Opsoclonus in organophosphate poisoning.

Transient opsoclonus was observed in a patient who attempted suicide with the organophosphate insecticide Malathion (diethyl[dimethoxyphosphinothioyl]thiobutanedioate). Several toxins can cause opsoclonus, and these must be considered in its differential diagnosis. Eye movement disorders are one of the more common manifestations of organophosphate intoxication, and opsoclonus should now be included among these. Acetylcholine may be a neurotransmitter in the ocular motor pathway.

Involvement of nigrotecto-reticulospinal pathways in the iminodipropionitrile (IDPN) model of spasmodic dyskinesias: a 2-deoxy-D-[1-14C]glucose study in the rat.

Chronic administration of iminodipropionitrile (IDPN) to rats causes a persistent behavioral syndrome characterized by lateral and vertical head twitches, random circling, and increased tactile and acoustic startle responses. In order to identify brain areas which are affected in rats manifesting this syndrome, we used the autoradiographic 2-deoxy-D-[1-14C]glucose ([14C]DG) method to map cerebral glucose utilization in IDPN-treated rats. One day after the development of the dyskinetic syndrome, there were significant decreases in local glucose utilization in the substantia nigra pars reticulata (SNr) and compacta (SNc), the dorsal raphe, the superficial and deep layers of the superior colliculus, the inferior colliculi, the interpeduncular nucleus, the medial and dorsolateral geniculate nuclei, and the superior and lateral vestibular nuclei. There were also significant decreases in layer 2 of the cingulate cortex and in the temporal and occipital cortices. In contrast, there were no changes in the motor cortex, the caudate-putamen, the nucleus accumbens, or the median raphe. These findings suggest that deleterious effects of IDPN on the nigrotectal pathways which affect head and neck movements and circling behaviors via the brainstem reticulospinal tracts may play an important role in the IDPN-induced persistent spasmodic dyskinetic syndrome in rats.

Pemoline-induced abnormal involuntary movements.

Plasma pemoline levels were measured in 6- to 12-year-old, severely hyperactive males coincident with onset of abnormal involuntary movements. Acute exposure to pemoline (2 mg/kg orally) was associated with choreoathetoid movements of face, limbs, and trunk in five of 20 subjects in an acute study of pemoline pharmacokinetics. Also reported is a series of four chronically treated patients who developed choreiform movements and dyskinesias after variable periods of exposure from 3 weeks to 3 months with pemoline (1.5-2.0 mg/kg/day). Abnormal movements following acute or chronic exposure to pemoline cleared after pemoline discontinuation. Pemoline pharmacokinetics does not seem to be a primary determinant in the development of abnormal involuntary movements after chronic exposure. Total amount of pemoline absorbed may play a role in the development of choreoathetoid movements following acute exposure.

Deficits in reaction times and movement times as correlates of hypokinesia in monkeys with MPTP-induced striatal dopamine depletion.

1. We quantitatively assessed deficits in the initiation and execution of arm movements occurring after destruction of nigrostriatal dopamine neurons by systemic administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (Sigma). Three monkeys performed a reaction time task in which they reached toward a single and constant target for food reward. 2. After administration of MPTP, all three monkeys showed hypokinesia necessitating dopamine precursor or receptor agonist treatment. The partial recovery of one animal from initial akinesia after 19 days permitted discontinuation of dopaminergic drug therapy, although marked hypokinesia remained present. The two other animals displayed additional, intermittent phases of rigidity and activation tremor and needed continuous dopaminergic drug therapy for most of the postlesion period. 3. Administration of MPTP significantly prolonged EMG reaction time in prime mover muscles and arm movement reaction time by 47-225% and 18-129%, respectively, on the six sides of the three animals, compared with control measurements before the lesion. EMG and arm movement reaction time increased over consecutive trials in most sessions comprising 110-130 movements, the first 20 movements showing almost normal values. The delay time between onsets of EMG and arm movement showed unsystematic changes. These deficits in movement initiation were observed both with and without dopamine precursor therapy. They lasted during the whole testing period of several months. 4. Linear correlations between arm movement onset and EMG onset in the two prime mover muscles, the extensor digitorum communis and the biceps, showed coefficients of mostly 0.7-0.9, both before and after MPTP. These data suggest that the temporal relationship between onsets of arm movement and EMG were not substantially affected by MPTP. 5. Arm movement time was divided into two phases. The duration of movement between the resting key and the target, a small food-containing box located ahead of the animal, was denoted as reaching movement time. The following hand manipulation inside the food box was measured as box movement time. After MPTP, both measures were significantly prolonged by 10-103% and 12-251%, respectively, on the six sides of the three monkeys. These deficits in movement execution were observed both with and without dopaminergic drug therapy and during the whole testing period. 6. Task performance after MPTP treatment was studied in one monkey in the absence of dopaminergic drug therapy. EMG and arm movement reaction times recovered partially over several weeks, while the prolongations in reaching and box movement times remained unchanged.(ABSTRACT TRUNCATED AT 400 WORDS)

Intrathecal GABA, glycine, taurine or beta-alanine elicits dyskinetic movements in mice.

Dyskinetic, writhing-like movements, similar to those produced in mice after an intraperitoneal (IP) injection of acetic acid, were elicited by intrathecal (IT) injection of GABA, glycine, taurine or beta-alanine. Baclofen and muscimol failed to produce this behavior. While acetic acid-induced writhing is inhibited by narcotic and nonnarcotic compounds, GABA-induced writhing was found to be insensitive to pretreatment with either morphine or capsaicin. Moreover, acetic acid-induced writhing does not appear to involve GABAergic transmission as IT injections of nipecotic acid did not alter the intensity of response to IP acetic acid while it enhanced the response to IT GABA. Writhing induced by glycine was not inhibited by strychnine at subconvulsive doses, suggesting that it involves an action at strychnine-insensitive receptors. Together these data suggest that while the dyskinetic movements produced by inhibitory amino acids do not appear to reflect an alteration in nociception, they may mimic either the motor response to abdominal pain or spasticity.

Effects of 5-HT1A agonists and 5-HT2 antagonists on haloperidol-induced dyskinesias in squirrel monkeys: no evidence for reciprocal 5-HT-dopamine interaction.

Dyskinetic movements and dystonic postures may be induced by neuroleptics in monkeys that have undergone previous neuroleptic treatment, and these motor abnormalities constitute a primate model of drug-induced extrapyramidal symptomatology. In view of previous suggestions that brain serotonergic systems may tonically inhibit dopamine neurons, the effects of several new and selective 5-HT2 receptor antagonists and 5-HT1A receptor agonists were investigated in this model. Setoperone, a dopamine D2 receptor antagonist with extremely potent 5-HT2 antagonism, caused dyskinetic movements. Although ritanserin is a potent 5-HT2 antagonist with very weak dopamine antagonist properties, this drug did not antagonize dyskinesias but induced them when administered at a high dose (30 mg/kg). Buspirone induced dyskinesias and blocked apomorphine-induced climbing, supporting prior reports that it has dopamine antagonist effects. Gepirone, a 5-HT1A agonist with less marked dopamine antagonist properties, induced dyskinesias in only one of six monkeys at 30 mg/kg and did not block haloperidol-induced dyskinesias. 8-OH-DPAT partly attenuated haloperidol-induced dyskinesias, an effect possibly attributable to its weak dopamine agonist properties. Tonic inhibition of brain extrapyramidal dopamine systems by serotonin systems does not appear to characterize neuroleptic-related dyskinesias in squirrel monkeys.

Rats administered chronic neuroleptics develop oral movements which are similar in form to those in humans with tardive dyskinesia.

Oral movements (OMs) in rats chronically administered haloperidol (HAL), fluphenazine (FLU), or no drug were recorded using a computerized video analysis system which measured the distance between two fluorescent dots painted above and below the rat's mouth. The resulting data was analyzed using fast-fourier analysis. Following an initial period of sedation (decreased energy at all frequencies), the drugged animals (and especially the FLU animals) began to show increased oral movements of 1-2 Hz, an effect which increased substantially upon drug withdrawal. This is precisely the altered energy spectrum observed in humans with tardive dyskinesia.

Effects of classical and atypical antipsychotic drugs on isolation-induced aggression in male mice.

A series of classical, atypical and putative antipsychotic drugs were compared for their ability to inhibit isolation-induced intraspecies aggression with affinity for D-2 dopamine receptors and induction of akinesia. The majority of drugs tested significantly inhibited aggressive behavior only after doses that greatly decreased the ability of mice to move. Even though akinesia seemed to account for inhibition of aggression there was no apparent correlation with binding to striatal D-2 receptors.

Allylnitrile: a compound which induces long-term dyskinesia in mice following a single administration.

A single oral dose of allylnitrile (ALN) in mice pretreated with CCl4 induced behavioral abnormalities such as circling, hyperactivity, and head twitching, which lasted for a 4-month observation period. Histopathologically hemorrhage, demyelinated fibers and necrotic neurons were observed in the midbrain and pons 40 to 50 days after the administration of ALN. The head twitching was either reduced by treatment with serotonin and dopamine antagonists or enhanced by a serotonin releaser, suggesting that both serotonin and dopamine systems are involved in the behavioral abnormalities by ALN. These disorders by ALN may be used as an animal model of the dyskinetic syndrome.

A comparison of the anticonvulsant effects of 1,4- and 1,5-benzodiazepines in the amygdala-kindled rat and their effects on motor function.

Studies suggest that the 1,5-benzodiazepine clobazam possesses a favorable anticonvulsant profile due to its minimal neurotoxicity. The anticonvulsant and motor impairment effects of clobazam and 2 1,4-benzodiazepine, diazepam and clonazepam, were compared by dose-response analysis in amygdala-kindled rats and on 3 tests of motor function: gross motor impairment, a vertical screen test, and muscle tone. All drugs produced a significant, dose-dependent decrease in the duration of both behavioral and electrographic kindled seizure measures. Forelimb clonus suppression was the most sensitive measure of anticonvulsant drug effect. The order of potency for all effects was clonazepam greater than diazepam greater than clobazam. ED50s for the benzodiazepines' effects on motor impairment were compared to their ability to protect rats from forelimb clonus. Different spectrums of action for the various benzodiazepines were found depending on the comparison measure. Clonazepam had the most favorable ratio of potency for anticonvulsant vs. motor impairment activity when ataxia rating was the comparison measure. Diazepam had the most advantageous profile when the more sensitive screen test was used for comparison. Clobazam was not found to have a superior spectrum of action when compared across these measures. The results emphasize the importance of dose-response analyses and the consideration of behavioral measures used to assess beneficial and adverse effects of anticonvulsants.

[Clinical picture and dynamics of neurologic complications of drug therapy in epilepsy]. / Klinicheskaia kartina i dinamika nevrologicheskikh oslozhnenii u bo'lnykh épilepsiei pri medikamentoznoi terapii.

The authors have investigated the neurological complications in 108 epileptic patients treated for many years with anticonvulsants. The early diagnostic criteria were determined and the course of clinical manifestations described. The principles of treatment of the disease were grounded in terms of pathogenic diversity of its complications.

Effects of etybenzatropine and diazepam on levodopa-induced diphasic dyskinesias in Parkinson's disease.

Levodopa-induced onset and end-of-dose dyskinesia are rare but disabling disorders. Although they can be attenuated by increasing and dividing the daily dose of levodopa, this does not constitute a therapeutic approach. In this pilot study, etybenzatropine, an anticholinergic drug, and diazepam, a selective benzodiazepine, were administered in addition to a single dose of levodopa in nine patients with Parkinson's disease. Both drugs tended to decrease the severity and the duration of onset and end-of-dose dyskinesia and to increase the duration of action of levodopa on parkinsonian symptoms.

The prevalence and aetiology of long-term L-dopa side-effects in elderly parkinsonian patients.

Fifty-one elderly parkinsonian patients (mean age 80 years) on long-term (greater than 5 years) L-dopa therapy were identified from the patients within the three geriatric units in Edinburgh. Side-effects were identified in 57% of patients and tended to be mild in severity. Mean duration of disease was 10.2 years in those with side-effects and 6.7 years in those without (p less than 0.01). Past and present L-dopa side-effects are more likely to be caused by disease progression than by L-dopa therapy. It is therefore recommended that L-dopa should be prescribed at disease onset to elderly Parkinsonian patients.

Deficits in operant behaviour in monkeys treated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Six adult Macaca fascicularis monkeys were trained to perform an instrumentally conditioned, visually-guided forearm reaching task for fruit juice reinforcement. Once animals were overtrained on this task, they were given intravenous injections of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (0.15 to 0.33 mg/kg). Animals were tested daily for performance in the previously learned behavioural task and were assessed daily for abnormalities in motor functioning. Monkeys developed deficits in operant task performance characterized by termination of responses after an initial series of responses and long pauses between responses. Once an animal stopped responding to the task, responses could often be reinitiated if the experimenter guided the monkey through the task. This type of performance deficit was seen both before and without the appearance of distinct parkinsonian motor signs. Animals which developed motor signs had extensive ventral mesencephalic cell loss while an animal with performance deficits but without motor signs had cell loss restricted to the ventral substantia nigra pars compacta. The results demonstrate that operant performance deficits can be observed in MPTP-treated monkeys independent of the appearance of motor deficits.

Dextromethorphan does not protect against quinolinic acid neurotoxicity in rat striatum.

Dextromethorphan (DM, 40 or 80 mg/kg, i.p.) and MK-801 (3 or 10 mg/kg, i.p.) were compared in their ability to prevent the depletion of choline acetyltransferase (ChAT) activity in the rat striatum following intrastriatal injection of quinolinic acid. DM did not reduce striatal ChAT depletion following injection of either 300 or 150 nmol of quinolinic acid. Following injection of 300 nmol of quinolinic acid, MK-801 significantly reduced striatal ChAT depletion at a dose of 3 mg/kg and completely prevented striatal ChAT depletion at a dose of 10 mg/kg. In contrast to the potent neuroprotective action of MK-801, DM does not protect striatal cholinergic neurons from an acute challenge by an NMDA receptor agonist.

Screening and characterization of antiepileptic drugs with rapidly recurring hippocampal seizures in rats.

A method to efficiently screen antiepileptic drugs (AED) for their actions against complex partial and secondarily generalized seizures is presented. The procedure relies on rapidly recurring hippocampal seizures (RRHS) in rats which are first used to bring epileptic responses to a stable, fully kindled state and then to test 3 parameters--behavioral seizures, electrographic seizures, and afterdischarge thresholds--before and after drug administration. With the methods described, the effects of a given drug treatment can be thoroughly determined in a single study period. Quantitative determinations of dose-response, time-action and relative potency characteristics are readily ascertained. A battery of known AED, encompassing those in common clinical use, was studied with this system. Kindled motor seizures (classes 4 and 5) were more readily suppressed than limbic behavioral seizures (classes 1-3). Electrographic seizures were usually, but not always, shortened concurrently with suppression of behavioral seizures. Under the conditions of this study, afterdischarge thresholds were not elevated, indicating that a critical role of AED is to counteract seizure spread and prolongation. The overall behavior of the RRHS test system with AED was identical to that with traditional amygdala kindled seizures and results were in good agreement with the clinical responsiveness of the kinds of seizures that these experimental systems model. The features of RRHS make it a useful system for screening new agents for antiepileptic effects, even in circumstances where little or no information about the drug under study is available.