Hyperactivity and instrumental learning deficits in methylazoxymethanol-treated rat offspring

Archer, Trevor; Hiltunen, Arto J.; Järbe, Torbjörn U. C.; Kamkar, M.Reza; Luthman, Johan; Sundström, Erik; Teiling, Anna

doi:10.1016/0892-0362(88)90037-2

Cited by 27 publications

(10 citation statements)

References 22 publications

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“…This overall pattern of results may be indicative of a deficit in interval timing, and might suggest that MAM-treated animals overestimate the passage of time, as has been shown to occur in schizophrenic patients (Elvevag et al, 2003(Elvevag et al, , 2004Penney et al, 2005). The finding of a deficit in DRL performance in MAM-treated animals is somewhat at odds with previous reports, which have shown a lack of deficit on this task following embryonic day 15 MAM treatment (Archer et al, 1988). It is possible that differences in procedure may explain these discrepancies or that the deficit observed on the current task may be specific to the disruption of developmental processes occurring around embryonic day 17.…”

Section: Discussioncontrasting

confidence: 54%

Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

Featherstone

Rizos

Nóbrega

et al. 2006

Neuropsychopharmacol

100

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Gestational methylazoxymethanol acetate (MAM) exposure has been suggested to produce neural and behavioral abnormalities similar to those seen in schizophrenia. In order to assess MAM treatment as a model of schizophrenia, pregnant female rats were injected with MAM (22 mg/kg) on gestational day 17 and their offspring were assessed in adulthood on a series of cognitive tasks. The first experiment involved an attentional set-shifting task, a rodent analog of the Wisconsin card sort task. In experiment 2, animals were tested on the 5-choice serial reaction time task, a rodent analog of the continuous performance task. In the final experiment animals were assessed on a differential reinforcement of low rate of responding 20 s schedule of reinforcement (DRL-20), a task that is sensitive to changes in inhibitory control. In the first experiment, MAM-treated animals required a greater number of trials than controls to successfully learn an extradimensional shift on the set-shifting task, and had difficulties in learning to reverse a previously acquired discrimination. In contrast, MAM-treated animals showed little impairment on the 5-choice task, aside from a modest but consistent increase in premature responding. Finally, MAM exposed animals showed substantial impairments in DRL performance. Post-mortem analysis of brain tissue showed significant decreases in tissue weight in the hippocampus, parietal cortex, prefrontal cortex, and dorsal striatum of MAM-treated animals. These results support the notion that MAM treatment may simulate some aspects of schizophrenic cognition.

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Section: Discussioncontrasting

confidence: 54%

Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

Featherstone

Rizos

Nóbrega

et al. 2006

Neuropsychopharmacol

100

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“…Since the introduc tion of the catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA), as an effective pharmacological tool for the study of the functional roles of DA and noradrenaline (NA) [6,7], major efforts have been aimed at the elucidation of the functions of these neu rotransmitters. Thus, 6-OHDA-induced le sions have been usefully applied to both the neonate as well as the adult animal [8], and a modicum of selectivity has been achieved through the differential use of uptake inhibi tors for either NA or DA [9], Selective de struction of brain DA neurones through intracerebroventricular administration of 6-OHDA to newborn rats pretreated with the NA uptake inhibitor desipramine invariably causes a permanent hyperactive condition, as indexed with several different methods of measuring motor activity in rats [10][11][12][13][14][15][16][17]. Other behavioral changes following neonatal 6-OHDA treatment include deficits in the performance of shock avoidance tasks [18,19], and a retarded acquisition of lever press ing responses on a fixed-ratio schedule of wa ter reinforcement in an operant conditioning chamber [20], The purpose of the experi ments outlined below is to demonstrate a recurring pattern of behavioral alteration in volving hyperactivity, performance deficits in spatial navigation learning tasks as a result of postnatal DA depletion, and particular reac tions to low doses of stimulant compounds (e.g.…”

mentioning

confidence: 99%

Functional Changes Implicating Dopaminergic Systems following Perinatal Treatments

Archer¹,

Fredriksson²

1992

Dev Pharmacol Ther

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A series of experiments, involving diverse perinatal treatments of either rats or mice, have been performed in order to investigate the effects of these treatments upon certain selected spontaneous and learned behaviors in the laboratory. Rat dams were administered either metallic mercury, organic tin or neuroleptic compounds, and the offspring of these dams was studied with behavioral tests at adult ages, prenatal studies. Newborn rat pups were administered either 6-hydroxydopamine (6-OHDA) (at various doses), or metallic mercury and then tested at adult ages. Newborn mice were administered either metaclopramide, an antiemetic compound, or haloperidol, a neuroleptic compound, and tested for spontaneous and d-amphetamine induced activity as adults. The behavioral battery the rats were tested with consisted of measures of spontaneous motor activity, including locomotion/ambulation, rearing, and head dipping behaviors, and a parameter under which diverse behaviors were collected, total activity. Alterations to instrumental maze learning performance were studied through application of the spatial learning tasks: the radial arm maze and the circular swim maze. Possible changes in dopaminergic pathways were assessed by measuring the effects of perinatal treatments upon d-amphctamine- induced activity. It was shown that prenatal metallic mercury, organic tin and the neuroleptic compounds, haloperidol and remoxipride altered various parameters of spontaneous motor activity, retarded maze learning in the radial arm maze and potentiated d-amphetamine-induced activity. Metallic mercury rats were not subjected to the amphetamine test and remoxipride rats were not retarded according to the learning task. Postnatal metallic mercury, 6-OHDA, haloperidol and the antiemetic compound, metaclopramide, also altered spontaneous and d-amphetamine- induced activity as well as radial arm maze performance, excluding in this case haloperidol and metaclopramide. None of these treatments altered performance in the circular swim maze, except for 6-OHDA where doses inflicting severe depletions (greater than 85 % depletion compared to control values) caused notable impairments. One tentative conclusion from the pattern of behavioral changes, generally in the absence of any measurable neurochemical changes, observed after these treatments is that the functional development of dopaminergic systems had, to a greater or lesser degree, been altered.

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“…However, administration of these drugs to MAM-treated rats produce contradictory results. Archer et al (1988) and Watanabe et al (1990) reported that these drugs drastically increased motor activity in MAM-treated rats, while in other studies MAM-treated rats show reduced motor stimulation in response to these drugs (Sanberg et al, 1985;Balduini et al, 1986). This discrepancy may be due to methodological differences and different ages at which motor activity of MAM-treated rats was examined.…”

Section: Neurochemical Correlates Of Abnormal Motor Activity In Mam-tmentioning

confidence: 95%

“…However, since MAM-induced microencephalic rats exhibited hyperactivity (Kiyono et al, 1980;Hanada et al, 1982;Cannon-Spoor and Freed, 1084;Vorhees et al, 1984;Kabat et al, 1985;Plonsky et al, 1985;Nagayoshi et al, 1986;Archer et al, 1988), it is still possibile that these deficits cause hyperactivity and/or disrupted attention processes originating from hyperinnervation of catecholaminergic neurons to the forebrain regions. Other factors in the impairment of spatial learning of MAM-treated rats should be considered.…”

Section: Hmentioning

confidence: 99%

Neurochemical Correlates of Learning Impairment in Microen‐cephalic Rats Induced by Methylazoxymethanol Acetate*

Tamaru

1994

Congenital Anomalies

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Newborn infants with histogenetic brain malformations can be long‐lived with mental retardation, which is considered a major problem in social medicine. Among these infants with mental retardation, many cases are accompanied by microencephaly. Experimentally induced microencephaly in rats presents a useful model for understanding human cerebral disorders. We have studied how neurochemical changes in the brains of microencephalic rats induced by prenatal treatment with methylazoxymethanol acetate (MAM) can affect their learning abilities. We reported that densities of monoaminergic transmitters in the atrophic cerebral hemisphere (CH; consisting of cerebral cortex and hippocampus) of MAM rats was markedly elevated, but that their total quantity per CH unchanged. As for the ability of operant discrimination learning, MAM rats could discriminate tasks. However, excitatory amino acid receptors, in which N‐methyl‐D‐aspartate (NMDA) is well known to be involved in spatial memory, showed decreased total binding in the CH of MAM‐treated rats. Spatial recognition ability evaluated using an 8‐armed radial maze task was impaired. These results suggest that the condensation of monoaminergic terminals in the atrophic CH of MAM rats may compensate for disability in discrimination learning, but the significant reduction of NMDA receptors may impair spatial memory in MAM rats.

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Hyperactivity and instrumental learning deficits in methylazoxymethanol-treated rat offspring

Cited by 27 publications

References 22 publications

Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

Functional Changes Implicating Dopaminergic Systems following Perinatal Treatments

Neurochemical Correlates of Learning Impairment in Microen‐cephalic Rats Induced by Methylazoxymethanol Acetate*

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