Loss of intrinsic striatal neurons after methylazoxymethanol acetate treatment in pregnant rats

Balduini, Walter; Abbracchio, Maria P.; Lombardelli, G.; Cattabeni, Flaminio

doi:10.1016/0165-3806(84)90149-4

Cited by 28 publications

(3 citation statements)

References 16 publications

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“…MAM is an alkylating substance that is easily transported through the placenta and methylates the nitrogen in position 7 of the guanine of brain nucleic acids of cells preparing for, or undergoing mitotic division, G1 and M phase of the cell cycle, respectively (Nagata and Matsumoto, 1969;Matsumoto et al, 1972). Previous reports mentioned neuronal depletion of the neocortex (Cattabeni et al, 1989;Johnson and Coyle, 1979;Jones et al, 1982), striatum (Balduini et al, 1984), and hippocampal neuronal ectopia (Sing, 1982) after transplacental exposure to MAM. These studies, however, lack systematic description of the effects of MAM on brain development.…”

Section: Introductionmentioning

confidence: 96%

Transplacentally induced neuronal migration disorders: An animal model for the study of the epilepsies

Germano

Sperber

1998

J. Neurosci. Res.

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Recent clinical and laboratory data suggest that there is a link between neuronal migration disorders (NMD) and increased seizure threshold. To characterize an animal model with features similar to human NMD and to assess seizure susceptibility, NMD were induced in the rat at the time of neuroblastic division (PG15) and three other gestational ages (PG 13, PG14, PG16) by transplacental exposure to methylaxozymethanol (MAM, 25 mg/kg). Offspring pups were monitored for spontaneous and electrographic seizures. At postnatal day 14, randomly selected rat pups were sacrificed for histological examination. In other MAM-exposed pups and controls, status epilepticus was induced by intraperitoneal administration of kainic acid. On histology, NMD were found in all PG 15 MAM-exposed rats, in comparison to 63% of PG 13, 70% of PG 14, 80% of PG16. Histological features included cortical laminar disorganization, ectopic neurons in the subcortical white matter and in cortical layer I, persistent granular layer, marginal glioneuronal heterotopia, and discrete areas of neuronal ectopia in the CA1 subfield of the hippocampus. Based on the severity of the neuronal migration abnormalities, rats were divided into three categories: severe, moderate, and mild. Severe and moderate NMD were only found in the PG 15 MAM-exposed rats. EEG recording in rats with NMD did not disclose spontaneous seizures; however, rats with severe NMD had higher slow wave activity compared to controls (P < .05). MAM-exposed rats with severe NMD were more susceptible to kainic-induced seizures compared to controls (P < .05). In rats with severe NMD, kainic acid-induced status epilepticus produced hippocampal damage in the CA3/4 region. These results demonstrate that MAM-induced NMD have histological and electrographic characteristics similar to human NMD. The severity of neuronal abnormality depends on the time of transplacental exposure as the most severe NMD were found after exposure to MAM at the time of neuroblastic division. The degree of NMD positively correlates with seizure susceptibility, since only rats with severe NMD have decreased seizure threshold. The occurrence of status epilepticus-induced hippocampal damage in pups with severe NMD suggests that the severely compromised hippocampus is less resistant to seizure-induced injury than the normal developing brain.

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Section: Introductionmentioning

confidence: 96%

Transplacentally induced neuronal migration disorders: An animal model for the study of the epilepsies

Germano

Sperber

1998

J. Neurosci. Res.

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“…The interest of these, as well as of other data (Beaulieu and Coyle, 1981;Slevin et al, 1982;Balduini et al, 1984), suggests that it may be useful to extend the research to other brain regions and also to increase the number of the neurochemical markers studied as well as of the developmental stages at which the treatment is performed. In the present study, we report data on cholinergic, GABAergic, and excitatory amino acidic neurons in several brain regions of rats treated with MAM at two distinct developmental stages (approximately gestational days 13.5 and 16.5 ((313.5 and G16.5)).…”

Section: Introductionmentioning

confidence: 99%

Regional‐ and Age‐Specific Neurochemical Alterations in Rats Rendered Microencephalic by Differentially Timed Gestational Methylazoxymethanol Treatment

Virgili

Barnabei

Contestabile

1989

Eur J of Neuroscience

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Rats with different degrees of microencephaly were obtained by injecting pregnant mothers with methylazoxymethanol acetate (MAM) at gestational days 13.5 or 16.5. Specific markers for cholinergic (choline acetyltransferase, ChAT), GABAergic (glutamate decarboxylase, GAD), and glutamatergic (D-3H aspartate high affinity uptake) neurons, were measured in several brain regions (cortex, hippocampus, anterior and posterior striatum, medial septum plus nucleus of the diagonal band, globus pallidus) in young and adult microencephalic rats. In adult rats born to mothers injected with MAM at gestational day 16.5 (G16.5) ChAT level was increased in the cortex, hippocampus and striatum but decreased in the septal complex; GAD was decreased in the globus pallidus and, to a little extent, in the hippocampus while D-3H aspartate uptake was decreased in the striatum. One month old rats belonging to the same group showed comparable differences with the exception of larger increase of ChAT in the cortex and striatum. In adult rats born from mothers injected with MAM at gestational day 13.5 (G13.5) differences in the cholinergic marker were in general less pronounced; GAD was not decreased in the globus pallidus and D-3H aspartate uptake was unchanged in the striatum but significantly decreased in the hippocampus. The results are correlated with morphological brain alterations caused by differentially timed MAM treatment and with available information on the generation time of various neuronal populations. They show that the balance between different neurotransmitter systems can be experimentally altered and suggest that MAM treatment may provide an experimental tool for studying the development of this balance.

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“…MAM treatment did not appear to affect the binding of a dopamine D 2 antagonist, [ 3 H]spiperone, and a dopamine D 1 antagonist, SCH23390, to D 2 and D 1 receptors, respectively (Beaulieu & Coyle, 1981; Watanabe et al, 1990). However, Balduini, Abbracchio, Lombardelli, and Cattabeni (1984) found that there was a decrease in D 1 -stimulated cyclic adenosine monophosphate production. Thus, MAM treatment appears to result in a relative increase in dopamine activity in the presence of a normal number of D 1 and D 2 receptors available for binding, but the D 1 receptors may be functionally abnormal.…”

Section: Discussionmentioning

confidence: 96%

Effects of neuroleptic and anticonvulsant drugs on repeated acquisition learning in microencephalic and normal rats.

Loupe¹,

Schroeder²,

Tessel³

1997

Experimental and Clinical Psychopharmacology

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Neuroleptic and anticonvulsant drugs are used to reduce the occurrence of aberrant behaviors, seizures, or both in individuals with mental retardation. However, their use may disrupt the learning of desired skills, and the extent to which anatomical (e.g., microencephaly) or biochemical abnormalities or both in such individuals alter the effects of drugs on learning is not known. In this study, the effects of neuroleptics and anticonvulsants on learning and performance in a repeated acquisition task in methylazoxymethanol-induced microencephalic and saline control rats were assessed. Thioridazine was more potent in microencephalic rats than in control rats in increasing errors and decreasing response rates. Clozapine was equally potent in both microencephalic and control rats in increasing errors and decreasing response rates. The effect of carbamazepine was biphasic in both rat groups: Low doses decreased errors and increased response rates, whereas higher doses did the opposite.

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Loss of intrinsic striatal neurons after methylazoxymethanol acetate treatment in pregnant rats

Cited by 28 publications

References 16 publications

Transplacentally induced neuronal migration disorders: An animal model for the study of the epilepsies

Transplacentally induced neuronal migration disorders: An animal model for the study of the epilepsies

Regional‐ and Age‐Specific Neurochemical Alterations in Rats Rendered Microencephalic by Differentially Timed Gestational Methylazoxymethanol Treatment

Effects of neuroleptic and anticonvulsant drugs on repeated acquisition learning in microencephalic and normal rats.

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