to control the spread of seizures in various seizure models. Potentiation of γ-aminobutyrate (GABA)-mediated transmission in this region by intranigral administration of drugs such as muscimol has been shown to inhibit seizure propagation in such models, including the kindling model of epilepsy. More recent studies have shown that the effects on seizures are site-specific within the substantia nigra pars reticulata. Using flurothyl to induce clonic seizures, it was reported that bilateral microinfusions of muscimol into the anterior substantia nigra pars reticulata were anticonvulsant, while similar infusions into the posterior pars reticulata were proconvulsant. This prompted us to reevaluate the effects of intranigral muscimol in the kindling model with particular emphasis on the anterior substantia nigra pars reticulata. In amygdala kindled rats, muscimol was bilaterally infused into the anterior pars reticulata at doses of either 60 or 120 ng. Thirty minutes later, the threshold for induction of afterdischarges in the amygdala and the threshold for generalized seizures were determined in each rat. Furthermore, severity and duration of seizures at threshold currents were recorded. Unexpectedly, muscimol failed to increase seizure thresholds or to significantly reduce seizure severity or duration of motor seizures, although there was a moderate reduction in motor seizure duration in several rats. The data indicate that, in contrast to flurothyl seizures, in kindled rats the anterior pars reticulata of the substantia nigra is not a site at which muscimol causes robust anticonvulsant effects.

Combining nefazodone and midazolam during ECT

We report the case of a patient suffering from dysthymia. He underwent successful ECT treatment and was medicated with nefazodone and midazolam. Comparing the EEG and motor seizure duration in the periods with and without midazolam, no significant differences were recorded, but the dosage of thiopental and of succinylcholine had to be increased markedly after midazolam was discontinued ( P < 0.05; ANOVA). This case indicates a substantial pharmacodynamic interaction between nefazodone, midazolam, thiopental, and succinylcholine.

Acute hemodynamic responses to electroconvulsive therapy are not related to the duration of seizure activity

Study Objective: To test the hypothesis that the magnitude of the acute hemodynamic response to electroconvulsive therapy (ECT) is related to the duration of the seizure activity in patients receiving different dosages of intravenous (IV) lidocaine. Design: Randomized, double-blind, placebo-controlled, cross-over study. Setting: University-affiliated hospital. Patients: 21 ASA physical status I, II, and III patients undergoing four consecutive maintenance ECT treatments for chronic depression. Interventions: Patients received lidocaine 50 mg, 100 mg, 200 mg IV, or saline prior to induction of anesthesia via a standardized anesthetic technique. Measurements and Main Results: Noninvasive blood pressure (BP) and heart rate (HR), as well as the duration of motor and electroencephalographic (EEG) seizure, were measured. The duration of motor and EEG seizures (means ± SD) were 37 ± 13 sec and 64 ± 21 sec, 25 ± 11 sec and 52 ± 43 sec, 17 ± 12 sec and 32 ± 17 sec, 1 ± 3 sec and 18 ± 10 sec in the saline, lidocaine 50 mg, 100 mg, 200 mg groups, respectively. Although the duration of seizure activity was decreased in a dose-related fashion after lidocaine pretreatment, the peak increases in BP and HR were similar in the lidocaine and saline treatment groups. Conclusions: Despite producing dose-related decreases in the duration of both motor and EEG seizure activity, lidocaine failed to attenuate the acute hemodynamic response to ECT. Thus, the acute hemodynamic response to ECT is not related to the duration of seizure activity.

Effect of methohexitone and propofol with or without alfentanil on seizure duration and recovery in electroconvulsive therapy

We have studied the effects of methohexitone and propofol with and without alfentanil on seizure duration and recovery in this observer-blinded, prospective, randomized, crossover study involving 24 patients undergoing electroconvulsive therapy (ECT). Each patient had four treatment sessions, and received the following four i.v. regimens in random order: methohexitone 0.75 mg kg-1, methohexitone 0.50 mg kg-1 and alfentanil 10 micrograms kg-1, propofol 0.75 mg kg-1, propofol 0.50 mg kg-1 and alfentanil 10 micrograms kg-1. Additional methohexitone or propofol was given as needed in 10-20-mg increments until loss of consciousness. Suxamethonium 1.0 mg kg-1 i.v. was given for muscular paralysis. Mean motor and EEG seizure durations were longer with methohexitone-alfentanil (44.7 (SD 15.0) and 70.5 (29.7) s) than with methohexitone (37.6 (12.6) and 52.6 (15.3) s) and similarly, seizures were longer with propofol-alfentanil (36.8 (15.2) and 54.5 (20.9) s) than with propofol alone (27.2 (11.9) and 39.2 (3.9) s). Seizures were longest with methohexitone-alfentanil and shortest with propofol. Recovery time was statistically shorter in patients receiving propofol compared with methohexitone-alfentanil and methohexitone alone. Alfentanil with a reduced dose of methohexitone or propofol provided unconsciousness and increased seizure duration in patients undergoing ECT. We conclude that the combination of methohexitone with alfentanil is a good regimen for ECT, especially for patients with short seizure duration.

The Comparative Effects of Methohexital, Propofol, and Etomidate for Electroconvulsive Therapy

The intravenous anesthetics which are commonly used for electroconvulsive therapy (ECT) possess dose-dependent anticonvulsant properties. Since the clinical efficacy of ECT depends on the induction of a seizure of adequate duration, it is important to determine the optimal dose of the hypnotic for use during ECT. We compared the duration of seizure activity and cognitive recovery profiles after different doses of methohexital, propofol, and etomidate administered to induce hypnosis prior to ECT. Ten outpatients with major depressive disorders receiving maintenance ECT participated in this prospective, randomized, cross-over study. Patients were premedicated with glycopyrrolate, 0.2 mg intravenously (i.v.), and labetalol, 20-30 mg i.v., and hypnosis was induced with an i.v. bolus injection of methohexital or propofol (0.75, 1.0, and 1.5 mg/kg), or etomidate (0.15, 0.2, and 0.3 mg/kg), administered over 10-15 s. Adequate muscle paralysis was achieved with succinylcholine, 1.0-1.4 mg/kg i.v. Each patient's seizure threshold was determined prior to enrollment in the study and the electrical stimulus variables were kept constant throughout the study period. After delivery of a bilateral electrical stimulus, the duration of the resulting electroencephalographic (EEG) and motor seizures were recorded. A total of 90 ECT treatments were evaluated. The durations of EEG and motor seizures were longest after etomidate and shortest after propofol. There were no significant dose-related differences in motor and EEG seizure durations (means +/- SD) after the low, intermediate, and high doses of etomidate of 44 +/- 11 and 77 +/- 19, 43 +/- 10 and 76 +/- 34, 42 +/- 16 and 78 +/- 56 s, respectively. Conversely, both methohexital and propofol, 0.75, 1.0, and 1.5 mg/kg, produced dose-dependent decreases in motor and EEG seizure durations (i.e., 37 +/- 10 and 58 +/- 12, 36 +/- 8 and 62 +/- 24, and 29 +/- 13 and 48 +/- 20 for methohexital; 34 +/- 15 and 56 +/- 29, 31 +/- 8 and 50 +/- 17, and 20 +/- 6 and 33 +/- 12 for propofol, respectively). The awakening times were similar, regardless of the hypnotic or dose administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia for Electroconvulsive Therapy

The influence of methohexital and propofol on seizure activity and recovery profiles was assessed in a randomized, crossover study involving 13 adult outpatients undergoing electroconvulsive therapy (ECT). Arterial blood pressure, heart rate, hemoglobin oxygen saturation, and electroencephalogram (EEG) activity were monitored during the ECT procedure. After premedication with glycopyrrolate, 0.2 mg intravenously (i.v.), and labetalol 20-30 mg i.v. hypnosis was induced with a bolus injection of either methohexital or propofol, 0.75 mg/kg. Muscle paralysis was achieved by administering succinylcholine, 1.4 mg/kg i.v. Ventilation was assisted using a face mask while administering 100% oxygen. Thereafter, an electrical stimulus was administered and the length of the resulting motor and EEG seizures was measured. Mood level and cognitive function were assessed prior to induction of anesthesia and after ECT. A total of 72 treatment sessions were evaluated. Each patient underwent a minimum of four treatments and received both induction drugs equally. Although the use of propofol was associated with significantly shorter motor and EEG seizure durations (mean +/- SEM) compared with methohexital (34 +/- 1.6 s and 52 +/- 2.9 s vs 39 +/- 1.5 s and 61 +/- 3.0 s, respectively), this difference was not clinically significant because the durations exceeded 30 s in both groups. Although awakening times were similar, both hemodynamic stability and cognitive recovery were more favorable after propofol. Compared with methohexital, the use of propofol was associated with a clinically insignificant decrease in seizure duration. However, propofol was associated with improved hemodynamic stability and an earlier return of cognitive function after ECT.

Anesthesia for Electroconvulsive Therapy

The influence of methohexital and propofol on seizure activity and recovery profiles was assessed in a randomized, crossover study involving 13 adult outpatients undergoing electroconvulsive therapy (ECT). Arterial blood pressure, heart rate, hemoglobin oxygen saturation, and electroencephalogram (EEG) activity were monitored during the ECT procedure. After premedication with glycopyrrolate, 0.2 mg intravenously (IV), and labetalol 20–30 mg IV, hypnosis was induced with a bolus injection of either methohexital or propofol, 0.75 mg/kg. Muscle paralysis was achieved by administering succinylcholine, 1.4 mg/kg IV. Ventilation was assisted using a face mask while administering 100% oxygen. Thereafter, an electrical stimulus was administered and the length of the resulting motor and EEG seizures was measured. Mood level and cognitive function were assessed prior to induction of anesthesia and after ECT. A total of 72 treatment sessions were evaluated. Each patient underwent a minimum of four treatments and received both induction drugs equally. Although the use of propofol was associated with significantly shorter motor and EEG seizure durations (mean ± sem) compared with methohexital (34 ± 1.6 s and 52 ± 2.9s vs 39 ± 1.5s and 61 ± 3.0s, respectively), this difference was not clinically significant because the durations exceeded 30 s in both groups. Although awakening times were similar, both hemodynamic stability and cognitive recovery were more favorable after propofol. Compared with methohexital, the use of propofol was associated with a clinically insignificant decrease in seizure duration. However, propofol was associated with improved hemodynamic stability and an earlier return of cognitive function after ECT.

Repeated anticonvulsant testing: contingent tolerance to diazepam and clobazam in kindled rats

The acute anticonvulsant efficacy of diazapam (1.5 mg/kg i.p.) was evaluated by repeated test injection in kindled rats subcutaneously implanted with diazepam-filled or empty silastic tubes for 3 weeks. Tolerance developed to acute test injections in both diazepam- and sham-implanted rats. Tolerance developed to a lesser extent in another group of diazepam-implanted rats which did not receive acute intermittent anticonvulsant tests. The hypothesis that contingent tolerance had developed to the anticonvulsant actions of benzodiazepines (diazepam, 1.5 mg/kg i.p. and clobazam, 10 mg/kg i.p.) in kindled rats given acute intermittent injections was investigated using a ‘before-after’ design. Significant contingent tolerance developed in rats which received intermittent benzodiazepine treatment before, but not after, amygdala stimulation. Tolerance developed to different extents depending on the seizure measure evaluated (forelimb clonus duration, amygdala afterdischarge duration, motor seizure latency and duration, and seizure stage). Contingent tolerance to both benzodiazepines developed at a similar rate. The findings suggest that contingent tolerance may contribute a sizeable component to the overall functional benzodiazepine tolerance measured in long-term anticonvulsant drug studies in kindled rats. Several questions regarding contingent tolerance phenomena are posed and the implications of these findings for studies using repeated anticonvulsant testing are discussed.

Apparent disappearance of postseizure inhibitions and intensity of seizures during the development of rapid kindling in rabbits

The evolution of seizures and postseizure inhibitions in the course of ‘rapid kindling’ and after the termination of stimulation were studied in rabbits with chronically implanted electrodes (neocortex, dorsal hippocampus, amygdala, caudate nucleus). The amygdala ( n=4) or hippocampus ( n=7) was electrically stimulated every 5 min. Generalized convulsions and wide-spread electrographic epileptic changes together with a striking shortening of postictal refractory periods were produced by this procedure within 2–6 h. In most cases, these epileptogenic effects continued their progression after the termination of stimulation for more than 2–4 weeks. The degree of reduction of postseizure inhibition durations was significantly greater than the degree of increase of generalized motor seizure durations. These may be mediated by mechanisms which facilitate the onset of seizure but do not significantly influence seizure expression.

What is an adequate treatment in convulsive therapy?

The parameters of the induction of an effective electroconvulsive therapy (ECT) treatment are poorly defined. We find variations in outcome, with changes in electrode placement and energy levels, despite measures of motor seizure duration greater than 25 s. To maximize the outcome of ECT, attention is again focused on the electrophysiologic and biochemical features of seizures, much as Ottosson studied them in 1960.

The effect of interstimulation interval on the assessment of anticonvulsant drug potency in fully kindled rats

Multiple stimulation regimes with interstimulation intervals of 0.25–2 h were investigated in fully kindled rats as methods of testing the time course and potency of anticonvulsant drugs after a single administration. Protocols with conventional interstimulation intervals of 1–3 days were used for comparison. Prior to the drug experiments, the different stimulation regimes were examined in drug-naive, kindled rats in order to determine the extent of postseizure inhibition occurring with such protocols. All stimulations were carried out with a suprathreshold current of 500 μA. Using protocols with 3–9 stimulations within 8 h, seizure severity was relatively stable, but motor seizure duration was reduced in most experiments. Both decreases and increases were observed with respect to afterdischarge duration (ADD). The increases in ADD were primarily due to the appearance of ‘secondary’ afterdischarges with small amplitude, which were associated with immobility, intermittent facial clonus and head nodding. After a series of stimulations at short intervals, reduced seizure severity was observed after this series for at least 1 week, so that an interval of at least 2 weeks had to be interposed between multistimulation experiments in the same group of rats. When the effects of carbamazepine, 15 mg/kg, were determined with 4 different stimulation regimes, it was found that the anticonvulsant potency of the drug was higher in experiments with short interstimulation intervals compared to conventional protocols with interstimulation intervals of 1–3 days, indicating synergistic effects between the drug and postictal inhibition. Indication for such synergism was also found when the animals were only stimulated once daily durine the drug experiments. With higher doses of carbamazepine or phenobarbital, 30 mg/kg, the difference between the stimulation protocols was less marked. Furthermore, the time course of anticonvulsant action determined with different stimulation regimes was similar. The data indicate that multistimulation regimes can be used in kindled rats to determine the time course following single administration of anticonvulsant drugs, but such protocols may lead to an overestimation of anticonvulsant potency.

Evidence that superior colliculi are involved in the control of amygdala-kindled seizures

The effects of bilateral high radiofrequency lesions of superior colliculus (SC) were studied on amygdala kindling. The results demonstrate that a selective destruction of the SC only slightly facilitated the development of kindling. However, the most remarkable effect was the increase of afterdischarge and motor seizure duration observed when SC-lesioned animals reached the generalized seizures. These data confirm that the superior colliculi participate in controlling the generalization of kindled seizures.

Amygdala-kindling as a model for chronic efficacy studies on antiepileptic drugs: Experiments with carbamazepine

The anticonvulsant properties of carbamazepine were evaluated after single and multiple doses in the kindled amygdaloid seizure model in rats. Carbamazepine significantly reduced severity and duration of motor seizures and the duration of afterdischarges recorded from the stimulated amygdala after a single dose of 30 mg/kg (i.p.), but tolerance developed during chronic treatment of rats with three times daily intraperitoneal injection of 30 mg/kg of the drug for 2 weeks. Tolerance was also observed with respect to central side-effects (ataxia, muscle relaxation) of the treatment. Determinations of plasma levels confirmed previous studies in rats and other species in that concentrations of carbamazepine declined during chronic treatment, which may be related to autoinduction of the metabolism of the drug. Indeed, carbamazepine-10,11-expoxide, the major active metabolite of carbamazepine, could not be quantified in the plasma after the first dose but accumulated during chronic treatment, indicating an enhanced metabolism of the parent drug. As a consequence of decreasing concentrations of carbamazepine but increasing levels of the epoxide, the sum of concentrations of both compounds after 1 or 2 weeks of treatment did not differ from the concentration of unchanged carbamazepine initially determined. Determinations of the acute anticonvulsant potency in kindled rats indicated that carbamazepine-10,11-epoxide was about half as potent as the parent drug. In view of the anticonvulsant activity of carbamazepine-10,11-epoxide, the loss of anticonvulsant efficacy observed during chronic treatment with carbamazepine cannot be related solely to metabolic tolerance, i.e. due to enhanced metabolism of drug, but should also relate to functional tolerance, i.e. induced by central adaptation to the long-term presence of the drug and its metabolite.

Myoclonus inducing and seizure modifying effect of cysteamine on cortical and amygdaloid kindled rats

The effect of the somatostatin depleting substance, cysteamine (100 mg/kg, i.p.), on cortical and amygdaloid kindled seizures was investigated. Cysteamine was tested after the establishment of amygdaloid kindling (AM group) and at two different developmental stages of cortical kindling, namely ‘focal-cortical’ (FC group) and ‘cortico-generalized’ seizures (CG group). In control, non-kindled, sham operated animals, cysteamine did not induce any spike activity or myoclonus. However, in all kindled groups clustered spike bursting appeared in the cortex within 5–15 min of the injection. The kindled rats exhibited myoclonic jerks at 10 to 30 min after cysteamine injection, which coincided with the cortical spikes, and continued for about 40 min. In contrast, relatively small amounts of spiking were observed in the amygdala and this did not correlate with the myoclonus. At 4 h after cysteamine injection, the motor seizure and afterdischarge durations of the kindled seizure were prolonged in all kindled groups compared with preinjection levels. However, 24 h later the motor seizure duration and the afterdischarge duration were markedly reduced from the preinjection level in the AM and the CG groups and the tonic seizure components was suppressed in the FC group. This inhibitory effect on seizure activity lasted several days and gradually disappeared. These modifying effects of cysteamine were more marked in cortical kindled, than in amygdaloid kindled animals. The results suggest that the cortex is more sensitive to the effect of cysteamine than the amygdala, and that the effect of cysteamine on kindled seizures involves two phases. The first of these phases is excitatory and the second is inhibitory, presumably reflecting an early release-inducing and a later synthesis-inhibiting effect of cysteamine on brain somatostatin.

Effects of corticosterone on shaking and seizure behavior induced by deep prepyriform cortex kindling.

The influence of adrenocorticosteroids on seizures and wet dog shakes (WDS) induced by deep prepyriform cortex kindling was studied by bilateral adrenalectomy and corticosterone replacement. The rate of kindling, latency to the onset and duration of motor seizures were not significantly affected by adrenalectomy or corticosterone treatment. However, the number of WDS observed after stage 5 seizures was reduced in adrenalectomized animals and it was not restored until 3 h following corticosterone replacement. This delay in onset of action suggests that the effects of adrenocorticosteroids and/or ACTH on WDS may be mediated by an indirect mechanism.

Is adenosine an endogenous anticonvulsant?

The anticonvulsant properties of adenosine were tested pharmacologically on amygdala-kindled seizure activity in rats. The adenosine analogue 2-chloroadenosine and the adenosine uptake blocker papaverine both increased the latency to behavioral clonus as well as reduced the duration and severity of the clonic motor convulsion. Both drugs, however, failed to alter the postkindling afterdischarge (AD) threshold. Theophylline, an adenosine antagonist, had the opposite effects, prolonging the AD and motor seizure durations and facilitating partially kindled seizures, but again not altering the prekindling or postkindling AD thresholds of amygdala-elicited seizures. In contrast, carbamazepine raised AD thresholds, suggesting that it does not produce its anticonvulsant effects through adenosine systems. Since endogenous adenosine can impede seizure spread and seizure continuation, but does not affect seizure initiation from the amygdala, perhaps endogenous adenosine has the special property of being brought into play as an anticonvulsant only by the seizure itself.

Evaluation of different GABA receptor agonists in the kindled amygdala seizure model in rats

The effects of three specific GABA receptor agonists, muscimol, progabide, and gaboxadol, on kindled seizures were evaluated in amygdala-kindled rats. The only compound that exerted significant anticonvulsant effects at nonsedative doses was progabide. Thus, after i.p. administration of 100 mg/kg progabide, a significant increase in seizure latency and significant decreases in duration of motor seizures and amygdala afterdischarges were determined. A decrease in severity of motor seizures was found only after 200 mg/kg progabide which, however, gave rise to marked sedation and muscle relaxation. Muscimol and gaboxadol were almost inactive in attenuating kindled seizures even at doses that produced pronounced side effects. Assuming that the amygdala-kindled rat is a useful model of complex partial seizures with secondary generalization in the human, the data suggest that GABA receptor agonists are not effective against this type of epilepsy (muscimol, gaboxadol) or effective only at large doses (progabide).

Evidence implicating substantia nigra in regulation of kindled seizure threshold

We studied the effects of microinjected drugs and brainstem lesions on motor and limbic seizures in the kindling model of epilepsy. The duration of motor seizures was determined by timing the colonic and tonic movements of the extremities. The duration of limbic seizures was determined by measuring afterdischarge recorded on the electroencephalogram. Bilateral microinjection of a gamma-aminobutyric acid (GABA) agonist, muscimol, into the area of the substantia nigra (SN) markedly suppressed both motor and limbic seizures induced by stimulation of amygdala, olfactory structures, or lateral entorhinal cortex. Microinjection of saline did not suppress seizures. The suppressive effect of muscimol: (i) dissipated after several hours and was dependent on dose; (ii) was due to an elevation of the seizure threshold, since typical seizures could be elicited with electrical current far exceeding the threshold; and (iii) exhibited spatial specificity since muscimol injections 1 to 2 mm dorsal to the SN or into neocortex did not suppress the seizures. The actions of muscimol were probably mediated by its GABA agonist properties, since microinjection of an irreversible inhibitor of GABA transaminase (gamma-vinyl GABA) into the area of the SN also suppressed kindled seizures. Destruction of brainstem structures was produced by microinjection of the neurotoxin, N-methyl-D,L-aspartate. Seizures were markedly suppressed in animals with bilateral destruction of the SN but not in animals in which the SN was spared bilaterally. We interpret the data to indicate that the SN is the site at which the GABA agonists and lesions act to raise the threshold for kindled seizures. The suppression of limbic seizures indicates that this brainstem nucleus can regulate the intrinsic neuronal excitability of hemispheric sites.

The effects of naloxone and interstimulation interval on post-ictal depression in kindled seizures

Two experiments were conducted to investigate the effects of naloxone hydrochloride on seizure thresholds seizure afterdischarges (thresholds and durations) and on post-ictal depression. Experiment 1 examined the effects of naloxone dosage and interstimulation interval (ISI) on kindled seizures. Eight male hooded rats were exposed to a factorial combination of two ISIs (30 and 60 s) and 3 naloxone doses (2, 10 mg/kg and a saline control) during a threshold testing procedure. Naloxone was found to significantly shorten motor seizure duration and post-ictal depression. Experiment 2 examined the effects of naloxone on a subsequent suprathreshold-stimulation-induced seizure following an initial suprathreshold stimulation. A factorial combination of 3 naloxone doses (2, 5 and 10 mg/kg) and a saline control and two ISIs (2 and 6 min) separating the two stimulations was employed. While no main effects for either naloxone or ISI were found in the subsequent seizure activity, there was a significant interaction between naloxone and ISI for the subsequent motor seizure duration. It was concluded from the results of the present experiments that the direction and consistency of naloxone's effects on kindled seizures were present but not very strong. However, the effects of ISI on seizure activity were found to be consistent with the previous literature.

Pharmacological investigation of gamma-aminobutyric acid (gaba) and fully-developed generalized seizures in the amygdala-kindled rat

The effects of GABA-modulating drugs were assessed in a pharmacological study of amygdala-kindled seizures in the rat. Fully-kindled subjects were tested with a randomized dose regimen, including drug vehicle, for each of seven drugs. Afterdischarge duration, motor seizure latency, motor seizure duration and motor seizure stage were scored. The GABA synthesis inhibitor, 3-mercaptopro-pionic acid, the GABA antagonist, bicuculline, and the chloride ionophore blocker, picrotoxin, all decreased motor seizure latency, but did not otherwise alter the kindled seizure duration or seizure stage. The inhibitor of GABA metabolism, gamma-vinyl-GABA, and pentobarbital, which competes for the picrotoxin binding site, both antagonized kindled seizures. Gamma-vinyl-GABA, however, did not appear to antagonize kindled seizures by a specific effect on GABA neurotransmission. The GABA agonists, imidazole acetic acid and ¦alpha-(chloro-4'phenyl)fluoro-5-hydroxy-2-benzylidene-amino¦-4-butyramide (SL 76-002), did not alter the kindled seizures. The results of these experiments are not consistent with the hypothesis that kindled seizures result from a loss of GABA-mediated inhibition: however, GABA may have a role in the modulation of kindled seizure activity.