Effect of harmaline in monkeys with central nervous system lesions

Battista, Arthur F.; Nakatani, Susumu; Goldstein, Menek; Anagnoste, B

doi:10.1016/0014-4886(70)90189-5

Cited by 22 publications

(17 citation statements)

References 6 publications

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“…Several lines of evidence suggest that the tremor induced by these indole alkaloids results from excitation of inferior olivary neurons. The most thoroughly characterized of these drugs is harmaline, which causes a sustained 8 -12 Hz generalized tremor in all species tested, including mice (Z etler, 1957), rats (Z etler et al, 1972, 1974), cats , and monkeys (Battista et al, 1990). Ibogaline and ibogaine produce an identical 8 -12 Hz tremor in mice (Zetler et al, 1972) and in cats (De Montigny and Lamarre, 1974).…”

Section: Discussionmentioning

confidence: 99%

The Olivocerebellar Projection Mediates Ibogaine-Induced Degeneration of Purkinje Cells: A Model of Indirect, Trans-Synaptic Excitotoxicity

1997

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Ibogaine, an indole alkaloid that causes hallucinations, tremor, and ataxia, produces cerebellar neurotoxicity in rats, manifested by degeneration of Purkinje cells aligned in narrow parasagittal bands that are coextensive with activated glial cells. Harmaline, a closely related alkaloid that excites inferior olivary neurons, causes the same pattern of Purkinje cell degeneration, providing a clue to the mechanism of toxicity. We have proposed that ibogaine, like harmaline, excites neurons in the inferior olive, leading to sustained release of glutamate at climbing fiber synapses on Purkinje cells. The objective of this study was to test the hypothesis that increased climbing fiber activity induced by ibogaine mediates excitotoxic Purkinje cell degeneration. The inferior olive was pharmacologically ablated in rats by a neurotoxic drug regimen using 3-acetylpyridine, and cerebellar damage attributed to subsequent administration of ibogaine was analyzed using immunocytochemical markers for neurons and glial cells. The results show that ibogaine administered after inferior olive ablation produced little or no Purkinje cell degeneration or glial activation. That a lesion of the inferior olive almost completely prevents the neurotoxicity demonstrates that ibogaine is not directly toxic to Purkinje cells, but that the toxicity is indirect and dependent on integrity of the olivocerebellar projection. We postulate that ibogaine-induced activation of inferior olivary neurons leads to release of glutamate simultaneously at hundreds of climbing fiber terminals distributed widely over the surface of each Purkinje cell. The unique circuitry of the olivocerebellar projection provides this system with maximum synaptic security, a feature that confers on Purkinje cells a high degree of vulnerability to excitotoxic injury.

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Section: Discussionmentioning

confidence: 99%

The Olivocerebellar Projection Mediates Ibogaine-Induced Degeneration of Purkinje Cells: A Model of Indirect, Trans-Synaptic Excitotoxicity

1997

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“…179 It is abolished by placement of an additional lesion in the ipsilateral ventrolateral thalamic area, 11 in the globus pallidus, 188 or in the internal capsule. 189 The administration of Ldopa, 181,183,190 5-HTP, 181,183 or atropine 191 reduces its amplitude or abolishes the tremor.…”

Section: Modulation Of Tremor Intensity By Secondary Lesions or Pharmmentioning

confidence: 99%

Animal models of tremor

1999

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“…The systemic injection of harmaline, a beta-carboline derivative, produces a high-frequency 8-to 14-Hz tremor in mice (Agarwal and Bose 1967;Ahmed and Taylor 1959), rats (Busby and Lamarre 1980), cats (DeMontigny and Lamarre 1973, 1975Lamarre and Weiss 1973), and monkeys (Batista et al 1970;Poirier et al 1966). Although the precise mechanism of the tremorogenic effect of harmaline is unknown, several possible explanations have been proposed.…”

Section: Introductionmentioning

confidence: 99%

EMG analysis of harmaline-induced tremor in normal and three strains of mutant mice with Purkinje cell degeneration and the role of the inferior olive

Milner

Cadoret

Lessard

et al. 1995

Journal of Neurophysiology

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1. The effects of intraperitoneal injections of 10 mg/kg harmaline were tested in normal mice and three strains of cerebellar mutant mice with Purkinje cell degeneration. Ten normal (wild-type) mice (+/+), as well as five lurcher (lc/+), six nervous (nr/nr), and eight Purkinje cell degeneration (pcd/pcd) mutants were implanted with chronic electromyogram (EMG) electrodes in the hamstring and quadriceps muscle groups of the right hindlimb. 2. EMGs were recorded in each of the mice during spontaneous activity before and after intraperitoneal injections of 0.3 ml harmaline (10 mg/kg). Spectral analysis was used to quantify the amplitude and frequency of tremor found in the EMGs after harmaline administration. Normal mice responded to harmaline with strong, continuous 11- to 14-Hz tremor. Mutants from the pcd/pcd strain also reacted with continuous tremor, but of lower amplitude and frequency. In contrast, nr/nr mutants exhibited intermittent paroxysmal tremor lasting for only a few seconds, and lc/+ mutants showed no evidence of tremor whatsoever. 3. In order to detect covert tremor that was possibly not revealed by focal intramuscular EMG recordings, several mutant and normal mice were also tested on a suspended platform to which an accelerometer was attached. The results confirmed the findings from EMG recordings. 4. An incidental observation made during the course of this study was that harmaline tremor disappeared from the normal mouse during swimming and reappeared when the animal was withdrawn from the water. 5. Although Purkinje cells appeared to increase both the depth of modulation and the frequency of tremor, the inhibitory action of the cerebellar cortex does not seem to be essential for the generation of tremor. 6. Parasagittal cerebellar sections of the normal, wild-type mice and the three strains of cerebellar mutant mice of various ages were stained with cresyl violet and examined for Purkinje cell degeneration. Purkinje cell degeneration was found to be complete in the pcd/pcd and lc/+ strains. Although an initial examination of parasagittal sections of the nr/nr strain failed to find any surviving Purkinje cells, further examination of sections cut in the coronal plane revealed small clusters of Purkinje cells in the vermal area of the posterior lobe. 7. The retrograde transport of wheat-germ-agglutinin-conjugated horseradish peroxidase (WGA-HRP) pressure-injected into the cerebellar cortex was used to study the olivocerebellar projections in the wild-type mice and the three strains of cerebellar mutant mice.(ABSTRACT TRUNCATED AT 400 WORDS)

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Effect of harmaline in monkeys with central nervous system lesions

Cited by 22 publications

References 6 publications

The Olivocerebellar Projection Mediates Ibogaine-Induced Degeneration of Purkinje Cells: A Model of Indirect, Trans-Synaptic Excitotoxicity

The Olivocerebellar Projection Mediates Ibogaine-Induced Degeneration of Purkinje Cells: A Model of Indirect, Trans-Synaptic Excitotoxicity

Animal models of tremor

EMG analysis of harmaline-induced tremor in normal and three strains of mutant mice with Purkinje cell degeneration and the role of the inferior olive

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