René Boucher

Chronic treatment withl-DOPA, but not bromocriptine induces dyskinesia in MPTP-parkinsonian monkeys. Correlation with [3H]spiperone binding

A group of 5 monkeys developed a severe parkinsonian syndrome after intravenous administration of the toxin MPTP. One remained untreated while two animals were treated daily for 5 months with supramaximal doses of Sinemet and two with bromocriptine orally. Both drugs relieved the parkinsonian symptoms but the animals on Sinemet developed after 2 weeks prominent lingual dyskinesia which remained visible after each dose until the end of the experiment. In the two animals on bromocriptine no dyskinesia was observed. After sacrifice, the levels of dopamine and [3H]spiperone binding were studied bilaterally in the anterior and posterior caudate nucleus, anterior and posterior putamen and in the nucleus accumbens. The loss of dopamine was equivalent in the Sinemet and the bromocriptine treated animals (more than 90%) and there was a complete disappearance of the substantia nigra pars compacta. In all structures studied, the Bmax for [3H]spiperone binding was on average 10% higher in the Sinemet than in the bromocriptine-treated animals. We therefore believe that L-DOPA and bromocriptine affect denervated postsynaptic dopamine receptors differently, that bromocriptine is less likely to induce agonist supersensitivity and that this probably explains the lesser tendency to induce dyskinesia after chronic treatment.

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 output organization of the substantia nigra in primate as revealed by a retrograde double labeling method

The cellular origin and degree of collateralization of the efferent projections of the substantia nigra pars reticulata (SNr) in the squirrel monkey (Saimiri sciureus) were studied using the following combinations of fluorescent retrograde tracers: Evans blue and DAPI-Primuline, Fast blue and Nuclear yellow, True blue and Nuclear yellow. In a first series of experiments one tracer was injected in the ventral anterior (VA) and ventral lateral (VL) thalamic nuclei, and the complementary tracer was delivered in the peribrachial area of midbrain tegmentum. After thalamo-tegmental injections numerous nigrothalamic neurons occur in clusters, particularly in rostrolateral part of SNr, whereas the nigrotegmental neurons prevail in caudomedial segment of SNr. However, a significant overlap exists between these two populations. The nigrothalamic and nigrotegmental neurons are present in about equal number in SNr with as much as 60% of these neurons being double-labeled. In a second series of experiments injections were made concomitantly in VA/VL nuclei and in superior colliculus. After thalamo-collicular injections the nigrothalamic neurons are found in larger number than the nigrocollicular neurons which are mostly confined to the middle third of SNr. About 15-20% of all SNr positive neurons are double-labeled, although this proportion climbs to 30-40% in certain sections taken through the middle third of SNr. Finally, injections were made concomittantly in superior colliculus and in midbrain tegmentum. In contrast to the findings obtained after thalamo-tegmental and thalamo-collicular injections, only about 10% of SNr neurons appear to be double-labeled after colliculo-tegmental injections. All injections made in present study have produced retrograde cell labeling in contralateral SNr. However, by far the largest number of contralateral labeled neurons is found after superior colliculus injection. These findings reveal that the SNr neurons in primate, as those in rat and cat, display a high degree of axonal branching. As such, the output organization of SNr appears to differ markedly from that of the substantia nigra pars compacta, but is remarkably similar to that of the internal pallidum which is the other major output structure of the basal ganglia.

The origin of forebrain afferents to the habenula in rat, cat and monkey

Injections of horseradish peroxidase (HRP) involving the entire habenular complex in rat, cat and squirrel monkey (Saimiri sciureus) label (1) numerous cells in anterior lateral hypothalamic area, (2) a moderate number of cells in lateral preoptic area, substantia innominata, nucleus of diagonal band and postcommissural septum, and (3) a few cells in medial hypothalamus, ipsilaterally, in all three species. Some labeled cells also occur in corresponding regions contralaterally. The contribution of these limbic structures to the innervation of habenula is thus strikingly similar in the three groups. In contrast, significant species variations are found in respect to pallidal afferents. Whereas the entopeduncular nucleus in rat stands out as the main source of forebrain habenular afferents, the same structure in cat appears to contribute less substantially than adjoining lateral hypothalamus to the innervation of habenula. In monkey habenular afferents also arise principally from lateral hypothalamic neurons. At pallidal levels, labeled cells are nevertheless abundant in the rostral pole of primate internal pallidum. More caudally, they are found in significant number along internal and accessory medullary laminae where they intermingle with acetylcholinesterase-containing neurons which do not themselves project significantly upon habenula. This heterogeneous distribution of labeled pallidal cells indicates that the pallidohabenular projections in primate may arise, at least in part, from specific neuronal subpopulations within internal pallidum.

Long-term effects of MPTP on central and peripheral catecholamine and indoleamine concentrations in monkeys

5 Macaca fascicularis monkeys developed a severe parkinsonian syndrome in the days following intravenous administration of the toxin MPTP. One monkey remained untreated while two groups of two animals were treated daily for 5 months with supramaximal oral doses of either Sinemet or bromocriptine. Both drugs relieved the parkinsonian symptoms. Plasma prolactin concentrations were elevated in MPTP-treated monkeys compared to intact monkeys. MPTP caused a rapid decrease of homovanillic acid (HVA) concentrations in the CSF of these monkeys within days of the toxin injection and these values remained low until sacrifice of the animals 5 months later. By contrast, CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations were elevated a few days after the start of MPTP treatment and these values returned to control levels by 5 months. Five months after the start of MPTP treatment, epinephrine (E) and dopamine (DA) levels were decreased in the adrenal medulla while the norepinephrine (NE) concentration remained unchanged. Catecholamines were assayed in the caudate putamen, nucleus accumbens, amygdala and frontal cortex of these monkeys. NE concentrations were decreased in the frontal cortex of MPTP-treated monkeys while a decrease of E concentrations after MPTP was only observed in the n. accumbens. Dopamine and its metabolites dihydroxyphenylacetic acid (DOPAC) and HVA were reduced in the caudate, putamen, n. accumbens and frontal cortex. Our results show that MPTP treatment in the long-term (5 months) not only affects the dopaminergic system of the caudate-putamen but also has effects on dopaminergic systems in other regions as well as on noradrenergic and adrenergic systems in the brain and the periphery.

Behavioral and biochemical effect of chronic treatment with D-1 and/or D-2 dopamine agonists in MPTP monkeys

Monkeys developed a severe parkinsonian syndrome after intravenous administration of (MPTP). L-DOPA/carbidopa (D-1 and D-2) or bromocriptine (D-2) treatment relieved the parkinsonian symptoms, whereas SKF 38393 (D-1) was ineffective. No dyskinesia was seen in monkeys receiving bromocriptine or SKF 38393 as opposed to the L-DOPA-treated animals, in which the dyskinetic response appeared to increased with time. MPTP induced a significant increase (25%, P less than 0.01) in the number of [3H]spiperone binding sites (Bmax) in the caudate nucleus and in putamen. The Bmax of spiperone binding in the L-DOPA-treated monkeys was on average 18% lower (P less than 0.01) than that of the animals treated with MPTP alone. The Bmax for the bromocriptine-treated group was 29% (P less than 0.01) less than that in the MPTP-treated group or 11% (P less than 0.05) less than that in the L-DOPA-treated monkeys. The SKF 38393 treatment induced a 23% (P less than 0.01) decrease in the Bmax as compared to that of animals treated with MPTP alone, and no significant change compared to the L-DOPA- or bromocriptine-treated animals. These results suggest that stimulation of D-1 and D-2 dopamine receptors can differently influence the mechanisms controlling dopamine agonist-induced dyskinesia in MPTP-treated monkeys.

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.

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.

Effect of D1 receptor stimulation in normal and MPTP monkeys

The effect of a selective agonist of the dopamine D1 receptor (SKF 38393) and of the D2 receptor (LY-171555) was tested acutely in normal and in monkeys with a parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The D2 agonist induced a strong locomotor response and lingual dyskinesia in both normal and parkinsonian monkeys. The D1 agonist however had no locomotor effect by itself but induced tongue protrusions in normal monkeys only. It appeared to potentiate the dyskinetic effect of LY 171555 in MPTP monkeys but it antagonized the locomotor action of the D2 agonist in both normal and MPTP monkeys. The selective D1 and D2 antagonists SCH 23390 and sulpiride were also tested. Both compounds were able to suppress the dyskinetic action of the combined agonists in normal animals but only the D2 antagonist was effective in the same conditions in MPTP monkeys. These findings emphasize the importance of the D2 receptor in mediating the locomotor response as well as dyskinesia in monkeys.

Acetylcholinesterase-containing neurons in cat neostriatum: A morphological and quantitative analysis

When examined in brain sections prepared according to the Butchers pharmaco-histochemical method, the large acetylcholinesterase (AChE)-containing cells in cat putamen appear morphologically different, more numerous per mm2, and significantly larger than those in caudate nucleus. Such a finding supports the view that the feline neostriatum is not a homogeneous structure. In addition, horseradish peroxidase (HRP) injected into the various target nuclei of neostriatum labels numerous medium-sized striatal cells and a few large-sized putaminal neurons. However, no HRP material could be detected in the large AChE cells themselves, suggesting that these cells are not output neurons.