L.J. Poirier

Non-specific histopathological changes induced by the intracerebral injection of 6-hydroxy-dopamine (6-OH-DA)☆

Abstract The injection of 6-hydroxy-dopamine (6-OH-DA) directly into the brains of rats and cats results in necrosis of all tissue surrounding the site of the injection. Under such conditions monoaminergic cells degenerate only in so far as their cell bodies or their axonal processes are within the area of destruction resulting from the injection of 6-OH-DA. In this regard 6-OH-DA-induced lesions are not different from lesions produced by electrocoagulation. The injection of 6-OH-DA into the lateral ventricle of the brain results in the destruction of the ependyma and the adjacent nervous tissue at the level of the corresponding injected ventricle and foramen of Monro, the third ventricle, the cerebral aqueduct and the fourth ventricle. It is also associated with an enlargement of the whole ventricular system. Therefore the hypothesis that 6-OH-DA injected intracerebrally more specifically destroys catecholaminergic neurons is not supported by the data disclosed in this study. The toxic effect of 6-OH-DA is more likely to be related to the formation of peroxide (H2O2) as a consequence of its rapid auto-oxidation at pH 7.

The nigrostriatal pathway: a correlative study based on neuroanatomical and neurochemical criteria in the cat and the monkey.

Abstract Localized lesions of the corpus striatum result in a regional cell loss in the ipsilateral substantia nigra. Unilateral lesions of the ventromedial tegmental area (Tsai) in the upper midbrain or caudal hypothalamus result in a complete cell loss in the corresponding substantia nigra and nucleus parabrachialis pigmentosus. The latter morphological changes are associated with a decreased concentration of dopamine in the ipsilateral corpus striatum. Lesions of the rostrolateral hypothalamus involving the region of the medial forebrain bundle (MFB) produce similar morphological and chemical changes. Caudolateral lesions of the substantia nigra result in a decreased concentration of dopamine in the laterocaudal part of the corpus striatum corresponding to the caudal putamen. The interruption of the striatonigral fibers does not produce any cell change in the substantia nigra. Lesions of the entopeduncular nucleus or of the ventral thalamus do not produce any cell change in the substantia nigra and are associated with a normal concentration of dopamine in the corpus striatum. These results suggest that the nigrostriatal fibers establish a topographical relationship between corresponding regions of the substantia nigra and the corpus striatum similar to that disclosed in the striatonigral pathway. This striato-nigro-striatal loop represents a peculiar mechanism involved in the synthesis of striatal dopamine.

Cholinesterasic striatopallidal and striatonigral efferents in the cat and the monkey

Summary The study of the topographical distribution of the cholinesterases in the monkey and cat brain revealed that groups of fibers in the internal capsule, in both divisions of the pallidum, in the comb system and in the substantia nigra have an intense acetyl-cholinesterase activity. By comparison with normal material stained for fibers the above cholinesterasic fiber bundles correspond to the striatopallidal and striatonigral fibers which stained green after fast blue or greyish after hematoxylin. These fibers which lose their cholinesterase activity several weeks after lesions in the caudate nucleus but not after lesions associated with a complete cell loss in the substantia nigra have the same origin, course and termination as the striatopallidal and striatonigral fibers disclosed after silver impregnation in experimental animals. These striatal efferents to the pallidum and substantia nigra represent the richest cholinesterasic pathway within the central nervous system. In addition they contribute to a striatonigrostriatal loop apparently acting on the dopaminergic neurons of the substantia nigra and thus maintaining a proper level of dopamine in the striatum. This cholinergic system and its related structures are better developed in the monkey than in the cat.

The rubro-olivo-cerebello-rubral loop and postural tremor in the monkey.

Abstract The interruption of the rubro-olivary (from the small-celled red nucleus) or olivocerebellar fibres or of the superior cerebellar peduncle or destruction in the area of the lateral cerebellar nuclei did not result in any important and sustained motor impairment. The injection of harmaline following the interruption of the olivocerebellar (before their crossing) or rubro-olivary fibres induces postural tremor in the contralateral limbs. The injection of harmaline following lesions of the superior cerebellar peduncle or the interruption of the olivocerebellar fibres (after their crossing) or lesions in the area of the lateral cerebellar nuclei induces postural tremor in the ipsilateral limbs. It is concluded that the interruption of the rubro-olivo-cerebello-rubral loop and its interconnections represents an important feature in the appearance of postural tremor. Sustained postural tremor, however, will appear only after the concomitant involvement of certain upper brain stem monoaminergic mechanisms, a disturbance which is apparently duplicated by the effect of harmaline.

Parkinsonian akinesia, rigidity and tremor in the monkey

Parkinsonian postural tremor and rigidity most likely involve the disruption of the dopaminergic (DA) nigrostriatal mechanisms and the corresponding rubro-olivo-cerebello-rubral loop without excluding the involvement of related dentato-rubral and dentato-thalamic nervous fascicles. The integrity of the magnocellular division of the red nucleus and of the rubrotegmentospinal pathway, however, is apparently essential for the expression of rigidity. Akinesia most likely results from the bilateral involvement of brain stem catecholaminergic (CA) mechanisms including the DA nigrostriatal pathways. Finally the integrity of the pallidothalamic fibers seems to represent an essential feature for the improvement of these motor disorders by DA agonists, suggesting that certain of these agents, such as apomorphine, exert their main effects through the neostriatal DA receptors.

Morphological characteristics of the acetylcholin-esterase-containing neurons in the CNS of DFP-treated monkeys ☆: Part 1. Extrapyramidal and related structures

Abstract The distribution of acetylcholinesterase (AChE, EC3.1.1.7) within extrapyramidal and related structures was studied in 4 monkeys following the i.m. administration of bis-(1-methylethyl) phosphorofluoridate (di-isopropylfluorophosphate: DFP). In 1 animal, sacrificed 4 hr after the injection of 0.43 mg/kg DFP, AChE is virtually absent in all structures. In the other 3 animals, which received 0.20 mg/kg DFP 10, 12 and 18 hr prior to sacrifice, AChE activity is greatly reduced in the neuropil of those structures which normally show intense AChE activity in pharmacologically unmanipulated monkeys. As a consequence of the lower background AChE activity in the latter 3 DFP-treated monkeys, the perikarya and processes of several groups of neurons can be readily identified. The perikarya and processes of two types of neurons of the neostriatum, representing a small percentage of all neurons in this structure, are intensely stained. They apparently correspond to the chromatic giant aspiny neurons and the achromatic medium-size “spidery aspiny” neurons. Most perikarya and processes of the neurons of the medial and lateral divisions of the pallidum, as well as the morphologically similar neurons of the pars reticulata of the substantia nigra, display light to moderate AChE activity. The pars compacta of the substantia nigra contains a small number of intensely stained elongated and triangular neurons and numerous moderately stained ovoid neurons whose processes are very lightly reactive. The cell bodies of the neurons of the subthalamic nucleus and associated groups of neurons (nucleus ansae peduncularis) are moderately stained whereas the perikarya and processes of the subnucleus compactus of the pedunculopontine tegmental nucleus are intensely and moderately stained, respectively. Numerous large and multipolar neurons associated with the lenticular nucleus (intralamellar groups) or the pallidum (peripallidal groups) including the nucleus ansae lenticularis have somata and processes which show an intense AChE activity. Certain of the latter groups of neurons, partially interspersed with the neurons of the substantia innominata, correspond in part to the nucleus basalis of Meynert. The present data are compatible with the idea that the large AChE neurons of the neostriatum may be the source of the acetylcholinesterasic striatopallidal and strionigral fibers. The similarity between the neurons of the pallidum and those of the pars reticulata of the substantia nigra suggests that the latter structure may represent a caudal extension of pallidal tissue. Therefore, the nigrothalamic projection, which has been claimed to originate in the pars reticulata of the substantia nigra, would correspond to pallidothalamic projections.

Correlative neuroanatomical and neuropharmacological study of tremor and catatonia in the monkey

Abstract A parkinson-like tremor of the limbs in monkeys with certain brain lesions results from the combined involvement of the rubro-olivo-cerebello-rubral loop and the corresponding nigrostriatal dopaminergic mechanism. The interruption of the dopaminergic mechanism may be pharmacologically duplicated by the administration of α-methyltyrosine, 3, α-dimethyltyrosine, α-methyldopa, thioproperazine or reserpine; these drugs induce postural tremor in monkeys with lesions of the rubral loop. Thioproperazine, reserpine and α-methyltyrosine given in sufficient amounts lead to a gradual decrease of locomotor activity, progressing to a catatonic state in the operated or unoperated monkeys. 3,4-dihydroxyphenylalanine has a transient, reversible effect on the tremor in lesioned monkeys and on the catatonia in unoperated animals when these states have been induced by α-methyltyrosine or reserpine. Apomorphine can rapidly alleviate reserpine-induced tremor. Benztropine also has a favourable effect on the tremor and catatonia induced in these ways, as well as on the thioproperazine-provoked motor impairments. Furthermore, the administration of apomorphine or d-amphetamine reverses the reserpine-induced catatonia and causes behavioral excitement. These facts underline the importance of both the impairment of dopaminergic fibers and the release of cholinergic mechanisms, especially at the level of the neostriatum, in the production of tremor, akinesia and catatonia. Akinesia and catatonia apparently depend on a more profound and generalized disturbance of dopamine metabolism than that associated with tremor. The production of tremor, however, involves the impairment of nervous mechanisms as well as those affected by the administered drug.

The effect of brain stem lesions on tyrosine and tryptophan hydroxylases in various structures of the telencephalon of the cat

Abstract Unilateral lesions of the ventromedial tegmental area of the upper brain stem are associated with decreased concentrations of tyrosine and tryptophan hydroxylases without any reduction of succinic dehydrogenase in different telencephalic structures on the corresponding side of the brain in the cat. Unilateral lesions of the intralaminar nuclei of the thalamus have no effect on the concentrations of any of these enzymes in the same tissues. These results indicate that the syntheses of dopamine and serotonin in the striatal and other tissues are dependent on the integrity of separate neuronal systems originating in specific cell groups of the brain stem.

Physiopathology of the cerebellum in the monkey

Abstract Complete cerebellectomy is associated with almost total cell loss in the reticulotegmental, lateral reticular and pontine nuclei and in the principal and accessory olivary nuclei but not in the perihypoglossal and reticular paramedian nuclei in the monkey. The latter structure which is a prominent structure in the cat is underdeveloped or absent in this species. It also results in important retrograde degenerating changes of the neurons of the lateral cuneate nucleus, the dorsal nucleus of Clarke and the border cells of Cooper and Sherrington as disclosed in 1 monkey with a short-term cerebellectomy. A few neurons of the principal cuneate nucleus also undergo retrograde degeneration in the immediate postoperative period. The present findings suggest that the caudal part of the medial accessory olive and its “dorsal cap” are anatomically related to the contralateral nodulus and flocculus, respectively, whereas the rostral part of the medial accessory olive is more directly related to the neovermis. The dorsal accessory olive appears to be related to the contralateral cerebellar nuclei and more specifically, the fastigial nucleus. These results also favour the existence of cerebellopetal fibers from the principal cuneate nucleus and of a few non-cerebellopetal fibers from the lateral cuneate nucleus. The present findings support the suggestion of Cooper and Sherrington pointing to the existence of spinocerebellar fibers originating in the border cells of the ventral horn at the level of the low thoracic and lumbar segments of the cord. However the possibility that such “spinocerebellar” fibers may distribute collateral endings to the dorsolateral area of the medulla or even terminate in this area cannot be entirely ruled out on the basis of the present material. A similar feature possibly explains the fact that most (if not all) cells of the dorsal nucleus of Clarke resist the interruption of their axons at cerebellar level as suggested by the findings in monkeys with long standing lesions.

Effect of dorsal rhizotomy on postural tremor in the monkey

SummaryRhizotomy of the dorsal roots of the upper limb in lesioned monkeys with lesioned-induced and harmaline-induced tremor caused complete anaesthesia and akinesia of the corresponding limb, which only showed purposeless movements. The rate and rhythm of postural tremor and the reciprocality of the bursts in opposite muscles were not affected by the rhizotomy; the incidence of tremor episodes was greater in some animals. Rhizotomy apparently interfered with the amplitude of the bursts which, at times, was less regular in the deafferented limb. In four out of six animals the rhizotomy involved the blood supply of the dorsal part of the lateral column. This caused a degeneration of the corresponding lateral corticospinal and dorsal spinocerebellar tracts, producing a weakness of the ipsilateral lower limb which gradually improved. Faster bursts (12–13/sec) were also noted on the EMG in response to harmaline in monkeys with cerebellar lesions.These findings suggest that the influence transmitted through the spinal dorsal roots does not play an important role in initiating postural tremor. The rate and rhythm of tremor episodes are uninfluenced by impulses transmitted through the dorsal roots which, however, apparently exert a stabilizing effect on the amplitude of the bursts.