Potentiating effects of methamphetamine on the hyperactivity of microencephalic rats treated prenatally with methylazoxymethanol: possible implication of hyperdopaminergia

Watanabe, Masayuki; Shimizu, Kunio; Kodama, Yoshio; Takishima, Kunio; Mamiya, Gunji; Ichinowatari, Naomichi

doi:10.1016/0006-8993(94)01307-4

Cited by 13 publications

(13 citation statements)

References 20 publications

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“…Administration of MAM to a pregnant rat dam can potently and selectively disrupt embryonic brain development (Eriksdotter-Nilsson et al 1986;Haddad et al 1972). Exposure to MAM on or prior to E15 leads to abnormalities in corticocortical synaptic transmission (Chevassus-Au-Louis et al 1998), striatal hyperdopaminergia with increased responsiveness to psychostimulants (Archer et al 1988;Watanabe et al 1995), and cognitive and sensorimotor gating deficits (Mohammed et al 1986;Talamini et al 2000). While these abnormalities are relevant to a number of developmental brain disorders (Cattabeni and Di Luca 1997;Chevassus-Au-Louis et al 1998;Coyle et al 1984), their validity for modeling schizophrenia is limited due to the microcephaly produced by MAM exposure on or before E15 (Dambska et al 1982;Jongen-Relo et al 2004;Kabat et al 1985;Singh 1980).…”

Section: Introductionmentioning

confidence: 99%

A Neurobehavioral Systems Analysis of Adult Rats Exposed to Methylazoxymethanol Acetate on E17: Implications for the Neuropathology of Schizophrenia

Moore

Jentsch

Ghajarnia

et al. 2006

Biological Psychiatry

321

405

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Background-As a test of plausibility for the hypothesis that schizophrenia can result from abnormal brain, especially cerebral cortical, development, these studies examined whether, in the rat, disruption of brain development initiated on embryonic day (E) 17, using the methylating agent methylazoxymethanol acetate (MAM), leads to a schizophrenia-relevant pattern of neural and behavioral pathology. Specifically, we tested whether this manipulation leads to disruptions of frontal and limbic corticostriatal circuit function, while producing schizophrenia-like, regiondependent reductions in gray matter in cortex and thalamus.

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Section: Introductionmentioning

confidence: 99%

A Neurobehavioral Systems Analysis of Adult Rats Exposed to Methylazoxymethanol Acetate on E17: Implications for the Neuropathology of Schizophrenia

Moore

Jentsch

Ghajarnia

et al. 2006

Biological Psychiatry

321

405

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“…Three independent groups have reported cortical and hippocampal size reductions in MAM E17 rats [35], [42], [47]. More recently, the MAM E17 model was found to reproduce whole neuronal density changes from the PFC and parvalbumin-positive-cell density deficits from the hippocampus and the PFC of patients with schizophrenia [45], [48].…”

Section: Introductionmentioning

confidence: 99%

Neuropathological and Reelin Deficiencies in the Hippocampal Formation of Rats Exposed to MAM; Differences and Similarities with Schizophrenia

et al. 2010

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BackgroundAdult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied.Principal FindingsCompared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged.ConclusionsOur results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.

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“…2002a,b), while prenatal methylazoxymethanol (MAM) treatment (MAM‐rats) results in perturbed brain development, in association with hyperactive behavior (Hallman & Jonsson 1984; Archer et al . 1988; Watanabe et al . 1995; Flagstad et al .…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, exaggerated hyperactivity has been observed in MAM rats treated with psychostimulants (Archer et al . 1988; Watanabe et al . 1995), while inconsistent results were reported in the case of the SHR model (Wultz et al .…”

Section: Introductionmentioning

confidence: 99%

Dopamine transporter density and behavioral response to methylphenidate in a hyperlocomotor rat model

Muneoka

Kuwagata

Iwata

et al. 2006

Congenital Anomalies

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Rats exposed prenatally to 5-bromo-2'-deoxyuridine (BrdU-rats) display hyperlocomotive activity, making them a possibly useful animal model for the study of attention deficit hyperactivity disorder (ADHD). Using this model, we investigated dopamine transporter (DAT) density and behavioral outcomes in BrdU-rats, some of which were also administered methylphenidate, a psychostimulant that is widely used for the treatment of ADHD. Pregnant rats were exposed to BrdU from gestational day 9 through 15. In male offspring, DAT densities in different regions of the striatum were quantified at three weeks of age. At seven weeks of age, locomotor, rearing and grooming behaviors were evaluated in an open-field setting, with or without methylphenidate treatment (1 mg/kg or 4 mg/kg). The results revealed no significant changes in striatal DAT densities in BrdU-rats compared with controls. Extreme hyperlocomotion of BrdU-rats was detected in the open-field environment, an effect that was exacerbated following treatment with the lower and higher dose of methylphenidate. Such increase in locomotor activity was observed only with the higher dose in control animals. In summary, degeneration of dopaminergic neurons in the terminal field was not detected in juvenile BrdU-rats, although adult animals displayed hyperactive behavior in a mildly stressful environment as well as hypersensitivity to a psychostimulant that facilitates dopaminergic neurotransmission.

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Potentiating effects of methamphetamine on the hyperactivity of microencephalic rats treated prenatally with methylazoxymethanol: possible implication of hyperdopaminergia

Cited by 13 publications

References 20 publications

A Neurobehavioral Systems Analysis of Adult Rats Exposed to Methylazoxymethanol Acetate on E17: Implications for the Neuropathology of Schizophrenia

A Neurobehavioral Systems Analysis of Adult Rats Exposed to Methylazoxymethanol Acetate on E17: Implications for the Neuropathology of Schizophrenia

Neuropathological and Reelin Deficiencies in the Hippocampal Formation of Rats Exposed to MAM; Differences and Similarities with Schizophrenia

Dopamine transporter density and behavioral response to methylphenidate in a hyperlocomotor rat model

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