dizocilpine-maleate and methylazoxymethanol

Developmental neurotoxicity (DNT) testing assesses potentially adverse effects on the developing nervous system. The present DNT study was conducted to generate historical data with the Wistar Han (WH) and Sprague Dawley (SD) rat strains, commonly used in Europe and the US, respectively. Potential differences between these strains in DNT endpoints have not been extensively investigated. Motor activity, startle response, learning and memory testing, and neurological (quantitative and qualitative) examinations were conducted using three groups of control, prenatally exposed (to Methylazoxymethanol [MAM] on gestation Day 15) and acutely treated (with IDPN, MK-801 or Chlorpromazine) animals for each strain. The positive controls produced clear effects in most endpoints investigated, with limited functional differences in baseline behavior and positive control sensitivity. However, SD rats were considerably more susceptible to MAM-induced learning and memory impairments and neurological damage. These data highlight differential sensitivity between the strains, which may require risk assessment consideration for developmental neurotoxicants.

Topics: Animals; Behavior, Animal; Brain; Chlorpromazine; Control Groups; Dizocilpine Maleate; Female; Learning; Male; Memory; Methylazoxymethanol Acetate; Motor Activity; Neurotoxicity Syndromes; Neurotoxins; Nitriles; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reflex, Startle; Species Specificity

Exposure to methylazoxymethanol (MAM) at embryonic day 17 (E17) in the rat has been proposed to be a promising model for schizophrenia that mimics behavioural abnormalities and deficits in prefrontal cortex (PFC) networks. In this study, we investigated for the first time the effects of antipsychotics on abnormal behaviours observed in prenatally MAM-exposed rats. We first examined spontaneous and MK-801-induced locomotor activity in an open field in adult E17 MAM- or saline-exposed rats. Then, the effect of single injections of haloperidol, clozapine and risperidone was investigated in MAM- or sham-exposed rats on spontaneous and MK-801 (0.05 mg/kg)-induced hyperactivity. Risperidone more selectively counteracted the spontaneous hyperactivity in MAM than in sham rats, while haloperidol and clozapine induced similar effects on spontaneous locomotion in both groups. The main result of this study is that all the tested antipsychotics were more effective in attenuating the MK-801-induced hyperlocomotion in MAM than in sham rats. These findings further support the validity of E17 MAM exposure as a model for schizophrenia and add to its heuristic value in screening therapies for schizophrenia.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dizocilpine Maleate; Female; Hyperkinesis; Methylazoxymethanol Acetate; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Schizophrenia

Prenatal methylazoxymethanol (MAM) administration at gestational day 17 has been shown to induce in adult rats schizophrenia-like behaviours as well as morphological and/or functional abnormalities in structures such as the hippocampus, medial prefrontal cortex (mPFC) and nucleus accumbens (NAcc), consistent with human data.. The aim of the present study was to further characterize the neurochemical alterations associated with this neurodevelopmental animal model of schizophrenia.. We performed simultaneous measurements of locomotor activity and extracellular concentrations of glutamate, dopamine and noradrenaline in the mPFC and the NAcc of adult rats prenatally exposed to MAM or saline after acute systemic injection of a noncompetitive NMDA antagonist, MK-801 (0.1 mg/kg s.c.).. A significant attenuation of the MK-801-induced increase in glutamate levels associated with a potentiation of the increase in noradrenaline concentrations was found in the mPFC of MAM-exposed rats, whereas no significant change was observed in the NAcc. MAM-exposed rats also exhibited an exaggerated locomotor hyperactivity, in line with the exacerbation of symptoms reported in schizophrenic patients after administration of noncompetitive NMDA antagonists.. Given the importance of the mPFC in regulating the hyperlocomotor effect of NMDA antagonists, our results suggest that the prefrontal neurochemical alterations induced by MK-801 may sustain the exaggerated locomotor response in MAM-exposed rats.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Male; Methylazoxymethanol Acetate; Microdialysis; Motor Activity; Norepinephrine; Nucleus Accumbens; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Schizophrenia

Schizophrenia is thought to be associated with abnormalities during neurodevelopment although those disturbances usually remain silent until puberty; suggesting that postnatal brain maturation precipitates the emergence of psychosis. In an attempt to model neurodevelopmental defects in the rat, brain cellular proliferation was briefly interrupted with methylazoxymethanol (MAM) during late gestation at embryonic day 17 (E17). The litters were explored at pre- and post-puberty and compared with E17 saline-injected rats. We measured spontaneous and provoked locomotion, working memory test, social interaction, and prepulse inhibition (PPI). As compared with the saline-exposed rats, the E17 MAM-exposed rats exhibited spontaneous hyperactivity that emerged only after puberty. At adulthood, they also exhibited hypersensitivity to the locomotor activating effects of a mild stress and a glutamatergic N-methyl-D-aspartate receptor antagonist (MK-801), as well as PPI deficits whereas before puberty no perturbations were observed. In addition, spatial working memory did not undergo the normal peri-pubertal maturation seen in the sham rats. Social interaction deficits were observed in MAM rats, at both pre- and post-puberty. Our study further confirms that transient prenatal disruption of neurogenesis by MAM at E17 is a valid behavioral model for schizophrenia as it is able to reproduce some fundamental features of schizophrenia with respect to both phenomenology and temporal pattern of the onset of symptoms and deficits.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Brain; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Inhibition, Psychological; Interpersonal Relations; Maze Learning; Methylazoxymethanol Acetate; Motor Activity; Pregnancy; Prenatal Exposure Delayed Effects; Psychotic Disorders; Rats; Recognition, Psychology; Reflex, Startle; Time Factors