Hair trace elements in Friedreich's disease.

Concentrations of zinc, copper, manganese, chromium, cobalt and selenium were measured in the hair obtained from subjects with Friedreich's disease, other inherited ataxias and neurological control patients. Although zinc and copper concentrations were significantly higher in Friedreich than in the two control groups, the mean values for all groups were well within the normal range. No major deficiency in zinc or selenium was demonstrated in Friedreich's disease using the approach. This does not, however, indicate that there is no defect in zinc and selenium metabolism, availability or transport in this disorder.

Oral lecithin and linoleic acid in Friedreich's ataxia: I. Design of the study, material and methods.

A clinical and biochemical evaluation of twenty-two patients with Friedreich's Ataxia and ten normal controls was undertaken in 1980 to assess the effect of lecithin and linoleic acid supplements on the course of the disease. The trial consisted of two consecutive six months periods on either supplements in a double-blind crossover fashion. Clinical appraisal was performed with regards to the following parameters: joints mobility, muscle strength, equilibrium, coordination, motor accuracy, speech and numerous day to day activities. Blood samples were obtained at the beginning and in the course of the trial for enzymatic determinations. This paper describes the methodology of the study.

Effect of brain peptides on hypokinesia produced by anterolateral hypothalamic 6-OHDA lesions in rats.

Intraventricular injections of substance P, TRH and somatostatin were administered to rats rendered hypokinetic by bilateral microinjections of 6-hydroxydopamine into the anterolateral hypothalamus, Only substance P in a dose of 0.30 micrigrams/rat significantly increased motor activity as determined by photocell counts in a 5 min test session immediately after administration of the peptide. Behavioral observations indicated that grooming and not locomotion was mainly responsible for the greater activity scores. None of the three peptides at the doses examined potentiated or reduced the increased activity induced by 1 mg/kg apomorphine. Stereotyped behavior was also not affected by previous injections of substance P and somatostatin but was enhanced in animals which had received 5 micrograms/rat TRH 30 min prior to apomorphine.

Ouabain induced seizures: site of production and response to anticonvulsants.

Ouabain, an inhibitor of Na+ -K" -ATP'ase, has been administered intraventricularly to rats to study the effect of impairment of membrane transport mechanisms on the genesis of seizures. Running and leaping seizures occur rapidly after injection of ouabain in a low volume (10 microliter) when the maximal uptake of ouabain (39.8%) is the hippocampus. Generalized clonic-tonic seizures are induced by higher volume injections (50 microliter) associated with wider distribution of ouabain, including the cerebellum and brainstem. Ouabain was injected into cerebral cortex, caudate nucleus, dorsal hippocampus, fastigeal nucleus, ventrolateral mesencephalic reticular formation and cerebellar cortex. The cerebellar injections produced both running and leaping and generalized clonic-tonic seizures. It is suggested that this results from decreased inhibitory effect of vermal and paravermal Purkinje cells on intra-cerebellar nuclei, which alters cerebellar influence on the reticular formation and the limbic system. Diphenylhydantoin, phenobarbitone, phenacemide, carbamezepine and clonazepam but not ethosuximide are effective against generalized clonic-tonic seizures, suggesting that this is a model for "grand mal" but not "petit mal" seizure mechanisms. It is furthermore suggested that running and leaping are subcortical, probably limbic, seizures that are most relevant as a model for temporal lobe seizures.

Differential behavioral activities from anterior and posterior hypothalamic lesions in the rat.

Bilateral 6-hydroxydopamine injections into the anterolateral (AL) or posterolateral (PL) portions of the hypothalamus produced hypokinesia, catalepsy, rigidity and severe weight losses due to aphagia and adipsia. Subcutaneous administration of apomorphine, 1 mg/kg, 48 hr after 6-OHDA injections reversed temporarily the hypokinesia in both AL and PL 6-OHDA groups. However, qualitative and quantitative differences in the behavioral responses to the drug were observed. Motor activity as measured by photocell counts was significantly greater in AL 6-OHDA rats. Apomorphine induced stereotyped behavior in both groups; however, the predominant behavioral responses were oral stereotypies in PL 6-OHDA animals and sniffing in AL 6-OHDA rats.

Hypokinesia produced by anterolateral hypothalamic 6-hydroxydopamine lesions and its reversal by some antiparkinson drugs.

Hypokinesia produced by stereotaxic microinjection of solutions of 6-hydroxydopamine into the anterolateral hypothalamus of male rats is accompanied by a generalized reduction in brain noradrenaline levels and a reduction of dopamine in the striatum and cerebral cortex. The hypokinesia is reversed by the putative dopamine-receptor agonists apomorphine, ET-495 and CB-154 as well as by the amino acids L-Dopa and m-tyrosine when administered in combination with the peripheral decarboxylase inhibitor Ro 4-4602. The relative importance of noradrenergic and dopaminergic systems in the mediation of the action of anti-akinesia drugs is discussed.

Behavioral effects in rats following intrastriatal microinjection of manganese.

We have demonstrated that injection of manganese into one caudate nucleus in rats results in a predominant ipsilateral turning behavior, accompanied at higher doses by an intermittent, alternating and dose-related incidence of contralateral turning and stereotypies. Although the pharmacological evidence produced (effect of alpha-MT, L-DOPA, pargyline) indicates a definite participation of the dopaminergic system in the latter two phenomena, it is probable that ipsilateral turning is the result of involvement of other transmitter systems as well. Tegmental serotoninergic and intrastriatal cholinergic pathways appear to be involved in the production of the basic postural asymmetry resulting in turning. The amount of interference with the nigrostriatal and mesolimbic dopaminergic pathways may determine the speed of circling, and the concurrent inhibition of locomotion. This is more evident with bilateral injections. Manganese appears to act at presynaptic levels within the striatum by blocking release of the transmitter, thus creating a localized, relative deficit in caudate function. The end result is the release of the dominant "ipsilateral syndrome-inducing system' from its inhibitory control. Repeated or chronic administration of this metal in man or animals is known to result in a brain dopamine and/or serotonin deficit commensurate with the clinical manifestations of bradykinesia and dystonia. Our results are compatible with the anatomical findings of Poirier and collaborators and tend to support the dual ipsilateral and contralateral syndrome-inducing systems in the caudate postulated by Cools, and the complementary roles of dopamine, serotonin and acetylcholine within that nucleus. No one transmitter is involved alone in the experimental production of the manganese syndrome, or of its component symptoms.

Progress in understanding Huntington's chorea.

The present paper analyses the new data accumulated since 1972 concerning the etiology and pathogenesis of Huntington's chorea. Particular attention is paid to the respective roles of the dopaminergic and GABA-ergic systems.

Apomorphine: sterotyped behavior and regional distribution in rat brain.

The distribution of apomorphine following subcutaneous injection of 20 mg/kg (as the hydrochloride) was measured spectrofluorometrically in specific regions of rat brain. Measurable concentrations were found in the brain within a few minutes of injection, the drug was still detectable for at least 60 min in all regions, and maximum concentration was observed 20 min after injection. Stereotyped behavior, characteristic of apomorphine action, followed a time course parallel to accumulation of the drug in the brain.

Apomorphine and piribedil in rats: biochemical and pharmacologic studies.

We studied the biochemical and pharmacologic modes of action of piribedil and apomorphine in the rat. Although both drugs have many points in common, they are also different in many of their manifestations. Apomorphine causes high-intensity, short-duration stereotyped behavior; it is distributed within the brain in uneven fashion, the striatum being the area of lowest concentration as measured by fluorometry. Direct stereotactic injection within the dopaminergic mesolimbic system, and particularly the tuberculum olfactorium, produced constant intense responses. All effects of apomorphine can be blocked by pimozide, but propanolol, a beta blocker, only reduces aggression and ferocity, leaving stereotyped behaviors intact. Finally, L-5-HTP tends to reduce aggression, ferocity, and to a lesser extent stereotypy; MIF or piribedil, as well as reserpine, potentiates the stereotyped behaviors induced by apomorphine, whereas L-DOPA usually decreases them. Piribedil, on the other hand, causes low-intensity, long-duration stereotyped behavior. It is distributed within the brain almost uniformly. Most effects of piribedil can be blocked by pimozide, but propanolol blocks only aggression and ferocity, leaving stereotyped behaviors intact. On the other hand, clonidine, an alpha-receptor agonist, blocks stereotyped behaviors induced by piribedil but markedly increases aggression, ferocity, and motor activity. L-5-HTP and L-DOPA have little effect on piribedil-induced manifestations. Reserpine decreases piribedil stereotypy. The main metabolite of piribedil, S 584, had no clear-cut pharmacologic action in our hands at the dosage used. It is concluded that both apomorphine and piribedil produce stereotyped behavior by modifying the physiologic balance between mesolimbic and nigrostriatal dopaminergic systems. The other actions of apomorphine and piribedil upon aggression, ferocity, and motor activity are not always in parallel and depend probably on the fact that piribedil is less specific, affecting also noradrenergic, serotonergic, histaminergic, and/or cholinergic circuits. The usefulness of piribedil against some forms of human tremor and its low-intensity antiakinetic action probably result from this pattern of pharmacologic activity.