Gamma hydroxybutyrate in the monkey. II. Effect of chronic oral anticonvulsant drugs.

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.     

Gamma hydroxybutyrate in the monkey. III. Effect of intravenous anticonvulsant drugs.

Monkeys were treated intravenously with various anticonvulsant drugs before and after the intravenous administration of gamma hydroxybutyrate (GHB). Continuous electroencephalographic (EEG) and temperature monitoring was performed throughout all experiments. The GHB-induced EEG changes were abolished by ethosuximide and clonazepam, marginally improved by diazepam, and unaffected by phenobarbital. The GHB-induced myoclonic jerks were abolished by ethosuximide, significantly improved by diazepam, and worsened by clonazepam. Phenobarbital was effective in diminishing the frequency of GHB-induced myoclonic jerks only when given prior to administration of GHB. The GHB-induced stupor was improved only by ethosuximide. The GHB model of petit mal seizures is quite specific for drugs used in this disorder. GHB may play a role in the pathogenesis of absence seizures in children.     

gamma-Hydroxybutyric acid-induced seizures bear no relation to core temperature

The hypothesis that the absencelike seizures induced by gamma-hydroxybutyrate (GHB) are secondary to the effect of this drug on body temperature was tested using the prodrug of GHB, gamma-butyrolactone (GBL). Dosages of GBL less than 400 mg/kg produced a consistent profound hypothermia associated with bilaterally synchronous spike-wave discharges (SWD), whereas higher doses were associated with a more complex effect on core temperature associated with an EEG pattern of burst suppression. The threshold dose for the hypothermia and SWD was the same, but the temperature changes occurred later and lasted longer than the SWD induced by GHB. Rats aged less than 28 days were less sensitive to the hypothermia but more sensitive to the SWD produced by GHB than adult animals. The antiepileptic drug (AED) ethosuximide (ESM), known to attenuate GHB-induced SWD did so, but had no effect on the hypothermia, whereas GHB-induced hypothermia, but not SWD, was blocked by raising the ambient temperature from 26 degrees to 32 degrees C. These data do not support the hypothesis that GHB-induced absencelike seizure activity is a result of the hypothermia produced by this drug. Rather they suggest that the SWD and hypothermia are caused by separate, independent mechanisms.     

Gamma hydroxybutyrate in the monkey. IV. Dopaminergic mechanisms.

The electrical seizure activity and trancelike state induced in the rhesus monkey by gamma-hydroxybutyrate (GHB) were abolished by dextroamphetamine. Dextroamphetamine blockade of this neurophysiologic effect was overcome with chlorpromazine, a dopamine receptor blocker. These results suggest that the electroencephalographic (EEG) and behavioral effects of GHB are related to effects on dopaminergic systems. Such a relationship, if substantiated by further studies, might indicate that anticonvulsant drugs used to treat petit mal epilepsy have a dopaminergic mode of action.     

Decreased catalepsy response to haloperidol in the genetically dystonic (dt) rat

The ontogeny of petit mal-like seizures induced by gamma-hydroxybutyrate (GHB) was investigated. The prodrug of GHB, gamma-butyrolactone (GBL) was administered in varying dosages under continuous EEG monitoring from cortical and depth electrodes to rats varying in postnatal age from 1 to 85 days. The brain pharmacokinetics of GHB were determined at various ages as was the effect of ethosuximide on GBL-induced EEG changes. In adult rats, GBL produced a predictable sequence of electrical events beginning with spike bursts and progressing to polyspiking separated by low voltage activity. In 1-day-old rats, GBL produced voltage suppression with stupor. Poorly organized spiking appeared at postnatal day 3 and by day 9 marked burst suppression with polyspiking separated by low voltage activity was noted. However, the full array of electrical events seen in adult rats did not appear until day 28. Ethosuximide was ineffective against GHB seizure until the third postnatal week of life. GHB had a longer half-life in brain in the first week of postnatal life. These data suggest that in the rodent, petit mal-like seizure activity may require a fully mature brain and raise the possibility of different mechanisms being responsible for the various stages of EEG changes induced by GBL.     

Δ-Tetrahydrocannabinol: EEG changes, bradycardia and hypothermia in the rhesus monkey

Administration of delta 9-tetrahydrocannabinol (THC; 0.75-4.0 mg/kg IP) to rhesus monkeys produced a biphasic pattern of high-voltage slow waves (HVSW) and fast waves (HVFW) EEG, along with behavioral depression and alertness, respectively. The HVSW phase appeared 20 to 30 min after drug injection and was uniquely characterized by spike-bursts in frontal and temporal lobes and hypothalamus, theta-waves in parietal and occipital lobes, and generalized HVSW in subcortical regions. During the HVSW phase, bradycardia and hypothermia occurred, and animals exhibited depression or sedation. After the HVSW phase lasting for 3-4 hr, HVFW predominated in overall EEGs with marked decrease in neocortical spike-bursts. Bradycardia and hypothermia occurred simultaneously 20 to 30 min after drug injection and reached maximal levels (30-40 percent decrease in heart rate, 1.5-2.0 degrees C decrease in body temperature) 2 to 3 hr after injection. The dose- and time-response relationships for bradycardia and hypothermia paralleled the HVSW phase with behavioral depression. Animals were alert and calm during recovery from bradycardia and hypothermia. THC levels and disposition in blood correlated with bradycardia, hypothermia and EEGs and behavioral changes following THC administration.     

Appearance of EEG changes reminiscent of a secondary generalized epilepsy in a rhesus monkey inoculated with a strain of kuru.

In a group of rhesus monkeys (Macaca mulatta) inoculated intracerebrally and intravenously with a strain (Enage strain rhesus L6 56) of kuru already passaged in rhesus monkeys, 1 monkey presented the typical EEG pattern of epileptogenic encephalopathy reminiscent of the Lennox-Gastaut syndrome. This observation provides no direct evidence for the viral origin of epilepsies of this type. It does, however, show that it is possible to induce an epileptogenic encephalopathy by an unconventional infectious agent.     

Experimental kuru in the rhesus monkey: a study of EEG modifications in the waking state and during sleep.

EEG patterns recorded in the waking state and during sleep were studied in 6 rhesus monkeys inoculated with a strain of Kuru previously passaged in rhesus monkey (ENAGE strain, rhesus L6 56). The onset of the disease was confirmed by the appearance of various clinical signs in 4 monkeys 15 months after inoculation. At the 16th month, the first EEG modifications appeared during sleep, which became lighter. The waking EEG was abnormal during the mature phase of the disease; it was characterized by slow anomalies and scattered spikes. The sleep EEG still presented 3 stages of Slow Wave Sleep which, however, were totally unlike the physiological stages. REM sleep rapidly disappeared, as did the cyclic organization pattern. Irritative phenomena became very significant and, in particular, very frequent 'tonic seizures' were observed. Experimental Kuru thus appears, in the rhesus monkey, as an epileptogenic encephalopathy, which is differentiated from both the human disease and the experimental disease in the chimpanzee.     

Effects of gamma-hydroxybutyrate on the performance of monkeys in a Go/No-go visual discrimination task

It has been suggested that monkeys, administered gamma-hydroxybutyrate (GHB), manifest a state resembling petit mal status. This implies that an animal would produce erroneous responses immediately prior to, and discontinue behaviors requiring any cognitive effort concurrently with, an episode of GHB-induced generalized 3 cps wave-spike bursts in the EEG. This prediction was not confirmed in the present study. Rhesus macaques (Macaca mulatta) were trained to perform in a visual discrimination Go/No-go test. Thereafter bipolar transcortical electrodes were implanted in the hemisphere contralateral to the preferred hand. All monkeys discontinued to lever-press for water reward when administered GHB (125 or 250 mg/kg, esophageal intubation) and exhibited signs of reduced postural control and somnolence punctuated by episodes of hypermotility about 40-50 min after GHB. However, the monkey's difficulties in completing the program were not associated with the development of generalized hypersynchronous EEG activity. While occasional wave-spike bursts did occur, they were poorly regulated, often 'focal' (i.e. developed only in isolated areas), and had a frequency of 1.5-2 cps. In this state, animals could be easily roused by sensory stimuli. All of them reacted with a characteristic aversive-aggressive display when confronted by a direct gaze. These effects are interpreted to be more consistent with characterization of GHB activity as that of a potent hypnotic rather than a convulsant agent.     

Reversal of cognitive impairment by heptyl physostigmine, a long-lasting cholinesterase inhibitor, in primates.

Cholinergic replacement therapy for Alzheimer's disease using existing cholinesterase inhibitors is compromised by short duration, meagre benefits restricted to subgroups of patients, and peripheral toxicity. Heptyl physostigmine is a lipophilic carbamate derivative of physostigmine. In rhesus monkeys, heptyl physostigmine (0.2-0.9 mg/kg i.m.) fully reversed a scopolamine-induced cognitive impairment. Following oral administration in squirrel monkeys, heptyl physostigmine (8 mg/kg) induced long-lasting hypothermia (greater than or equal to 4 h), a centrally-mediated cholinergic effect. Erythrocyte acetylcholinesterase activity was inhibited by 86% at the time of peak hypothermia (180 min). Clinical trials with heptyl physostigmine will enable a more rigorous evaluation of cholinomimetic therapy for dementia.     

Convulsive effects of 4-deoxypyridoxine and of bicuculline in photosensitive baboons (Papio papio) and in rhesus monkeys (Macaca mulatta)

EEG and motor epileptic phenomena have been studied in 18 adolescent baboons from Senegal (Papio papio) and in 12 adult rhesus monkeys. The responses to intermittent photic stimulation (ILS) were recorded before and at various intervals after the i.v. administration of 4-deoxypyridoxine hydrochloride (4-DP) or of bicuculline.     

Experiential variables influencing play,foot-clasp mounting and adult sexual competence in male rhesus monkeys

(1) It is concluded that foot-clasp mounting, rather than social play, by juvenile rhesus monkeys is the appropriate index of the affectional development essential for normal adult heterosexual behavior in the male monkey. (2) The opportunity for continuous social interaction with peers, lasting at least three months, resulted in increased frequencies of display of foot-clasp mounts and decreased frequencies of social play by juvenile rhesus monkeys. (3) When the opportunity for continuous social experience was provided during the first year of life, the behavioral changes were manifested immediately and when this opportunity was delayed until late in the second year of life, changes in the frequency of play and mounting were correspondingly delayed. (4) Adult heterosexual competence was greatest in males that had the earliest opportunity for continuous social experience, intermediate in males with delayed social experience, and least in males with no opportunity for continuous social experience with peers. (5) Rearing conditions that produced the highest frequencies of foot-clasp mounting were associated with the highest adult heterosexual competence and rearing conditions that produced the highest frequencies of social play were associated with the lowest adult heterosexual competence.     

Seizure susceptibility and electroencephalogram power spectra alterations at various phases of the lipopolysaccharide-induced hypothermic response in biotelemetered rats

The neuronal excitability has been evaluated at various phases of lipopolysaccharide (LPS; E. coli O111:B4, 250 μg/kg, ip)-induced hypothermia including the initial phase, the plateau (including the nadir) and the end of the response in biotelemetered adult Wistar rats. The latency of pentylenetetrazole-induced seizures (60 mg/kg, ip) was lower at the initial phase, but a clear anticonvulsive activity was observed at the end of the hypothermic response. Seizure parameters did not change at the nadir. There was no electroencephalogram (EEG) spike-wave activity generation at either phase of the LPS-induced hypothermia. Meanwhile, the power of the 12-32 Hz beta band of the EEG spectra increased at the initial phase. This increment persisted at the plateau where there was also a decrease in the 1-4 Hz delta power. The data indicate that spike-wave activity is not facilitated during LPS-induced hypothermia but, proconvulsant and anticonvulsant activities occur sequentially depending on the phase of the response. The EEG power spectra also change. These effects may not be attributed merely to the reduction of body temperature. Thus, it is possible that pathophysiological mechanisms involved in the development of hypothermia may also be responsible for neuronal excitability changes in rats.     

An automated movement assessment panel for upper limb motor functions in rhesus monkeys and humans.

As part of our studies of age-associated changes in motor functions, we have designed an automated movement assessment panel (MAP) to evaluate upper limb and hand movements. Here we describe two versions of the MAP, one for human testing and one for nonhuman primates, and methods for conducting parallel tests in rhesus monkeys and human volunteers. The results are reported from a battery of tests on young adult rhesus monkeys (n = 10, 5-8 years old), young adult human subjects (n = 10, 18-22 years old) and ten aged human subjects (n = 10, 66-68 years old) to demonstrate the capability of the MAP in quantifying arm and hand movement times. The performance times on the two simplest tasks tested were consistent from trial to trial, demonstrating that a stable behavioral baseline could be established for evaluating changes in motor functions over time and assessing treatments for improving motor functions. Motor learning was seen in the more complex movement tasks tested, indicating their usefulness in analyzing this behavior. Finally, age-associated changes in performance times were robustly delineated by the four tasks evaluated in the human subjects.     

The immobilization response in rhesus monkey: a behavioral and electroencephalographic study.

Rhesus monkeys maintained in individual cages are rarely inactive when observed by humans unfamiliar to them. It has been observed that these animals display a greatly reduced behavioral repertoire after they are transferred to primate chairs. The present study used systemic behavioral observations to document those changes and to examine additional changes produced by arm restraint. Chair restraint was associated with a reduction in activity which was intensified when animals were further immobilized by arm restraint. This immobilization produced a reduction of tone in all limbs, a reduction of spontaneous behavior, and the appearance of eye closure. Electroencephalographic (EEG) correlates of the behavioral changes were examined also, using quantitative data generated through power spectral analysis of sensorimotor cortical EEG signals. Immobilization was accompanied by a significant increase in spectral density at 12 to 15 Hz which was most marked at mid and far lateral rholandic recording sites. No other significant changes were seen in the frequency bands studied. When the immobilized animal was alerted with novel stimuli, lower frequencies were attenuated but 12- to 15-Hz activity remained enhanced. These findings indicate that a unique immobilization response is elicited by restraint in the rhesus monkey which is associated with discrete changes in both behavior and accompanying EEG patterns.     

An application of long-term frequency analysis in measuring drug-specific alterations in the EEG of the cat.

A method is described for the quantitative measurement of "drug-specific" effects on the EEG of the cat. These effects are dose-related and are independent of the normal sources of EEG variation associated with the sleep-waking cycle. Drug-induced changes are expressed as characteristic alterations in frequency spectra and the time courses of these effects are followed for 5 h following administration of the test compounds. Atropine sulfate (0.5 and 2.0 mg/kg) and physostigmine salicylate (0.05 and 0.20 mg/kg) were administered to three unanesthetized and unrestrained cats and a broad-band frequency analysis was performed on the spontaneous brain electrical activity recorded from the prepyriform cortex, ventral hippocampus, lateral geniculate nucleus and the midbrain reticular formation. The resulting data were used as input to discriminant and canonical statistical analysis programs employed to abstract "drug-specific" patterns of frequency change. It was found that both atropine and physostigmine produce alterations in EEG frequency spectra which are clearly distinct from those patterns associated with the sleep-waking cycle and thus neither compound results in what has been characterized as an "EEG-behavioral dissociation".     

The Ontogeny of GABAergic Enhancement of the γ-Hydroxybutyrate Model of Generalized Absence Seizures

The ontogeny of GABAergic enhancement of generalized absence seizures was examined in the gamma-hydroxybutyrate (GHB) model of generalized absence seizures. The GHB seizure was quantitated in developing and adult rats in the presence of varying doses of the GABAa agonist muscimol or intracerebroventricularly (i.c.v.) administered GABA. Both GABA and muscimol potentiated GHB-induced seizures in an age-dependent fashion. The adult dose of 1 mg/kg muscimol was extremely potent in rats less than 28 days of age and resulted in the death of all younger animals tested secondary to profound hypothermia. A dose of 0.1 mg/kg muscimol was associated with a significant prolongation of GHB seizure in rats less than 35 days of age, but had no effect on older animals. The response to GHB was also age dependent, with the greatest sensitivity occurring during the fourth and fifth week of life. The developmental sensitivity of the rat to GHB seizure correlated with enhancement of the seizure by muscimol and GABA, and both phenomena parallel the maturation of thalamocortical recruiting mechanisms thought to play a role in the pathogenesis of the bilaterally synchronous spike wave discharges that characterize generalized absence seizures.     

脑超深低温下猴脑血流阻断时间窗的研究

目的 探明选择性脑超深低温技术对常温条件下猴脑血流阻断有效治疗时间窗.方法 10只恒河猴分为3组:常温组(n=3);深低温I组(n=4):脑血流阻断15min开始深低温治疗;深低温Ⅱ组(n=3):脑血流阻断20min开始深低温治疗.双侧颈动脉和颈静脉系统分离、脑血流阻断建立严重脑缺血缺氧模型.深低温组动物通过一侧颈内动脉灌注4~C林格氏液同侧颈内静脉回流,阻断其他颈动脉和颈静脉血管,脑温维持在(15.3±1.04)℃、中心体温(35.1±1.10)℃.维持深低温60min后恢复正常脑血流.常温组动物采用相同方法脑灌注37℃林格氏液.观察猴生存率、脑神经功能状况和病理形态.结果 4只脑血流阻断15min开始深低温治疗的猴死亡3只、1只长期存活;3只脑血流阻断20min开始深低温治疗和3只常温组猴全部死亡.死亡动物脑干出现神经元死亡.结论 常温条件下严重或完全脑缺血缺氧有效低温复苏时间为10min、15min内低温复苏成功率高,15min以上开始深低温复苏效果差.     

EEG and psychopharmacology.

The waking EEG bears direct relations to chemical changes in the brain induced by drugs. The waking EEG is responsive to the unique characteristics of psychoactive drugs. Their EEG signatures are predictive of their short-term behavioral effects and of their clinical efficacy. This association has led to the development of cerebral electrometry - a technique to predict a drug's clinical profile from experimental trials in normal volunteers. The technique is also useful in pharmacodynamic studies. Cerebral electrometry depends on careful control of behavioral variables, quantification of EEG effects and statistical processing of the data. The EEG-behavioral associations do not depend on a single method of quantification. Behavioral association is predicted for animal studies as well. Lacking, however, are studies in animals with adequate behavioral controls, clinical correlations of direct use to the individual patient and robust tests of this association hypothesis. The past decade has shown the utility of quantitative EEG studies and improved the methodology to a practical art. The next decade should see the techniques used by classical pharmacologists, mindful of the restraints inherent in animal models of the mental aspects of behavior.     

The influence of natural sleep on focal spiking in experimental temporal lobe epilepsy in the monkey.

In 12 rhesus monkeys, made epileptic by injection of alumina cream into the temporal lobe structures, the changes of spike frequency were studied in wakefulness and natural sleep on 78 occasions. Five monkeys had a focus in the lateral surface of the temporal lobe and seven had a focus in the mediotemporal structures. Basic cortical and subcortical EEG patterns, recorded through chronic indwelling electrodes, showed fairly consistent changes in the course of natural sleep, allowing a classification of the sleep into stages. During slow wave sleep, the focal spikes increased in all 12 cases. The increase was more prominent during the light stage of slow wave sleep in the neocortical foci and during deep stage in the mediotemporal foci. During REM sleep, the mediotemporal foci showed a marked decrease of spiking, whereas changes in the neocortical foci were inconsistent.