Michel Filion

ABNORMAL SPONTANEOUS ACTIVITY OF GLOBUS PALLIDUS NEURONS IN MONKEYS WITH MPTP-INDUCED PARKINSONISM

The goal of the study was to determine abnormalities in the spontaneous activity of globus pallidus neurons at the output of the basal ganglia, in cynomolgus monkeys rendered parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In parkinsonian compared to intact monkeys, the mean spontaneous firing rate of the neurons of the internal segment of the globus pallidus (GPi) increased but that of the prevailing neuronal population in the external segment (GPe) inversely decreased. Correspondingly, the mean modal interval between spikes shortened, suggesting increased excitation, in both the GPi and GPe. However, the mean proportion of intervals longer than 100 ms increased in the GPe but remained unchanged in the GPi, suggesting increased inhibition only in the GPe. In the two populations, bursting activities and the mean variability of firing rate increased. Concurrently, a small and distinct neuronal population located in the GPe and another located at the periphery of both the GPi and GPe displayed minor changes, which were however different from those observed in the GPi and in the prevailing neuronal population of the GPe. The intensity of changes varied with time and severity of nigral lesion. In severe parkinsonism, the neuronal activity at the output of the basal ganglia (GPi) is excessive.

Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys.

Extracellular single unit activity was recorded in the globus pallidus of waking Macaca fascicularis during passive limb movement. The main upper and lower limb joints were investigated bilaterally. The animals were either intact or rendered parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell counts showed that at least 90% of nigral neurons of the compacta-type were degenerated in the parkinsonian animals. In the intact animals, only 17% of the pallidal neurons responded to the natural stimulus. As already reported by others, the responses were typically related to movement about a single contralateral joint and in only one direction. In the parkinsonian animals, however, more neurons responded, often more vigorously, to the same stimulation. In many of these neurons the responses were elicited by movement about more than one joint of both upper and lower limbs or ipsi-and contralateral sides and in more than one direction. The increase in number and magnitude and loss of specificity of responses were much greater in the internal pallidal segment, where the number of responding neurons quadrupled. These results suggest that dopaminergic mechanisms regulate gain and selectivity in the basal ganglia. In animals with decreased dopaminergic functions, the excessive and unselective motor responses may explain all 3 major signs of parkinsonism: rigidity, tremor and akinesia.

Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism.

The mixed (D1 and D2) dopamine agonist apomorphine was injected (10-200 micrograms/kg, s.c.) to cynomolgus monkeys before and after they were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Motor behavior was examined together with corresponding neuronal activity in the external (GPe) and internal (GPi) segments of the globus pallidus, including a small population of neurons localized within the GPe and displaying a characteristic discharge at low frequency with bursts (LFB), and border (Bor) neurons localized at the periphery of the pallidal segments. In the intact animal strong but not weak doses of the drug induced generalized agitation without apparent neuronal effects. In 1 parkinsonian animal that showed some recuperation of normal behavioral and pallidal activity, weak doses induced agitation and partly reduced the signs of parkinsonism, again without apparent neuronal effects. The same results were obtained before day 21 after MPTP in a parkinsonian monkey that did not recuperate. After day 21, however, the drug acted at a shorter latency, completely abolished the signs of parkinsonism, induced dyskinesia, increasing with repetition of injections, and clear neuronal effects. The same results were obtained from the start in another monkey in which recordings were begun 398 days after MPTP. Nearly all GPi neurons decreased their firing rate following apomorphine. The reverse was true of the predominant neuronal population in the GPe. In both cases, the intensity of the changes in firing rate varied much between neurons following the same dose of apomorphine. When the changes in firing rate were moderate or null, abnormal bursting firing patterns were normalized. Both LFB and Bor neurons decreased their firing rate following apomorphine; LFB neurons being extremely sensitive. The selective D2 agonist RU-24213 induced behavioral and neuronal effects identical to those of apomorphine.

Activity of pallidal neurons in the monkey during dyskinesia induced by injection of bicuculline in the external pallidum

The present study was undertaken to determine whether dyskinesia, resulting from injection of the GABA antagonist bicuculline into the external globus pallidus of intact monkeys, is induced by hyperactivity of local external pallidal neurons and ensuing hypoactivity of neurons in the internal globus pallidus, at the output of the basal ganglia. Accordingly, 86% of responding external pallidal neurons increased and 56% of internal pallidal neurons decreased their activity, either exclusively or within biphasic responses. Whereas 29% of external pallidal neurons decreased and as much as 85% of internal pallidal neurons increased their activity. The latter unpredicted responses may be explained by diffusion of bicuculline from the external to the internal pallidum and by lateral monosynaptic inhibition within the external and its mirror image in the internal pallidum. With respect to individual injection sites, the hypoactive neurons in the internal pallidum tended to be grouped together and surrounded by hyperactive or unresponsive neurons. The changes occurred before and persisted during dyskinesia, suggesting that they were required to induce and maintain the dyskinesia. There were also changes in firing patterns, comprising long periods of silence, especially in external pallidal neurons close to the injection site. The periods of silence did not appear to result from depolarization block but rather from activation of receptors of inhibitory neurotransmission other than type A GABA. Dyskinesia therefore does not appear to result exclusively from a simple imbalance of activity between the pallidal segments, with hyperactivity in the external and hypoactivity in the internal segment, but also from imbalances within each pallidal segment, possibly with a center-surround organization.

Progressive increase of motor activity induced by 5-HTP in the rat below a complete section of the spinal cord

The greater part if not the whole amount of serotonin or 5-hydroxytryptamine (5-HT) present in the spinal cord I is contained within neurons whose cell bodies are located in the medulla 5. The immediate precursor of 5-HT, 5-hydroxytryptophan (5HTP), increases the excitability of spinal motoneurons located below a complete cord transection3, 9. It was shown that this occurs in the cat 9 and dog 7 not only immediately but also 3 weeks after spinalization, when all bulbospinal serotoninergic neurons are likely to be degenerated. On the other hand, the latency of the effect of 5-HTP was shown to be shorter in chronic than in acute spinal cats ~,9. This suggests that spinal neurons become more sensitive to 5-HT after spinal cord transection. We reinvestigated the effects of 5-HTP on motoneuronal activity in spinal rats. We used a simple method to quantify and determine the time course of change of motoneuronal activity induced by injections of 5-HTP at different times after spinalization. In female Wistar rats weighing 200 g, a complete spinal transection at the T-5 level was made under sodium thiamylal anesthesia. This was done by removing a portion of the cord by microdissection of vessels, and of nervous tissue under visual control through a microscope. The completeness of the section was further verified postmortem by visual and histological examination. For the next 10 days the rats were housed in individual cages and their bladders emptied manually twice a day. At intervals varying from one to 25 days after the section, silver wires were twisted around the quadriceps femoris and a reference electrode was fixed to the hip bone. These electrodes were linked by insulated wires coursing under the skin to a connector fixed on the back of the animal. Electromyographic (EMG) signals were amplified and displayed by a pen recorder (Nihon-Kohden RM45). The signals were also rectified, integrated and simultaneously displayed by the pen recorder. The integration was automatically reset at a fixed level. This produced deflections of the pen at a frequency proportional to the amount of E M G activity. The number of deflections per period of 5 min was counted to produce graphs. During the recording sessions, the animal was

Effects of agonists and antagonists of serotonin on spontaneous hindlimb EMG activity in chronic spinal rats

Abstract After spinal transection at the T-5 level in rats, 5-hydroxytryptophane (5-HTP) 100 mg/kg (i.p.) elicited discharges in both flexor and extensor muscles of the hindlimbs. This effect increased progressively after the transection until there was a 10-fold increase of the response at the twentieth day. This increase may correspond in part to denervation supersensitivity. The effect of 5-HTP could be suppressed by cyproheptadine, pizotiline, SQ 10 631 (a cinanserin derivative) chlorpromazine and also by methysergide. It could be mimicked by LSD, 5 MEDOMT, BOL 148, quipazine, and to some extent by tryptamine and methysergide. Drugs having a presynaptic action and drugs acting on noradrenaline, dopamine, acetylcholine receptors were without effect. The present model of integrated electromyography (EMG) in chronic spinal rats is a simple and sensitive method to study agonists and antagonists of 5-hydroxytryptamine (5-HT) in the lumbar segment of the spinal cord. The absence of 5-HT terminals makes it possible to distinguish drugs acting on presynaptic mechanisms.

Influence of contractile tension development on dynamic strength measurements of the plantarflexors in man

The influence of the contractile tension rise time on isokinetic force-angle records has been inferred from static force-time curves but has not been experimentally determined. The purpose of this study is thus to describe the influence of the contractile rise time on the force-angle curves produced during maximal voluntary, acceleration controlled, isokinetic plantarflexions at 30 degrees/s. Since we could not measure directly the period of force development unbiased by changes in muscle length during the movements, we devised an experimental strategy which allowed the computation of the dynamic force-time curve. Thus in five normal men, we first recorded force-angle curves produced during maximal voluntary plantarflexion movements preceded by maximal static pre-loading (D:-10 degrees Max) in order to eliminate the period of tension development from the force-angle record. Next, we recorded force-angle curves produced during maximal voluntary contractions initiated from two different starting angles without pre-loading (D:-10 degrees Min and D:0 degrees Min) to include the period of tension rise. The dynamic force-time curve was computed by correcting these force-angle curves (D:-10 degrees Min and D:0 degrees Min) for the hypothetical loss in force due to muscle shortening. We compared the relative (to remove the effects of force magnitude) computed dynamic force-time curves with relative static force-time curves measured at three different angles. We found the shape and several other parameters of all three static and both computed dynamic force-time curves to be similar (p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Brain nervous mechanisms involved in the so-called extra pyramidal motor and psychomotor disturbances.

2.3. The striopallidal (extrapyramidal) system 2.1.1. Outline of structures 2.1.2. Intrinsic nervous connections 2.1.3. Distribution of extrinsic nervous fascicles (outflow) 2.1.4. Relationship to thalamus, motor cortex and’cerebellofugal ascending nervous pathways The rubro-olivo-cerebella-rubral loop 2.2.1. Outline of structures 2.2.2. “Intrinsic” nervous connections 2.2.3. Distribution of extrinsic nervous fascicles (outflow) 2.2.4. Relationship to thalamus, striopallidal system, motor cortex and certain brain stem relay nuclei Brain stem relay nuclei and descending pathways 2.3.1. Rubrotegmentospinal tract 2.3.2. Vestibulospinal nervous pathways 2.3.3. Reticulospinal nervous pathways

Action of 5-Hydroxytryptamine, Substance P, Thyrotropin-Releasing Hormone and Clonidine on Motoneurone Excitability

We have investigated the influence on the excitability of lumbar motoneurons of 5-hydroxytryptamine (5-HT), substance P and thyrotropin releasing hormone (TRH), three substances which coexist in the same bulbospinal descending pathway and end in large part around motoneurons. We have also studied the effect of clonidine, an alpha 2 noradrenergic agonist. This was done in spinalized rats (T5) treated three weeks before with 5-7-dihydroxytryptamine. Under those circumstances 5-HTP (I.P.), 5-HT (intrathecally) TRH (I.P. or I.T.) and substance P (I.T.) all elicited a strong excitation of motoneurons as measured by integrated EMG of the hindlimb muscles. Substance P reduced by almost half the subsequent response to 5-HTP, 1 hour and 24 hours later. TRH given acutely did not modify the response to 5-HTP but given chronically for twenty one days by means of Alzet minipump, markedly increased the response to 5-HTP. Clonidine by itself decreased the excitability of motoneurons and antagonized the excitatory effect of 5-HTP and TRH. In a pilot trial, cyproheptadine, a 5-HT antagonist was shown to decrease the manifestations of spasticity in patients with a partial spinal lesion. Clonidine also appears to be of potential use in the treatment of spasticity.

Physiopathology of experimental Parkinsonism in the monkey.

Postural or Parkinson-like tremor, which results from the impairment of mechanisms which are predominantly lateralized in the brain, is most likely related to the combined impairment of the dopaminergic nigrostriatal pathway and the corresponding rubro-olivo-cerebello-rubral loop (without excluding the possiblity that other nervous mechanisms interconnected with these structures may represent an alternative disturbance). The integrity of the internal division of the pallidum and the ventrolateral area of the thalamus and their efferent fibers as well as the motor cortex and certain of its cortico-subcortico-spinal pathways (Figures 1 and 2) is apparently an essential feature for the elaboration of the rhythmic bursts associated with the appearance of postural tremor. The integrity of the spinal sensory roots and the rubro-tegmentospinal tract is not a prerequisite for the expression of postural tremor, a condition which seems essential for the production of rigidity. The latter facts suggest that the disturbances which subserve these two types of motor impairment, often concomitantly present in Parkinsonism, partially involve the impairment of different mechanisms although the loss of the DA fibers originating in the substantia nigra and ending in the neostriatum (Figure 1) appears to represent a disturbance common to both types of disorders. Bradykinesia which may be associated with an impairment of catecholamine metabolism (and more especially the neostriatal DA mechanisms) on both sides of the brain may also result from bilateral lesions of the pallidum or of its outflow corresponding, in the main, to the pallidothalamic fibers ending in the ventrolateral thalamus. The latter types of lesion most likely exclude the influence of the monoaminergic, cholinergic and gabaminergic activities normally originating in the striopallidal system and influencing the activity transmitted to other CNS mechanisms. Severe akinesia, however, apparently depends on more profound and generalized disturbances of brain monoamine metabolism with or without the involvement of other ill-defined mechanisms. At any rate the impairment of the brain DA mechanisms (and especially those of the neostriatum) seems to represent a major feature in the production of the Parkinsonian type of akinesia. Further work is needed to establish the relative importance of the loss of catecholaminergic mechanisms other than those of the neostriatum in the production of akinesia.