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G A Ricaurte

Publications and source records attributed to G A Ricaurte.

At least 91 records · Page 5Linked to original sources
PubMed1989

Chronic idiopathic ataxic neuropathy: neuropathology of a case.

A case of chronic, sporadic, slowly progressive, purely sensory, ataxic neuropathy is reported. In previously published similar cases only muscle and nerve biopsies have been available for study. In the present case the patient died of an unrelated illness 39 years after onset of the neuropathy. A full neuropathological study was performed. The disease process was limited to the dorsal root ganglia and their central and peripheral processes. Large myelinated fibers were preferentially involved. Involvement of the dorsal root ganglia has also been reported in certain toxic ganglioneuropathies and in the sensory neuropathy associated with carcinoma. The long duration and insidious development set the present case apart from those conditions. An inflammatory component was lacking. Except for a microscopic focus of adenocarcinoma of the prostate no malignancy was present. The etiology of chronic idiopathic ataxic neuropathy is unknown, but it is likely that the dorsal root ganglion is the main target for the disease process in most if not all cases.

Aged↗
PubMed1989

Distinct morphologic classes of serotonergic axons in primates exhibit differential vulnerability to the psychotropic drug 3,4-methylenedioxymethamphetamine.

Immunohistochemical methods were used to analyse the distribution and morphology of serotonergic axons in normal macaque monkeys and in monkeys given (+/-)3,4-methylenedioxymethamphetamine. In untreated monkeys, we observed two morphologic classes of serotonergic axon terminals, which differ in regional and laminar distribution. These two axon types, fine and beaded, correspond to the serotonergic axon types which have been described in the rat. In 3,4-methylenedioxymethamphetamine-treated monkeys, there is a profound loss of serotonergic axon terminals, yet some are consistently spared. The surviving axon terminals are nearly all of the beaded type; in contrast, fine serotonergic axons are markedly reduced in density. There are regional differences in the magnitude of denervation, which reflect differences in the distribution of these two types of serotonergic axons in controls. The present study demonstrates that 3,4-methylenedioxymethamphetamine has differential neurotoxic effects on fine and beaded serotonergic axons. These results indicate that in the primate there are two distinct classes of serotonergic axon terminals, which differ in morphology, distribution, and vulnerability to psychotropic drugs. We hypothesize that in the primate, as demonstrated in the rat, these two classes of serotonergic axon terminals may arise from different raphe nuclei. In both rodent and primate, the dorsal and median raphe nuclei give rise to parallel ascending serotonergic projections, which are likely to have different pharmacologic properties and functions.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Studies of MDMA-induced neurotoxicity in nonhuman primates: a basis for evaluating long-term effects in humans.

The results of the studies reviewed here show that the neurotoxic effects of MDMA generalize to the primate. Further, they indicate that monkeys are considerably more sensitive than rats to the serotonin-depleting effects of MDMA, and that the dose-response curve of MDMA in the monkey is much steeper than in the rat. Perhaps as a consequence of this, the toxic effects of MDMA in the monkey involve serotonergic nerve fibers as well as cell bodies, whereas in the rat, only nerve fibers are affected. The present studies also show that the toxic dose of MDMA in the monkey (5 mg/kg) closely approaches the dose typically used by humans (1.7 to 2.7 mg/kg). This finding heightens concern that MDMA may be neurotoxic in humans, particularly since the steepness of the dose-response curve of MDMA in the primate suggests a narrow margin of safety. Finally, preclinical studies in monkeys have shown that CSF 5-HIAA can be used to detect MDMA-induced serotonergic damage in the primate CNS. Studies now underway in MDMA-exposed humans should help determine if MDMA exerts long-term toxic effects on serotonergic neurons in the human brain.

3,4-Methylenedioxyamphetamine↗
PubMed1988

5-Hydroxyindoleacetic acid in cerebrospinal fluid reflects serotonergic damage induced by 3,4-methylenedioxymethamphetamine in CNS of non-human primates.

This study examined whether 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) could be used to detect serotonergic damage induced by (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in the central nervous system (CNS) of non-human primates. Monkeys were administered toxic doses of MDMA; two weeks later, the animals were lightly anesthetized with ether and CSF was obtained by means of cervical puncture. Later that same day, the animals were killed for direct determination of CNS serotonin and 5-HIAA concentrations. Monkeys with 73-94% depletions of serotonin and 5-HIAA in brain and 42-45% depletions of serotonin and 5-HIAA in the spinal cord had a 60 +/- 7% reduction of 5-HIAA in CSF, without any change in homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenethyleneglycol (MHPG). These findings indicate that CSF 5-HIAA can be employed to detect central serotonergic damage produced by MDMA in non-human primates, and suggest that CSF 5-HIAA may be useful for detecting MDMA-induced neuronal damage in humans.

3,4-Methylenedioxyamphetamine↗
PubMed1988

(+/-)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug that has been proposed to be useful as an adjunct to psychotherapy. This study assessed the neurotoxic potential of MDMA in nonhuman primates. Monkeys were repeatedly administered doses (2.50, 3.75, and 5.00 mg/kg) of MDMA subcutaneously and analyzed for regional brain content of serotonin and 5-hydroxyindoleacetic acid two weeks later. In all regions of the monkey brain examined, MDMA produced a selective dose-related depletion of serotonin and 5-hydroxyindoleacetic acid. These neurochemical deficits were associated with evidence of structural damage to serotonergic nerve fibers. In addition, MDMA produced pathological changes in nerve cell bodies in the dorsal, but not median, raphe nucleus. These results indicate that MDMA is a selective serotonergic neurotoxin in nonhuman primates and that humans using this drug may be at risk for incurring central serotonergic neuronal damage.

3,4-Methylenedioxyamphetamine↗
PubMed1988

Orally administered MDMA causes a long-term depletion of serotonin in rat brain.

Recent studies suggest that 3,4-methylenedioxymethylamphetamine (MDMA), when administered subcutaneously, is toxic to central serotonergic neurons in rats. Because humans typically self-administer this drug orally, we compared this route to the s.c. route of administration. Orally administered MDMA produced a dose-related depletion of serotonin comparable to that produced by the s.c. route. These findings suggest that MDMA, when given orally, retains it neurotoxic activity and that humans using MDMA may be at risk for developing a persistent depletion of brain serotonin.

3,4-Methylenedioxyamphetamine↗
PubMed1988

The sensitivity of nigrostriatal dopamine neurons to MPP+ does not increase with age.

The purpose of this study was to determine if the enhanced striatal dopamine depletion induced by MPTP in older mice is due to increasing sensitivity of older nigrostriatal neurons to MPP+ (1-methyl-4-phenylpyridinium ion). MPP+ (the putative toxic metabolite of MPTP) was administered intracerebroventricularly (i.c.v.) to 6- to 8-week-old and 8- to 10-month-old animals. No significant differences in the dopamine-depleting effects of this compound were observed between the two age groups, suggesting that older nigrostriatal neurons are not more sensitive to MPP+. To be certain that increased sensitivity in older animals was not being masked by (1) increased removal of MPP+ from the CNS compartment or (2) enhanced degradation of MPP+, the fate of i.c.v. administered MPP+ was determined in the two age groups using 3H-labeled MPP+ and gas chromatography/mass spectrometry (GC/MS) analysis. No differences were found in the elimination of radioactivity, all of which could be accounted for as MPP+. We conclude that kinetic factors which alter the concentration of MPP+ at its target site, rather than increased sensitivity of older nigrostriatal neurons to MPP+, account for the age-related effects of systemically administered MPTP.

1-Methyl-4-phenylpyridinium↗
PubMed1988

Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration.

This study compared the toxic effects of oral versus subcutaneous and single versus multiple doses of 3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in non-human primates. Orally administered MDMA was approximately one-half as effective as subcutaneously administered drug. Multiple doses were more effective than single doses, but a single 5 mg/kg dose of MDMA given orally still produced a long-lasting depletion of serotonin in the monkey brain. These results indicate that when MDMA is given to monkeys in a manner similar to that employed by humans, it exerts toxic effects on central serotonergic neurons. This suggests that humans using MDMA may be at risk for incurring central serotonergic neuronal damage.

3,4-Methylenedioxyamphetamine↗
PubMed1988

The dopamine-depleting effect of 6-hydroxydopamine does not increase with aging.

The dopamine-depleting effects of intracerebroventricularly administered 6-hydroxydopamine (6-OHDA) were studied in young mature (6-8 weeks), older (8-12 months) and aged (18-24 months) mice. No differences were noted between age groups. To rule out the possibility that higher levels of monoamine oxidase (which degrades 6-OHDA) in older animals might be masking an increased sensitivity of older neurons to 6-OHDA, experiments were repeated after treatment with pargyline (50 mg/kg). Again, no differences between age groups were noted. We conclude that aging does not increase the sensitivity of dopaminergic neurons to 6-OHDA.

Aging↗
PubMed1987

[3H]3,4-methylenedioxymethamphetamine (MDMA) interactions with brain membranes and glass fiber filter paper.

The binding of [3H]3,4-methylenedioxymethamphetamine [( 3H]MDMA) to both rat brain membrane preparations and glass fiber filter papers was analyzed in the present study. Saturation studies indicate that [3H]MDMA binding is saturable and monophasic in both the presence and absence of rat brain membranes. This apparent 'specific' binding of [3H]MDMA in both the presence and absence of brain homogenates was totally eliminated by pretreating glass fiber filter papers with polyethylenimine. Drug competition studies demonstrated that [3H]MDMA binding displays a distinct 'pharmacological' profile in the absence of brain tissue. These data indicate that apparent [3H]MDMA binding to rat brain homogenates results from artifactual of [3H]MDMA to glass fiber filter paper. In addition, uptake of [3H]MDMA into rat brain synaptosomes could not be detected. We conclude the [3H]MDMA has limited usefulness in radioligand binding studies.

3,4-Methylenedioxyamphetamine↗
PubMed1987

3,4-Methylenedioxyethylamphetamine (MDE), a novel analogue of MDMA, produces long-lasting depletion of serotonin in the rat brain.

The present study was carried out to asses possible toxic effects of 3,4-methylenedioxyethylamphetamine (MDE) on serotonergic, dopaminergic or noradrenergic neurons in the rat brain. It was found that MDE produced a long-lasting, dose-related depletion of serotonin (5HT). However, even at high dosage, MDE did not reduce the concentration of either dopamine (DA) or norepinephrine (NE) on a long-term basis. When compared to 3,4-methylenedioxymethylamphetamine (MDMA), MDE was approximately one fourth as potent as producing a long-term depletion of 5HT. These results suggest that MDE, like MDMA, may be selectively toxic to central serotonergic neurons.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Aging and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of dopaminergic neurons in the substantia nigra.

This study assessed the influence of aging on substantia nigra degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive neuronal degeneration was found in the substantia nigra of older (8-12 months of age) but not younger (6-8 weeks of age) mice given MPTP. Older mice did not have higher brain concentrations of either MPTP or 1-methyl-4-phenylpyridinium (MPP+), the putative toxic metabolite of MPTP, to account for the greater toxicity. In fact, older mice metabolized MPTP more rapidly than younger mice, probably because of the increase in monoamine oxidase activity that occurs with aging. Striatal synaptosomes from older mice did not accumulate more [3H]MPP+ than synaptosomes from younger mice. Thus, it is concluded that the greater neurodegenerative effect of MPTP in older animals is not due to greater levels or uptake of MPP+, but rather is related to a true increase in sensitivity of older dopaminergic cells to MPTP. For comparative purposes, the toxic effect of another dopaminergic neurotoxin, methamphetamine, was tested. Older animals were not more sensitive than young mature animals to the toxic effect of methamphetamine. This finding indicates that the increased sensitivity of older dopaminergic neurons to MPTP is selective. The link established here between aging and the neurodegenerative effect of MPTP, a toxin which produces parkinsonism in humans, provides a mechanism by which an age-related neurodegenerative disorder such as Parkinson's disease could be caused by an MPTP-like toxin in the environment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Older dopaminergic neurons do not recover from the effects of MPTP.

Recent studies have shown that dopaminergic neurons in young mature mice recover fully from toxic injury induced by MPTP. The aim of the present study was to assess whether or not older dopaminergic neurons were capable of similar recovery. We now report that older dopaminergic neurons do not recover from the effects of MPTP. This suggests that with age, neurons in the nigrostriatal system begin to lose their regenerative capacity. This phenomenon could underlie the process of neuronal degeneration known to occur in a number of age-related diseases, including Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

1,2,3,6-tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine: studies on the mechanism of action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Two analogs of the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were examined for their deleterious effects on nigrostriatal neurons. 1,2,3,6-Tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine (TMMP), but not 1-methyl-4-(1-methylpyrrol-2-yl)-4-piperidinol, caused persistent depletion of striatal dopamine and induced histologic evidence of nerve terminal degeneration in mice. These findings differ diametrically from results previously reported for the two analogs. TMMP produced larger dopamine depletions than MPTP when the two drugs were given in equivalent doses. Further experiments demonstrated that TMMP is preferentially oxidized by mouse brain monoamine oxidase B to a water-soluble compound, most likely the pyridinium ion species. Prior treatment of mice with either the monoamine oxidase inhibitor pargyline or the dopamine reuptake inhibitor bupropion blocked the ability of TMMP to deplete striatal dopamine. Thus, the pharmacologic profile of TMMP closely resembles that of MPTP. That TMMP and MPTP induce dopamine depletions by a similar mechanism tends to support the proposed neurochemical sequence of events thought to lead to the expression of MPTP-induced neurotoxicity. The authors' observations provide further evidence that MPTP is not unique in its capability to damage nigrostriatal neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Fate of nigrostriatal neurons in young mature mice given 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: a neurochemical and morphological reassessment.

The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on nigrostriatal dopaminergic neurons in the mouse was re-examined in view of recent conflicting reports regarding the neurotoxic effect of MPTP in this experimental animal. It was found that while MPTP destroyed a substantial number of dopaminergic nerve terminals in the striatum of young mature (6-8 weeks old) mice, it left the majority of cells in the pars compacta of the substantia nigra (SNc) unaffected. It was also found that 5 months after MPTP treatment there was substantial, although incomplete, recovery of striatal DA nerve terminal markers (DA level, metabolites, uptake, [3H]mazindol binding). Given these observations, it is concluded that while the young mature MPTP mouse may not be a valid animal model of Parkinson's disease (since it does not develop severe SNc cell loss characteristic of this disorder), it will be valuable for the study of how MPTP destroys dopaminergic nerve terminals and may prove useful as an experimental system for studying recovery of dopaminergic fibers after injury and for exploring ways to accelerate this recovery.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys.

Systemic administration of the recently discovered neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces severe clinical parkinsonism and degeneration of the substantia nigra in humans and monkeys. In previous studies, no convincing structural damage to nerve cells outside the substantia nigra could be demonstrated in subhuman primates. Using a protracted MPTP regimen and older animals, we now report locus ceruleus lesions and eosinophilic inclusion bodies in squirrel monkeys. The inclusions were seen only in areas where Lewy bodies are found in human Parkinson's disease. No such abnormalities were seen in control animals. These findings suggest that similarities between the neuropathology of MPTP-induced parkinsonism in the monkey and human Parkinson's disease are greater than first thought and increase the usefulness of the MPTP monkey model for research in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗