Behavioral toxicity of chronic ethosuximide and sodium valproate treatment in the epileptic baboon, Papio papio.

The purpose of this study was to assess the effects of chronic administration of gradually increasing doses of the anti-petit mal agents, ethosuximide (15-60 mg/kg/day) and valproic acid (7.5-240 mg/kg/day) on the performance of incremental repeated acquisition and incremental fixed-ratio tasks in the epileptic baboon, Papio papio. At approximately equipotent anticonvulsant doses, ethosuximide (45-60 mg/kg/day) was more behaviorally toxic than valproic acid (7.5-60 mg/kg/day), as determined by the ability of each drug to suppress the incremental repeated acquisition of behavioral chains. The behavioral deficits induced by ethosuximide (60 mg/kg/day) were still present 8 weeks after cessation of drug treatment in two of four animals. Evidence of enhanced acquisition of behavioral chains (decreases in errors) was noted in two of six animals during chronic treatment with valproic acid at a dose of 60 mg/kg/day but was never seen during chronic treatment with ethosuximide. Responding under an incremental fixed-ratio schedule of reinforcement was only affected minimally by either drug. These data suggest that 1) cognitive processes are more vulnerable to disruption by chronic ethosuximide administration than they are to chronic valproic acid administration, 2) performance under the more complex incremental repeated acquisition schedule is more sensitive to disruption than that under an incremental fixed-ratio schedule and 3) the effects of ethosuximide and valproic acid on performance under the incremental repeated acquisition schedule are not due to decreases in motivation or ability to manipulate the response levers.

Evidence for neurotransmitter abnormalities related to seizure activity in the epileptic baboon.

The experimental evidence that indicates that alterations in neurotransmitter activity exacerbate or diminish seizure responses to intermittent light stimulation in the Papio papio model of epilepsy is reviewed. Studies of the effects of drugs known to modify the synthesis, storage release, or activity of known or putative neurotransmitters are included. Catecholamines, to a lesser extent the indolamine, serotonin, and the inhibitory transmitter gamma-aminobutyric acid all alter seizures as do less well understood intrinsic hormones and pentapeptides. The anticonvulsant profile of the model is briefly reviewed. It is concluded that there is as yet no concrete evidence of an intrinsic deficit in any of the neurotransmitters to which the genetic photosensitivity of this model can be attributed.

Effects of haloperidol-induced dopamine receptor supersensitivity on kindled seizure development.

By using kindling by repetitive amygdala stimulation as a model of generalized seizure development in the rat, we have shown that dopamine receptor subsensitivity has been shown to occur in selected brain areas after the development of seizures. In the present study, the influence of initially altered dopamine receptor sensitivity on the development of seizures was examined by inducing receptor supersensitivity through chronic haloperidol injection before amygdaloid kindling stimulation. Rats injected with haloperidol (5 mg/kg i.p.) for 18 or 30 days were stimulated in the amygdala daily until full seizures were elicited. Starting 2 days after the last injection, rats treated with 5 mg/kg of haloperidol i.p. required significantly more stimulations than their respective control groups. The slowed rate of seizure development was not significant if the kindling stimuli were initiated 6 days posthaloperidol treatment nor if 10-mg doses of haloperidol were used for 30 days. [3H]Spiroperidol binding assays were performed on tissue from striatum and amygdala-pyriform cortex at various times after drug treatment. Increased receptor binding was observed in striatum and amygdala-pyriform cortex of all haloperidol treatment groups. These observations lend support to the hypothesis that dopamine plays a role in seizure suppression as an increased receptor sensitivity to dopamine delayed kindled seizure development.

The effects of constant light on EEG and seizure activity in the epileptic baboon.

The effects of a change from a standard photoperiod (12:12 LD, 45 fc) to that of constant low level illumination (LL, 5 fc) on electroencephalographic activity (EEG), photic seizures and urine cortisol excretion were investigated in the baboon Papio papio. Unlike the normal circadian cycle, in which maximal urine cortisol excretion occurred at 08.00 h and minimal at 20.00 h, rhythms in cortisol excretion were free running under constant light, shifting an average of 2 h/week toward an earlier time of day. The rhythms in seizure susceptibility and EEG spectral power, which were found to be roughly in phase with urine cortisol under conditions of 12:12 LD, were also altered. Average sensitivity to seizures was found to be increased throughout the 24h cycle, although no seizure responses were of the maximal severity obtained in 12:12 LD. A loss of rhythmicity and an overall decrease in total spectral power over the 1-60 c/sec range were observed in background EEG in the LL environment. An 'instability' in relative power within higher (15-30 c/sec) bands over time was also noted. These data suggesting loss of synchronizing cues may lead to disruption of background EEG and exacerbation of epileptic seizures.

The influence of D-penicillamine treatment upon seizure activity and trace metal status in the Senegalese baboon, Papio papio.

Reports suggesting participation of trace metals in processes of seizure initiation and propagation in humans and experimental animals prompted an investigation of the relationship between copper and zinc status and seizure activity in the Senegalese baboon, Papio papio. An evaluation of serum trace metal concentrations in three species of nonhuman primates revealed the presence of elevated zinc levels in P. papio moderately sensitive to photically induced seizures, compared with mildly seizure-prone and nonseizure-prone P. papio as well as nonseizure-prone primates. Papio cynocephalus and Macaca mulatta. By contrast, copper levels appeared similar in all three species. Chronic oral treatment with D-penicillamine, a chelating agent, resulted in marked protection against photic-induced seizures in the P. papio baboon, as well as changes in the trade metal status of serum and urine. Oral dosages of 30 to 40 mg/kg/day were sufficient to establish anticonvulsant effect over a period of 4 to 9 weeks in all animals tested without signs of toxicity or tolerance. Results suggest that metal chelation treatment may represent a new approach to the management of certain forms of human epilepsy.

EEG and anticonvulsant effects of dipropylacetic acid and dipropylacetamide in the baboon Papio papio.

The ability of dipropylacetic acid (DPA) and dipropylacetamide (DPM) to modify EEG and seizure activity was assessed in 4 female and 3 male Papio papio. Doses of 30-60 mg/kg of DPA given at intervals over an 8 h period produced blood levels of 19-44 micrograms/ml which were not protective against intermittent light stimulation (ILS). Administration of 150-200 mg/kg doses at intervals over a 36 h period produced blood levels greater than 150 micrograms/ml and were highly protective against ILS. Similar results were obtained following adminstration of DPM; however, DPM appeared to offer greater protection against ILS. A moderate amount of seizure control was obtained at blood levels of 60-91 micrograms/ml (DPA) and complete blockade occurred at levels greater than 100 micrograms/ml DPA. Background EEG changes were similar following either DPA or DPM and consisted of a striking increase in total spectral power with relative power changes in 10-20 c/sec range, the magnitude of which was related to blood levels of DPA. Both agents produced a quieting effect on behavior without severe depression.

Circadian periodicity of brain activity and urinary excretion in the epileptic baboon.

A 24-H rhythm in the proclivity of the baboon Papio papio to exhibit a seizure response to intermittent light stimulation (ILS) has been uncovered. Seizure response to ILS was found to be greatest in the morning at about 0900 h, 2 h after lights on, and least severe in the evening at about 2000 h 1 h after lights off. Urine cortisol and potassium excretion rhythms followed the same pattern as seizure susceptibility and sodium rhythms were 3 or 4 delayed. Mean values for urine cortisol per 4 h ranged from 25 microgram/4 h at the maxima (0400 to 0800 h) to 2 microgram/4 h at the minima (2000 to 2400 h). Electrolyte rhythms ranged from 13 to 3 meq/4 h for potassium and 1 to 5 meq/4 h for sodium. Changes in electroencephalographic (EEG) activity also accompanied the change in urine cortisol and potassium, and seizure sensitivity, Changes in the EEG at the diurnal minima (2000 h) consisted of a decrease in slow waves concomitant with an increase in fast activity in the 18-25 Hz range,

The influence of cortisone on EEG and seizure activity in the baboon Papio papio.

The ability of cortisone to modify EEG and seizure activity was investigated in the baboon, Papio papio. Acute intramuscular doses (0.5-4 mg/kg) caused a dose-dependent increase in seizure response to a flashing light stimulus. This increase in seizure response was apparent in both seizure duration and the spread of convulsive activity. Along with enhancement of seizures, cortisone was found to cause marked changes in the EEG, ranging from the appearance of interictal paroxysmal activity to alterations in spectral characteristics of the wave forms. Increases in slow waves appeared concomitant with a decrease in fast activity in the 18-25 c/sec range. Since previous studies have indicated that seizure proclivity in the Papio papio is maximal at the time of the day when cortisol excretion rates peak, these findings lend further evidence to the idea that corticosteroids may be involved in the thythmic variation of seizure activity in the baboon.

Photomyoclonic seizures in the baboon, Papio papio.

The inborn seizure response of Papio papio to intermittent light stimulation has been reviewed as a model of human epilepsy. The electrographic and clinical features have been described and useful methodology has been outlined. A diurnal cyclicity in seizure responsiveness has been described with greatest seizure severity at 8 AM in parallel with a rise in urinary output of cortisol. Hormonal influences on the seizure response have been described for ethinyl estradiol, thyroxin, and triiodothyronine. Evidence regarding neurotransmitter involvement has been reviewed. Data regarding use of the animal for anticonvulsant testing in single and chronic doses has been discussed. Particular advantages of the model for study of age-related drug effects and the assessment of the effects of chronically administered anticonvulsant agents on learning and memory have been described.

Learning and behavioral abnormalities in the seizure-prone baboon.

A high incidence of behavioral and learning difficulties has been found in juvenile seizure-prone baboons presented with a graded series of operant behavioral task challenges. The animals fell into two distinct groups based upon the rate at which their operant performance was able to develop, the amount of day-to-day variability in performance level, their ability to tolerate change, and the frequency of appearance of symptoms of emotionality. The association between learning problems and behavior problems in these seizure-prone baboons may correlate well with the deficits in both intellectual performance and social behavior that have been reported in some studies with human epileptics. In addition, the data suggest a relationship between familial factors and trainability, and between predisposition to seizures and trainability.

Alterations in learning performance in the seizure-prone baboon: effects of elicited seizures and chronic treatment with diazepam and phenobarbital.

A comparison was made of the effects of chronically administered diazepam and phenobarbital with those of elicited seizures on repeated acquisition learning in 3 prepubertal Papio papio. The learning task required the baboons each day to perform different sequences of lever presses on a three-lever behavior panel. Middle dose levels of both diazepam and phenobarbital were found to improve learning performance relative to base-line control levels, as measured by total errors, efficiency, and time required to complete chains of various lengths to a fixed criterion. The doses were well within therapeutically relevant seizure control and clinical blood level ranges. Higher doses of both drugs generally abolished the performance gains achieved with the lower doses. Seizures elicited twice weekly for 2--3 weeks, or daily for 7 days, induced no overall decrement in performance. Cyclicity in subsequent performance was, however, induced by each individual seizure during the twice weekly seizure period, and learning performance was found to be significantly worse at 42 hr than at 18 hr after each seizure. Implications of these data for acquisition of learning in the epileptic are discussed.

Measurement of anticonvulsant activity in the Papio papio model of epilepsy.

The status of Papio papio as a model of clinical epilepsy has been reviewed. The anticonvulsant effects of single doses of various classic and experimental agents have been compared against seizures induced in the P. papio by intermittent light stimulation. Long-acting but not short-acting barbiturates have been shown fully to control seizures with minor sedative effects. Diphenylhydantoin (in chronic doses only) and trimethadione are often effective but not consistently so. Diazepam and clonazepam block seizures at very low doses both acutely and chronically. However, an initial dose well above threshold seems essential if anticonvulsant effects are to be maintained under chronic administration of these compounds. Carbamazepine and SC 13504 (1-benzhydryl-4(6 methyl-2-pyridylmethyleneimino)piperazine), as well as two nonstimulant analogues of amphetamine, were shown to be promising anticonvulsants in this model. A biphasic action of tetrahydrocannabinol, anticonvulsant at a few micrograms per kilogram but not at higher doses, was also demonstrated. Finally, the anticonvulsant action of intraventricular epinephrine and norepinephrine was reported.