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Twenty subjects, in a double-blind, controlled, rising dose study, were given ethosuximide either once daily or 3 times daily. Steady-state plasma levels and urinary throughput were proportional to dose and were equivalent whether the daily dose was given as a single or divided dose. This finding adds validity to consideration of the single daily dose regimen as a therapeutic possiblity. The metabolic principles should be considered both in patient management and in the treatment of overdosage.

Eighteen controlled studies investigating the psychotropic effect of anti-epileptic drugs are critically reviewed. The neurochemical evidence for existence of psychotropic properties is still speculative. It seems questionable on the basis of this survey that there exist genuine psychotropic effects of antiepileptic drugs, which are not related to antiepileptic efficacy and/or differences in toxicity.

The mechanisms of petit mal epilepsy remain a mystery despite successful therapy. Previous workers have proposed that paroxysmal activity of cortical inhibitory systems plays a role in absence seizures. In this study, we have compared the effects of bicuculline, a potent convulsive agent and GABA antagonist, with ethosuximide, a drug used to treat petit mal epilepsy, on the thalamocortical motor system of the cat. Under chloralose anesthesia, sequential pairs of pulses were delivered to ventrolateral thalamus (VL) varying either pulse amplitude or interval. The evoked responses were recorded from sensorimotor cortex, analyzed on-line by computer, and plotted as an excitability curve (mean response amplitude as a function of pulse interval), or a family of threshold curves (mean response amplitude as a function of stimulus amplitude at various fixed intervals). Administration of each drug resulted in increased thalamocortical excitability and decreased threshold to stimulation for short pulse-pair intervals, with diminished duration of the excitability curve. Increased alertness was produced by both drugs. Studies with grand mal anticonvulsants demonstrated entirely different effects. Because GABA is thought to be the primary inhibitory transmitter in VL and cerebral cortex, bicuculline would be expected to result in disinhibition. The similarity of the data for ethosuximide suggests that ethosuximide also suppresses inhibition in the thalamocortical motor system and adds further to the accumulating evidence of the role of inhibitory system in petit mal epilepsy.

Enzymatic production of prostaglandins (PGs) from exogenous arachidonic acid was studied in brain microsomal fractions prepared from mice following pentylenetetrazol (PTZ)-induced convulsions. Prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) measured either by radioimmunoassay or after incubation with [1-14C]arachidonic acid (AA) was significantly increased in microsomes from the convulsed animals. Pretreatment of the mice with the anticonvulsant ethosuximide prevented the enhanced PG production. The increased PG synthesis could not be attributed to an increased substrate availability nor to an activated phospholipase nor to a direct effect of the convulsant on the fatty acid cyclooxygenase. Evidence that a modification of the cyclooxygenase had occurred with seizure activity was obtained from kinetic analysis; the apparent Km for the AA was lowered from 30 +/- 3 microM in the controls to 12 +/- 1 microM in the PTZ-treated mice. Further evidence for a modification of the fatty acid cyclooxygenase was obtained from incubations of the microsomes with catalase to reduce peroxide formation. Limiting peroxide levels did not decrease the microsomal cyclooxygenase activity in the PTZ-treated mice to control levels. Seizure activity induced by picrotoxin and strychnine also increased the microsomal capacity of the convulsed animals to synthesize PGs. The increased brain fatty acid cyclooxygenase activity may result from a biochemical modification of the enzyme induced by seizure activity.

The effects of phenobarbital, clonazepam, valproic acid, ethosuximide, and phenytoin were examined in pigeons performing under a delayed matching-to-sample procedure. Clonazepam, valproic acid, ethosuximide, and phenytoin typically reduced the rate of responding to the sample stimulus, whereas phenobarbital usually increased response rates at high doses. Phenobarbital, clonazepam, and valproic acid produced generally dose-dependent decreases in accuracy; ethosuximide and phenytoin failed to do so. These results suggest that there are qualitative as well as quantitative differences in the effects of anticonvulsant drugs under the delayed matching-to-sample procedure.

Evoked potential (EP) analysis of the somatomotor pathway in cats revealed that the temporal lobe anticonvulsant carbamazepine suppresses the thalamic relay, whereas the petit mal antiepileptic ethosuximide acts on the cortex. Moreover, a history of temporal lobe epilepsy (amygdala kindling) maximized thalamic response to carbamazepine, especially during sleep states vulnerable to generalized kindled seizures. Ethosuximide accentuated cortical response during sleep and awakening states vulnerable to generalized spike-wave complexes, regardless of a history of petit mal seizures (systemic penicillin epilepsy). The findings provide a neural basis for differential drug effects on generalized temporal lobe and petit mal epilepsy and further suggest that a chronic seizure disorder can create a predisposition for antiepileptic drug sensitivity.

Enhancement of gamma-aminobutyric acid transmission within the substantia nigra has been shown to prevent the motor manifestations of chemically induced and kindled seizures. These findings raise the possibility that the substantia nigra might constitute a site of anticonvulsant drug action if these drugs share an ability to suppress propagation of seizure activity from the nigra to motor effector sites. The current studies monitored effects of a diverse group of anticonvulsant drugs on the extracellular, single unit activity of nondopaminergic neurons of the substantia nigra pars reticulata in awake, paralyzed and locally anesthetized male rats. Intravenous phenytoin (1.25-160 mg/kg) and carbamazepine (1.25-40 mg/kg) did not alter neuronal firing at any dose. Conversely, both diazepam (31.25-8,000 micrograms/kg) and clonazepam (2-500 micrograms/kg) partially inhibited firing (to 46 +/- 11% and 59 +/- 6% of base-line rates, respectively), although clonazepam was approximately 16 times more potent in eliciting equivalent degrees of inhibition. Valproic acid (5-640 mg/kg) and phenobarbital (1.25-80 mg/kg) also slowed firing to 65 to 70% of base-line rates, but did so only at the highest doses administered. However, the anesthetic barbiturate pentobarbital (0.3125-80 mg/kg) completely suppressed firing by the highest dose tested. Of those drugs used exclusively for treatment of absence seizures, trimethadione (12.5-800 mg/kg) caused dose-related inhibitions to 37.6 +/- 9.8% of base-line, whereas ethosuximide (12.5-800 mg/kg) markedly stimulated firing, nearly doubling firing rates after the 200 mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkyl-Substituted gamma-butyrolactones were synthesized and tested for their convulsant and anticonvulsant actions in mice and guinea pigs. The alpha-substituted compounds, alpha, alpha-dimethyl-, and alpha-ethyl-alpha-methyl-gamma-butyrolactone were anticonvulsant compounds with a spectrum of activity similar to that of ethosuximide. In contrast, beta-substituted compounds were convulsant agents similar to picrotoxinin. The alpha-substituted-gama-butyrolactones represent a new class of anticonvulsant drug with experimental and clinical potential.

Much longer trains of conditioning stimuli are required to elicit inhibition descending from the reticular formation than to elicit segmental inhibition in the trigeminal nucleus. In contrast, a single conditioning stimulus is the most effective in eliciting descending facilitation, while the test stimulus alone is most effective in eliciting segmental excitation. Ethosuximide (ESM) selectively depresses descending inhibition and to a lesser extent segmental inhibition. Thus, ESM only depresses pathways requiring repetitive stimulation, such as inhibitory pathways in the reticular formation. This action would account for ESM's specificity for absence seizures, which are probably due to paroxysmal activity in inhibitory pathways.

Previous research has shown that ethosuximide in high enough doses disrupts operant responding in pigeons. Whether or not these same doses protect against seizure activity in this species has not been determined. In the present study a system for scoring pentylenetetrazol-induced seizures in pigeons was developed and the effects of ethosuximide on such seizures were evaluated. Pentylenetetrazol at 15, 27 and 47 mg/kg reliably induced seizures in Experiment 1. In Experiment 2 six doses of ethosuximide were tested for their seizure-controlling effectiveness. Doses of 20, 40, 80, 160 and 320 mg/kg ethosuximide had little effect on seizures induced by 27 mg/kg pentylenetetrazol; 640 mg/kg significantly reduced but did not completely eliminate seizures. This dose (640 mg/kg) is several times higher than the doses found to disrupt operant behavior in our previous studies.

Low-threshold calcium current (LTCC) in thalamic neurons is important in generation of normal thalamocortical rhythms, and may be involved in the genesis of abnormal activities such as spike-wave discharges that characterize petit mal epilepsy. Ethosuximide and dimethadione, anticonvulsants effective in petit mal, reduced the LTCC when applied to thalamic neurons at clinically relevant concentrations. Therapeutic concentrations of phenytoin and carbamazepine, drugs ineffective in the control of petit mal, had minimal effects on calcium conductances. Reduction in LTCC may be an important mechanism of action by which specific petit mal anticonvulsants depress spike-wave activity.

The presence of gamma-hydroxybutyrate (GHB) (300-600 microM) in the incubation medium of rat hippocampal slices led to an increase of intracellular cyclic GMP and inositol phosphates. This phenomenon is dependent on the time and the dose of GHB used and might be the result of the stimulation of GHB receptor sites which are abundant in rat hippocampus. The increase of cyclic GMP and inositol phosphates is blocked by some anticonvulsants and opiate antagonists. These results seems to indicate that, like many substances inducing epileptic phenomena, GHB provokes neuronal depolarization in hippocampus which is accompanied by formation of cyclic GMP and inositol phosphates. The effect of opiate antagonists can be explained by the possible implication of an opiate synapse which mediates GHB effects in rat hippocampus.

Homozygous tottering mice (tg, autosomal recessive) exhibit frequent spontaneous "absence" seizures accompanied by bilaterally synchronous spike-and-wave or polyspike electrocorticographic discharges. In adult tottering mice, the antiepileptic effects of a single dose of ethosuximide, diazepam, phenobarbital, or phenytoin were assessed using continuous electrocorticographic recording to monitor seizure incidence. The dose chosen for each drug was selected to correspond to an effective antiepileptic dose in standard murine models. Ethosuximide, 150 mg/kg, diazepam, 1.4 mg/kg, and phenobarbital, 25 mg/kg were effective against absence seizures. In contrast, phenytoin at 5, 10, 30, or 60 mg/kg produced no significant reduction in the incidence of absence seizures. These results suggest that absence seizures in the tottering mutant may represent a relatively specific pharmacological model for the identification of drugs effective for clinical absence epilepsy, and emphasize the potential value of this new model for the study of fundamental mechanisms of absence of epilepsy and the actions of antiepileptic drugs.

Valproate is often administered with other antiepileptic drugs, a practice that can lead to clinically significant pharmacologic interactions. Concomitant administration of such enzyme-inducing antiepileptic drugs as carbamazepine, phenobarbital, primidone, or phenytoin will markedly accelerate the metabolic conversion of valproate, particularly in children. In response to the effects of enzyme induction, valproate dosage may need to be doubled to maintain therapeutic serum levels. Valproate does not appear to induce enzymatic drug metabolism, but rather acts as a metabolic inhibitor. Because of this inhibition, phenobarbital dosage must often be reduced after valproate is added to the therapeutic regimen. Valproate also may markedly increase concentrations of the active epoxide metabolite of carbamazepine. The interaction between phenytoin and valproate results primarily from displacement from plasma proteins. The resulting increase in the free fraction of phenytoin alters the relationship between total phenytoin concentration and the drug's pharmacologic effect. Thus, clinical evidence of toxicity may be present at concentrations usually considered to be in the therapeutic range.

The ability of five commonly used anticonvulsants to produce substrate induced difference specta was assessed. Only diphenylhydantoin (DPH) and phenobarbitone were observed to produce such spectra and were of Type I. Mean Ks values for DPH and phenobarbitone were 6.8 x 10(-5) and 4.0 x 10(-4)M, respectively. The anticonvulsants sulthiame, ethosuximide, sodium valproate and phenobarbitone exhibited inhibition of DPH substrate induced difference spectra to varying degrees. Analysis of data as in the classical enzyme/inhibitor models resulted in mean Ksi values for the four anticonvulsants of 1.3 x 10(-4), 0.53 x 10(-2), 3.0 x 10(-3), and 6.8 x 10(-3), respectively. Inhibition of DPH substrate induced difference spectra by sulthiame and phenobarbitone was strong and competitive. Inhibition by ethosuximide was weak and competitive, while sodium valproate's inhibition was weak and uncompetitive.

The actions of the anticonvulsants phenobarbital, ethosuximide and carbamazepine were examined electrophysiologically at the frog neuromuscular junction. Phenobarbital reduced miniature end-plate potential (MEPP) amplitude, did not significantly affect end-plate potential amplitude and increased quantal content. Ethosuximide decreased MEPP and end-plate potential amplitudes proportionally; quantal content was unchanged. Carbamazepine decreased end-plate potential amplitude more than MEPP amplitude; quantal content was decreased. In a solution containing elevated (7.5 mM) K+, phenobarbital and carbamazepine increased MEPP frequency, whereas ethosuximide had no effect. Carbamazepine had to be dissolved in a solvent, propylene glycol, which was shown to produce small, but sometimes statistically significant, alterations in the measured parameters of neuromuscular transmission. The results show that all three of these anticonvulsants depress postjunctional sensitivity to released acetylcholine producing parallel dose-response curves for MEPP amplitude inhibition. These experiments also show that these drugs exhibit different mechanisms of action with respect to nerve-stimulated neurotransmitter release from nerve terminals at the neuromuscular junction: phenobarbital enhances acetylcholine release, ethosuximide has no effect and carbamazepine decreases transmitter release.

Influence of ethosuximide (ESI, 125 mg/kg i.p.) and dipropylacetate (DPA, 300 mg/kg i.p.) pretreatment on electrocorticographic changes induced by pentamethylenetetrazole (PTZ, 20 mg/kg dose every 5 min) was studied in rats aged 7, 12, 18 and 90 days. PTZ alone induced isolated spikes and/or sharp waves as the first sign of its action in all age groups except in adult animals where rhythmic theta activity was elicited. The antiepileptic effect of DPA was observed in 12- and 18-day-old rats, ESI specifically inhibited rhythmic activity in adult rats. ECoG seizures induced by high doses of PTZ were inhibited by DPA in all age groups, ESI tended to be effective in adult rats only. DPA did not change the pattern of ECoG seizures, whereas ESI led to replacement of the spike-and-wave rhythm by serrated waves in adult animals. The low ability of immature brain to generalize ictal activity was further diminished by ESI.

Antiepileptic drugs probably act by preventing the spread of the abnormal paroxysmal activity from the epileptogenic focus to surrounding normal neurons. An investigation of the mechanism of action of established anticonvulsant drugs on normal neuronal systems may therefore offer useful insights into the pathogenesis of the seizure disorders that these drugs serve to control. Antiabsence drugs (ethosuximide, valproate) depress reticular inhibitory pathways. Drugs effective against generalized tonic-clonic seizures (phenytoin, carbamazepine, valproate) depress reticular excitatory pathways. Drugs that are also effective against trigeminal neuralgia (phenytoin, carbamazepine) also depress afferent excitation and facilitate segmental inhibition in the trigeminal complex. Drugs that depress afferent excitation and facilitate segmental inhibition but do not depress the reticular system (baclofen) are effective against trigeminal neuralgia but do not have clinical antiepileptic properties. These observations indicate that the ability to depress the reticular core is an important characteristic of antiepileptic drugs, and suggest that the reticular core is involved in the spread and generalization of clinical seizures.

The presence of gamma-hydroxybutyric acid (GHB) in synaptosome-enriched fractions of rat brain was ascertained using a GLC technique. The stability of GHB in synaptosomes was evaluated by addition of various gamma-aminobutyric acid (GABA) transaminase (GABA-T) inhibitors, GHB, or ethosuximide to the homogenizing medium. Furthermore, changes in whole brain GHB levels were compared with those in the synaptosomal fraction in animals treated with GABA-T inhibitors, GABA, or ethosuximide. GHB was present in synaptosome-enriched fractions in concentrations ranging from 40 to 70 pmol/mg of protein. There was no evidence for redistribution, leakage, or metabolism of GHB during the preparation of synaptosomes. The elevations of whole brain GHB level associated with GABA-T or ethosuximide treatment were reflected by a parallel increase in synaptosomal GHB content. These data add to the growing evidence that GHB may have neurotransmitter or neuromodulator function.

A conditioning stimulus to the periventricular gray matter inhibits the response of spinal trigeminal neurons to maxillary nerve stimulation. Sodium valproate and ethosuximide decrease the periventricular inhibition without significantly affecting the response of these neurons to the unconditioned maxillary nerve stimulus. We have now found that carbamazepine and phenytoin decrease the response to the unconditioned maxillary nerve stimulus, and only depress the periventricular inhibition secondarily. These results further support the hypothesis that the ability to depress selectively inhibitory pathways in the CNS is an important characteristic of antiabsence drugs, and that absence seizures may represent paroxysmal discharges in inhibitory pathways.

A semi-chronic model of cobalt-induced experimental epilepsy in the rat was used to investigate the action of two classic anticonvulsant drugs, phenytoin and ethosuximide. Single injections of ethosuximide lead to an inhibition of the epileptic discharges. We failed to demonstrate an inhibitory effect of phenytoin after preventive administration. The carbidopa-L-dopa association was investigated owing to the inhibitory effects of dopamine and its presence in the cortex. We showed that a dose of 100 mg/kg of L-dopa combined with 25 mg/kg of carbidopa is necessary and sufficient to produce an almost complete inhibition of the discharges.

Carbamazepine (CBZ) selectively suppressed kindled convulsions, whereas ethosuximide (ESM) suppressed spike-wave activity accompanying systemic penicillin epilepsy in cats. Evoked potential data indicated that CBZ acted at the thalamic level, whereas ESM acted at cortex. Reduction of seizures and thalamic or cortical excitability occurred throughout the sleep-wake cycle, but effects were most pronounced in seizure-prone sleep or awakening states. These findings extend previous work showing differential antiepileptic drug (AED) effects on temporal lobe and absence seizures. The results are also consistent with recent work suggesting that thalamocortical pathways provide a final common pathway for the manifestation of sleep and awakening epilepsy and also reflect a chronic, latent pathophysiology.

Morning steady-state (9 am) plasma levels were significantly higher than the corresponding evening (5 pm) plasma levels during a 3-week zero-order infusion of ethosuximide to six monkeys. These differences could not be explained by experimental variables such as GLC assay and infusion pump. Circadian periodicity in steady-state plasma levels was investigated in three monkeys over 4 months under controlled experimental conditions: blood sampling at 2-hr intervals for 26 hr, 1 day/week; fixed lighting, feeding, and noise schedules; and electroencephalogram monitoring. The plasma concentration-time curves showed two minima in the 12 noon-2 pm and 8 pm-12 midnight periods, and the later involved the largest percent change in plasma levels (4-8%). The plasma concentration-time data were subjected to cross-correlation analysis, which indicated a circadian rhythm in steady-state plasma levels with a period of 24-26 hr.

In cultured cortical neurons, ethosuximide (ESM) had unexpected actions for an antiepileptic drug; it slightly diminished the effects of inhibitory neurotransmitters, GABA, and glycine. ESM had no direct membrane effects, did not change action potential characteristics or alter spontaneous activity, and did not reverse the effects of convulsants that are GABA antagonists. The structurally related convulsant tetramethylsuccinimide (TMSM) reduced the amplitude of GABA-mediated inhibitory postsynaptic potentials and antagonized responses to applied GABA, effects not reversed by ESM. The convulsant effects of TMSM include a blockade of postsynaptic GABA actions, but the antiepileptic effects of ESM are not due to an enhancement of GABA-mediated inhibition.

The usefulness of the anticonvulsant drugs is determined by the mechanisms by which the agent acts and its pharmacokinetics. The general mechanisms of action of these agents include (1) effects on neurotransmitter action, (2) effects on repetitive neuronal firing mechanisms, (3) effects on neuronal networks, and (4) effects on neuronal ionic transport. Ethosuximide, valproic acid and clonazepam are used primarily in absence epilepsy. Valproic acid is also effective against generalized tonic-clonic epilepsy. Diazepam is used primarily in status epilepticus. Valproic acid enhances gamma aminobutyric acid (GABA)-mediated inhibition, reduces repetitive firing, and reduces both inhibition and excitation in neuronal networks. Clonazepam and diazepam enhance the inhibitory action of GABA, decrease inhibition in neuronal networks and affect calcium ion transport with lesser effects on repetitive firing. Ethosuximide reduces inhibition in neuronal networks, may interact with dopamine, and possibly affects sodium and potassium ion transport. Further work is needed to assess the degree of involvement of these effects in the anticonvulsant action versus the adverse effects of these agents.

The anticonvulsant effect of di-n-propylacetic acid (n-DPA) was studied in mice and compared to those of phenobarbital, trimethadione and ethosuximide. n-DPA was only weakly active in the maximal electroshock test, but had an ED50 of 420 mg/kg orally in the pentetrazole seizure threshold test, which corresponds rather well to the activity of trimethadione and ethosuximide. The duration of action was only short, and the first signs of neurotoxicity--inability to perform in the chimney test--appeared well below the anticonvulsant ED50 against pentetrazole. n-DPA proved to be most active against convulsions induced by picrotoxin (ED50 200 mg/kg orally), which might indicate a role of the elevation of the central levels of gamma-aminobutyric acid in the anticonvulsant effect of the drug.

Young (25-day-old) and adult (90-day-old) rats pretreated with ethosuximide (62.5 or 125 mg/kg i.p.) were injected with either s.c. pentylenetetrazole (100 mg/kg) or i.p. kainate (10 or 14 mg/kg). The incidences and latencies of minor (clonic) and major (tonic-clonic) seizures were registered. Ethosuximide (125 mg/kg) completely blocked clonic seizures induced by the lower dose of kainate, and slightly suppressed or delayed those induced by the higher dose of kainate or pentylenetetrazole in both age groups. The effect of ethosuximide on major kainate-induced seizures (elicited in young rats only) was insignificant (ethosuximide only partially decreased the incidence of major seizures), whereas ethosuximide abolished major pentylenetetrazole-induced seizures in both age groups. Ethosuximide also failed to affect the latencies of kainate-induced automatisms (e.g., scratching, wet dog shakes). Similarities between kainate- and pentylenetetrazole-induced clonic seizures, as well as a similar action of ethosuximide on both, suggest a common generator for the pattern of clonic seizures.

In vivo and in vitro experimental data are presented in support of the hypothesis that sodium valproate displaces diphenylhydantoin (DPH) from plasma protein binding sites. This interaction could have important practical implications in the management of patients on combined therapy with these two drugs. Acute neurological features of DPH intoxication may be precipitated as a result of an increased free (pharmacologically active) fraction, which would not be detected by routine plasma DPH estimations since these reflects largely the bound fraction.

The relative ability of phenytoin, ethosuximide and valproate to prevent minimal (clonic) threshold, maximal (tonic extension of the hindlimbs) threshold and supramaximal (tonic extension of the hindlimbs) seizures elicited by electrical and chemical (Metrazol, bicuculline, and picrotoxin) stimulation was determined. Ethosuximide and valproate were effective against minimal (clonic) threshold seizures, whereas phenytoin was ineffective and even activated them. All three anticonvulsants were effective against maximal (tonic extension of the hindlimbs) threshold seizures. Phenytoin and valproate, but not ethosuximide, were effective against supramaximal (tonic extension of the hindlimbs) seizures. The results suggest that the specificity of experimental models of epilepsy used in the evaluation of potential antiepileptic drugs is primarily due to the intensity rather than the nature of the stimulus used or the kind of seizure component evoked. Models based only on maximal (tonic extension of the hindlimbs) threshold seizures may identify anticonvulsant activity, but do not differentiate between substances that prevent seizure spread and those that increase seizure threshold.

Effects of four antiepileptic drugs, viz., diphenylhydantoin, trimethadione, phenobarbitone and ethosuximide, were studied on different in vitro and in vivo skeletal muscle preparations which consisted of frog rectus, rat phrenic nerve diaphragm and cat gastrocnemius sciatic nerve preparations. A dose related blockade of neuromuscular transmission was seen with all the compounds tested. The blockade was mainly confined to the neuromuscular junction, although direct stimulation of muscle was slightly affected. The blockade was partially antagonized by physostigmine, adrenaline, succinylcholine, choline, tetraethylammonium and KCl and was additive to that due to tubocurarine. Moreover, the drugs were found to possess moderate local anaesthetic activity. The blockade was therefore considered to be partly due to curariform activity and partly due to their local anaesthetic activity.

A population of New Zealand White rabbits exhibit behavioral convulsions when given low doses of psychoactive cannabinoids of marijuana. Carbamazepine, diazepam and phenytoin were most effective in blocking these convulsions caused by delta9tetrahydrocannabinol (delta9THC). Phenobarbital and ethosuximide also blocked convulsions but only at toxic doses. Cannabidiol was effective in blocking convulsions when given concurrently with, but not prior to delta9THC.

The effects of the anticonvulsant drugs clonazepam and ethosuximide were examined in pigeons performing under a fixed-consecutive-number schedule with and without an added external discriminative stimulus. Under these schedules, food was delivered whenever subjects responded between and 8 and 12 times on one response key (work key), and then responded once on a second response key (reinforcement key). For one group, an external discriminative stimulus signalled completion of the response requirement on the work key, while no stimulus change was programmed for the other group. Clonazepam (0.06-0.75 mg/kg) produced dose-dependent decreases in percentage of reinforced runs and rate of responding for both groups. The magnitude of the accuracy-decreasing effect was generally greater in the group without the external discriminative stimulus. For this group, the higher doses of clonazepam produced pronounced increases in switching to the reinforcement key before completing the minimum requirement of eight consecutive responses on the work key. No consistent patterns of errors were evident for the subjects with the added external discriminative stimulus. Although ethosuximide (20-160 mg/kg) produced dose-dependent decreases in rate of responding, it had little effect on the percentage of reinforced runs or the run length distributions. These findings are consistent with previous reports indicating that clonazepam, but not ethosuximide, substantially disrupts performance under operant tasks requiring conditional discriminations. These data also suggest that the addition of an external discrimination stimulus attenuates the disruptive behavioral effects of clonazepam.

After initial exposure to 80 mg/kg, pigeons trained on a two-key drug discrimination procedure rapidly learned to discriminate 120 mg/kg ethosuximide from saline. When 40-160 mg/kg doses of ethosuximide were administered during generalization tests, the percentage of responses directed to the ethosuximide-appropriate key varied directly with dose. Time-effect determinations revealed that the discriminable properties of ethosuximide were evident as early as 15 min after, and as late as 2 h after, intramuscular injection. The discriminative stimulus properties of ethosuximide failed to generalize to the anticonvulsant compounds clonazepam (0.5-4 mg/kg), methsuximide (25-200 mg/kg), and phenytoin (5-15 mg/kg). Generalization was apparent with certain doses of primidone (250, 300 mg/kg) and mephenytoin (80, 160, 240 mg/kg). The concomitant administration of pentylenetetrazol (5, 10, 20 mg/kg) partially blocked the discriminable properties of the training dose of ethosuximide.

The action of four antiepileptic drugs was studied in acute experiments in 98 rats. Two types of cortical self-sustained afterdischarges ( SSADs ) induced by rhythmic electrical stimulation of subcortical structures were used as models. SSAD formed by the spike-and-wave rhythm (most frequently induced by stimulation of thalamic somatosensory relay nucleus) was almost completely blocked by dipropylacetate (valproate, 400 mg/kg i.p.) and significantly shortened by ethosuximide (125 mg/kg i.p.). Diphenylhydantoin (60 mg/kg i.p.) tended to prolong this type of SSAD whereas carbamazepine did not influence it. SSAD formed by serrated waves (induced usually by stimulation of the dorsal hippocampus) was augmented by ethosuximide, uninfluenced by dipropylacetate and diphenylhydantoin, and significantly shortened by carbamazepine. The pharmacological profile of the two types of SSADs is in agreement with our hypothesis that the spike-and-wave type of SSAD represents a model of primary generalized seizures of the absence type whereas hippocampo -cortical SSAD could be used as a model of partial seizures with complex symptomatology.

The acute administration of an anticonvulsant dose of ethosuximide (150 mg/kg) had no effect on brain gamma-aminobutyric acid (GABA) concentration, whereas a toxic dose (400 mg/kg) increased significantly the concentration of brain GABA (1.23 +/- 0.05 vs. 1.92 +/- 0.14 mumol/g of wet tissue). The administration of 500 mg/kg/day of ethosuximide for 1, 2, 4, 6, 8 and 11 days induced neurotoxicity in 100, 100, 67, 0, 0 and 0% of animals, respectively, and increased brain GABA concentration 46, 38, 25, 14, 9 and 0%, respectively. These results imply that the tolerance that develops in response to the chronic administration of toxic doses of ethosuximide correlates well with the concentration of brain GABA. 4,5,6,7-Tetrahydroisoxazolo [5,4-c]pyridin-3-ol even in toxic doses had no effect on the anticonvulsant activity of ethosuximide. Combination studies with ethosuximide and progabide demonstrated that the antipentylenetetrazol activity of the individual components interacts additively. Likewise, combinations of either ethosuximide and 4,5,6-tetrahydroisoxazolo [5,4-c]pyridin-3-ol or ethosuximide and progabide showed an additive effect by the rotorod test. These results indicate that the antipentylenetetrazol activity of ethosuximide is unrelated to GABA function and that the increase in brain GABA concentration induced by toxic doses of ethosuximide contributes to its neurotoxicity.

The acute and chronic effects of the antiepileptic drugs clonazepam (0.06, 0.13, and 0.25 mg/kg), phenytoin (2.5, 5, and 7.5 mg/kg), ethosuximide (40, 80, and 120 mg/kg), and valproic acid (40, 80, and 120 mg/kg) were evaluated in pigeons responding under a repeated acquisition procedure. At certain doses, acute administrations of all drugs impaired learning (i.e., increased errors) and reduced rate of responding. Appreciable tolerance developed to these effects with chronic exposure, although the physiological mechanism responsible for this outcome is unknown.

Gamma hydroxybutyrate (GHB) was administered intravenously to monkeys that had been pretreated orally for 2 weeks with various anticonvulsant drugs or with L-DOPA at different dosage levels. Continuous electroencephalographic (EEG) monitoring was performed during and after GHB administration. Bloood was assayed for GHB and for the anticonvulsant drug the animal was receiving. The EEG and behavioral changes produced by GHB were improved by ethosuximide and phenobarbital, made worse by phenytoin, and unchanged by L-DOPA.

The purpose of this paper was to investigate the effects of anticonvulsant ethosuximide upon physiological parameters, psychomotor reactions and electromyographic criteria. Ethosuximide increased the reaction times to flashes and the choice reaction time in most subjects, often provoked a greater amount of errors during choice reactions and decreased the average heart frequency. The functional activation during the tasks was diminished. The EEG showed no marked qualitative or quantitative changes. Ethosuximide reduced the maximum conduction velocity of the motor nerve and changed the action potential duration but not the action potential shape. There is no exact parallelism between the increase in reaction time and decrease of nerve conduction velocity. The drug effect upon psychomotor reactions seems to be caused by reduction of vigilance and an inhibitory effect upon the individual's motor responsiveness. Like other anticonvulsants, ethosuximide may alter the electrical properties of all excitable membranes and, by this ubiquitous site of action, exerts the described effects.