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Anthony A. Grace - One of the best experts on this subject based on the ideXlab platform.

  • Nicotine Self-administration Is Not Increased in the Methylazoxymethanol Acetate Rodent Model of Schizophrenia.
    Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2019
    Co-Authors: Jillian J Weeks, Laura E. Rupprecht, Anthony A. Grace, Eric C. Donny, Alan F. Sved
    Abstract:

    INTRODUCTION Patients with schizophrenia (SCZ) smoke at a rate of 4-5 times higher than the general population, contributing to negative health consequences in this group. One possible explanation for this increased smoking is that individuals with SCZ find nicotine (NIC) more reinforcing. However, data supporting this possibility are limited. METHODS The present experiments examined self-administration of NIC, alone or in combination with other reinforcers, across a range of doses in the Methylazoxymethanol Acetate (MAM) rodent model of SCZ. RESULTS MAM and control animals did not differ in NIC self-administration across a range of doses and schedules of reinforcement, in both standard 1-hour self-administration sessions and 23-hour extended access sessions. However, MAM animals responded less for sucrose or reinforcing visual stimuli alone or when paired with NIC. CONCLUSIONS To the extent that MAM-treated rats are a valid model of SCZ, these results suggest that increased NIC reinforcement does not account for increased smoking in SCZ patients. IMPLICATIONS This study is the first to utilize nicotine self-administration, the gold standard for studying nicotine reinforcement, in the Methylazoxymethanol Acetate model of schizophrenia, which is arguably the most comprehensive animal model of the disease currently available. Our assessment found no evidence of increased nicotine reinforcement in Methylazoxymethanol Acetate animals, suggesting that increased reinforcement may not perpetuate increased smoking in schizophrenia patients.

  • The Methylazoxymethanol Acetate rat model: molecular and epigenetic effect in the developing prefrontal cortex: An Editorial Highlight for 'Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in th
    Journal of neurochemistry, 2017
    Co-Authors: Xiyu Zhu, Felipe V. Gomes, Anthony A. Grace
    Abstract:

    This Editorial highlights an article by Gulchina and colleagues in the current issue of the Journal of Neurochemistry, in which the authors describe molecular and epigenetic changes in the developing prefrontal cortex of the rats exposed to Methylazoxymethanol Acetate (MAM). They found an NMDAR hypofunction present in the prefrontal cortex of juvenile MAM rats which was associated with abnormal epigenetic regulation of the Grin2b gene. These changes may be related to early cognitive impairments observed in MAM rats and schizophrenia patients.

  • Loss of parvalbumin in the hippocampus of MAM schizophrenia model rats is attenuated by peripubertal diazepam
    The international journal of neuropsychopharmacology, 2016
    Co-Authors: Anthony A. Grace
    Abstract:

    Background: Loss of parvalbumin interneurons in the hippocampus is a robust finding in schizophrenia brains. Rats exposed during embryonic day 17 to Methylazoxymethanol Acetate exhibit characteristics consistent with an animal model of schizophrenia, including decreased parvalbumin interneurons in the ventral hippocampus. We reported previously that peripubertal administration of diazepam prevented the emergence of pathophysiology in adult Methylazoxymethanol Acetate rats. Methods: We used an unbiased stereological method to examine the impact of peripubertal diazepam treatment on parvalbumin interneuron number in the ventral subiculum, dentate gyrus of the hippocampus and the basolateral amygdala. Results: Methylazoxymethanol Acetate rats with peripubertal diazepam showed significantly more parvalbumin interneurons (3355±173 in the ventral subiculum, 1211±76 in the dentate gyrus) than Methylazoxymethanol Acetate without diazepam (2375±109 and 824±54, respectively). No change was found in the basolateral amygdala. Conclusions: Peripubertal diazepam attenuated the decrease of parvalbumin in the ventral hippocampus of Methylazoxymethanol Acetate rats.

  • Dopamine System Dysregulation and the Pathophysiology of Schizophrenia: Insights From the Methylazoxymethanol Acetate Model
    Biological psychiatry, 2015
    Co-Authors: Anthony A. Grace
    Abstract:

    Data from numerous studies have strongly implicated the dopamine (DA) system in the pathophysiology of schizophrenia. The data are particularly robust for the positive or the psychotic symptoms of schizophrenia, which can be mimicked by DA agonists and attenuated by D2 antagonist antipsychotic drugs. Nonetheless, there is little evidence for a major dysfunction within the DA system itself; instead, current research has focused on a disruption in the regulation of the DA system. One region in particular that has shown correlations with DA dysfunction is the limbic portion of the hippocampus, which comprises the ventralmost segment in rats analogous to the anterior aspect in humans. Thus, studies in patients with schizophrenia have shown hyperactivity in the hippocampus that correlates with psychosis as well as a loss of parvalbumin gamma-aminobutyric acid–ergic (GABAergic) inhibitory neurons (1). To examine the pathophysiology of schizophrenia, we employed a developmental disruption model that uses the mitotoxin Methylazoxymethanol Acetate (MAM). This drug is administered to pregnant rats at gestational day 17 to mimic the second trimester in humans, during which insults have a higher impact on inducing schizophrenia births. The offspring are then examined peripubertally for developmental changes and as adults to test for dysfunctions that correspond to schizophrenia in humans. The adult offspring of MAM-treated rats display many characteristics consistent with schizophrenia (2,3), including neuroanatomic changes (thinning of limbic cortices with an increase in cell packing density, loss of parvalbumin interneurons), behavioral deficits (prepulse inhibition of startle, reversal learning, extradimensional shift, latent inhibition, social interaction), and pharmacologic responses (hyperresponsivity to phencyclidine, increased locomotion to amphetamine). Furthermore, as in humans, there is hyperactivity in the ventral hippocampus (vHipp) and a disruption of rhythmic activity including delta and gamma rhythms (3). There was also a substantial increase in DA neuron population activity. In anesthetized and awake rats, DA neurons exhibit several activity states that are regulated by different systems and differentially affect system function (Figure 1). In the basal state, DA neurons discharge in a slow, irregular tonic firing pattern. However, if the organism is exposed to a behaviorally salient stimulus, DA neurons transition to a rapid burst-firing mode. Thus, burst firing is considered to be the behaviorally relevant phasic response to stimuli. Burst firing is driven by a glutamatergic input arising primarily from the brainstem pedunculopontine tegmentum (PPTg) acting on N-methyl-D-aspartate

  • Prior Antipsychotic Drug Treatment Prevents Response to Novel Antipsychotic Agent in the Methylazoxymethanol Acetate Model of Schizophrenia
    Schizophrenia bulletin, 2014
    Co-Authors: Kathryn M. Gill, James M. Cook, Michael M. Poe, Anthony A. Grace
    Abstract:

    Trials of novel compounds for the treatment of schizophrenia are typically tested in patients following brief withdrawal of ongoing medication despite known long-term changes in the dopamine (DA) system following chronic antipsychotic drug therapy. The present study explored the impact of withdrawal from repeated haloperidol (HAL) treatment, as well as the response to a novel α5 gamma-aminobutyric acid (GABAA) receptor positive allosteric modulator (α5PAM), on the activity of the DA system in the Methylazoxymethanol Acetate (MAM) neurodevelopmental model of schizophrenia. Electrophysiological recordings were conducted from DA neurons in the ventral tegmental area of MAM and saline (SAL) rats following 7-day withdrawal from repeated HAL (21 d, 0.6mg/kg, orally). In separate animals, amphetamine-induced locomotion was measured to assess changes in DA behavioral sensitivity. SAL rats withdrawn from HAL demonstrated reduced spontaneous DA neuron activity along with an enhanced locomotor response to amphetamine, indicative of the development of DA supersensitivity. Both α5PAM treatment and ventral hippocampal (vHPC) inactivation reversed the DA neuron depolarization block following HAL withdrawal in SAL rats. In contrast, MAM rats withdrawn from HAL exhibited reduced spontaneous DA activity and enhanced locomotor response to amphetamine compared with untreated SAL rats; however, this condition was unresponsive to α5PAM treatment or vHPC inactivation. Withdrawal from prior HAL treatment interferes with the therapeutic actions of this novel treatment in the MAM model of schizophrenia. Consequently, testing novel compounds on chronically treated schizophrenia patients may be ineffective.

Joram Feldon - One of the best experts on this subject based on the ideXlab platform.

  • Effects of prenatal Methylazoxymethanol Acetate (MAM) treatment in rats on water maze performance
    Behavioural brain research, 2005
    Co-Authors: Andreas Leng, Ana L. Jongen-rêlo, Helen H. J. Pothuizen, Joram Feldon
    Abstract:

    Prenatal Methylazoxymethanol Acetate (MAM) treatment has been shown to induce morphological abnormalities in cortical areas of the offspring. Based on the neuroanatomical and behavioural abnormalities, this treatment has been suggested as a useful animal model for schizophrenia. In a previous study (Jongen-Relo AL, Leng A, Luber M, Pothuizen HHJ, Weber L, Feldon J. The prenatal Methylazoxymethanol Acetate treatment: a neurodevelopmental animal model for schizophrenia? Behav Brain Res 2004;149:159-81) we have studied MAM-treated animals in a series of behavioural tests related to schizophrenia, such as latent inhibition and pre-pulse inhibition of the acoustic startle response to establish the validity of prenatal MAM treatment (20mg/kg i.p. on gestational days 9-15; MAM 9-MAM 15). We found that, apart from a marginal effect of increased activity in the open field, the MAM treatment on gestational day 15 was behaviourally ineffective. Here, we extended our previous study to a water maze experiment conducted in the same batch of animals as presented previously (MAM 12-MAM 15). MAM-treated animals showed similar water maze performance compared with control animals during the acquisition phase and the probe tests. However, during the reversal phase, MAM 15 animals showed impaired acquisition of the new platform location. This might indicate some cognitive deficits in MAM 15 animals in terms of working memory or behavioural flexibility. However, in combination with the lack of behavioural abnormalities of MAM 12-MAM 15 animals in several other tests related to schizophrenia in the previously reported study, the use of MAM treatment (MAM 12-MAM 15) as a valid model for schizophrenia still remains debatable.

  • The prenatal Methylazoxymethanol Acetate treatment: a neurodevelopmental animal model for schizophrenia?
    Behavioural brain research, 2004
    Co-Authors: Ana L. Jongen-rêlo, Andreas Leng, Helen H. J. Pothuizen, Marcel Lüber, Liz Weber, Joram Feldon
    Abstract:

    The prenatal Methylazoxymethanol Acetate (MAM) treatment has been proposed as a suitable model for the neurodevelopmental aspects of schizophrenia since the morphological abnormalities it induces in the brain are subtle and in line with most reports of neuropathology in schizophrenic brains. However, the functional aspects of this treatment have not been investigated with behavioural paradigms that are relevant for the psychopathology of the symptoms of schizophrenia. In the present study, we investigated the validity of the prenatal MAM treatment as a developmental model for schizophrenia with a prepulse inhibition of the acoustic startle reflex, latent inhibition, locomotor activity, and cognition and emotionality with freezing in fear conditioning paradigms. We have conducted two studies: in Study I, MAM was injected from E09 to E12, and in Study II, MAM was administered at later stages in the embryonic development, from E12 to E15. Morphologically, the prenatal MAM treatment induced mild to severe reduction in brain weights and in the entorhinal cortex, prefrontal cortex and striatum volumes, the severity of the effects depending on the timing of administration. However, despite the morphological abnormalities induced by the MAM treatments, no behavioural deficits were observed in the MAM-treated animals when compared to Controls in prepulse inhibition, latent inhibition with the two-way active avoidance, and in the freezing paradigms. Therefore, due to the consistent lack of treatment effect observed in the present investigation, we conclude that the prenatal MAM treatment has no validity as a behavioural model for schizophrenia.

Giorgio Battaglia - One of the best experts on this subject based on the ideXlab platform.

  • via Temolo 4,
    2016
    Co-Authors: Giovanni Carriero, Denise Locatelli, Annamaria Vezzani, Giorgio Battaglia
    Abstract:

    We have generated an experimental ‘double-hit ’ model of chronic epilepsy to recapitulate the co-existence of abnormal cortical structure and frequently recurrent seizures as observed in human focal cortical dysplasia. We induced cortical malformations by exposing rats prenatally to Methylazoxymethanol Acetate and triggered status epilepticus and recurrent seizures in adult methy-lazoxymethanol Acetate rats with pilocarpine. We studied the course of epilepsy and the long-term morphologic and molecular changes induced by the occurrence of status epilepticus and subsequent chronic epilepsy in the malformed methylazoxymetha-nol Acetate exposed brain. Behavioural and electroencephalographic analyses showed that Methylazoxymethanol Acetate pilo-carpine rats develop more severe epilepsy than naı̈ve rats. Morphologic and molecular analyses demonstrated that status epilepticus and subsequent seizures, but not pilocarpine treatment per se, was capable of affecting both cortical architectural and N-methyl-D-aspartate receptor abnormalities induced by Methylazoxymethanol Acetate. In particular, cortical thickness was further decreased and N-methyl-D-aspartate regulatory subunits were recruited at the postsynaptic membrane. In addition, Methylazoxymethanol Acetate pilocarpine rats showed abnormally large cortical pyramidal neurons with neurofilament over-expression. These neurons bear similarities to the hypertrophic/dysmorphic pyramidal neurons observed in acquire

  • Status epilepticus-induced pathologic plasticity in a rat model of focal cortical dysplasia.
    Brain : a journal of neurology, 2011
    Co-Authors: Francesca Colciaghi, Adele Finardi, Angelisa Frasca, Silvia Balosso, Paola Nobili, Giovanni Carriero, Denise Locatelli, Annamaria Vezzani, Giorgio Battaglia
    Abstract:

    We have generated an experimental 'double-hit' model of chronic epilepsy to recapitulate the co-existence of abnormal cortical structure and frequently recurrent seizures as observed in human focal cortical dysplasia. We induced cortical malformations by exposing rats prenatally to Methylazoxymethanol Acetate and triggered status epilepticus and recurrent seizures in adult Methylazoxymethanol Acetate rats with pilocarpine. We studied the course of epilepsy and the long-term morphologic and molecular changes induced by the occurrence of status epilepticus and subsequent chronic epilepsy in the malformed Methylazoxymethanol Acetate exposed brain. Behavioural and electroencephalographic analyses showed that Methylazoxymethanol Acetate pilocarpine rats develop more severe epilepsy than naïve rats. Morphologic and molecular analyses demonstrated that status epilepticus and subsequent seizures, but not pilocarpine treatment per se, was capable of affecting both cortical architectural and N-methyl-D-aspartate receptor abnormalities induced by Methylazoxymethanol Acetate. In particular, cortical thickness was further decreased and N-methyl-D-aspartate regulatory subunits were recruited at the postsynaptic membrane. In addition, Methylazoxymethanol Acetate pilocarpine rats showed abnormally large cortical pyramidal neurons with neurofilament over-expression. These neurons bear similarities to the hypertrophic/dysmorphic pyramidal neurons observed in acquired human focal cortical dysplasia. These data show that status epilepticus sets in motion a pathological process capable of significantly changing the cellular and molecular features of pre-existing experimental cortical malformations. They suggest that seizure recurrence in human focal cortical dysplasia might be an additional factor in establishing a pathological circuitry that favours chronic neuronal hyperexcitability.

  • Status epilepticus-induced pathologic plasticity in a rat model of focal cortical dysplasia
    Brain, 2011
    Co-Authors: Francesca Colciaghi, Adele Finardi, Angelisa Frasca, Silvia Balosso, Paola Nobili, Giovanni Carriero, Denise Locatelli, Annamaria Vezzani, Giorgio Battaglia
    Abstract:

    We have generated an experimental ‘double-hit’ model of chronic epilepsy to recapitulate the co-existence of abnormal cortical structure and frequently recurrent seizures as observed in human focal cortical dysplasia. We induced cortical malformations by exposing rats prenatally to Methylazoxymethanol Acetate and triggered status epilepticus and recurrent seizures in adult Methylazoxymethanol Acetate rats with pilocarpine. We studied the course of epilepsy and the long-term morphologic and molecular changes induced by the occurrence of status epilepticus and subsequent chronic epilepsy in the malformed Methylazoxymethanol Acetate exposed brain. Behavioural and electroencephalographic analyses showed that Methylazoxymethanol Acetate pilocarpine rats develop more severe epilepsy than naive rats. Morphologic and molecular analyses demonstrated that status epilepticus and subsequent seizures, but not pilocarpine treatment per se , was capable of affecting both cortical architectural and N -methyl-d-aspartate receptor abnormalities induced by Methylazoxymethanol Acetate. In particular, cortical thickness was further decreased and N -methyl-d-aspartate regulatory subunits were recruited at the postsynaptic membrane. In addition, Methylazoxymethanol Acetate pilocarpine rats showed abnormally large cortical pyramidal neurons with neurofilament over-expression. These neurons bear similarities to the hypertrophic/dysmorphic pyramidal neurons observed in acquired human focal cortical dysplasia. These data show that status epilepticus sets in motion a pathological process capable of significantly changing the cellular and molecular features of pre-existing experimental cortical malformations. They suggest that seizure recurrence in human focal cortical dysplasia might be an additional factor in establishing a pathological circuitry that favours chronic neuronal hyperexcitability. * Abbreviations : MAM : Methylazoxymethanol Acetate NMDA : N -methyl- d -aspartate PILO : pilocarpine

Andreas Leng - One of the best experts on this subject based on the ideXlab platform.

  • Effects of prenatal Methylazoxymethanol Acetate (MAM) treatment in rats on water maze performance
    Behavioural brain research, 2005
    Co-Authors: Andreas Leng, Ana L. Jongen-rêlo, Helen H. J. Pothuizen, Joram Feldon
    Abstract:

    Prenatal Methylazoxymethanol Acetate (MAM) treatment has been shown to induce morphological abnormalities in cortical areas of the offspring. Based on the neuroanatomical and behavioural abnormalities, this treatment has been suggested as a useful animal model for schizophrenia. In a previous study (Jongen-Relo AL, Leng A, Luber M, Pothuizen HHJ, Weber L, Feldon J. The prenatal Methylazoxymethanol Acetate treatment: a neurodevelopmental animal model for schizophrenia? Behav Brain Res 2004;149:159-81) we have studied MAM-treated animals in a series of behavioural tests related to schizophrenia, such as latent inhibition and pre-pulse inhibition of the acoustic startle response to establish the validity of prenatal MAM treatment (20mg/kg i.p. on gestational days 9-15; MAM 9-MAM 15). We found that, apart from a marginal effect of increased activity in the open field, the MAM treatment on gestational day 15 was behaviourally ineffective. Here, we extended our previous study to a water maze experiment conducted in the same batch of animals as presented previously (MAM 12-MAM 15). MAM-treated animals showed similar water maze performance compared with control animals during the acquisition phase and the probe tests. However, during the reversal phase, MAM 15 animals showed impaired acquisition of the new platform location. This might indicate some cognitive deficits in MAM 15 animals in terms of working memory or behavioural flexibility. However, in combination with the lack of behavioural abnormalities of MAM 12-MAM 15 animals in several other tests related to schizophrenia in the previously reported study, the use of MAM treatment (MAM 12-MAM 15) as a valid model for schizophrenia still remains debatable.

  • The prenatal Methylazoxymethanol Acetate treatment: a neurodevelopmental animal model for schizophrenia?
    Behavioural brain research, 2004
    Co-Authors: Ana L. Jongen-rêlo, Andreas Leng, Helen H. J. Pothuizen, Marcel Lüber, Liz Weber, Joram Feldon
    Abstract:

    The prenatal Methylazoxymethanol Acetate (MAM) treatment has been proposed as a suitable model for the neurodevelopmental aspects of schizophrenia since the morphological abnormalities it induces in the brain are subtle and in line with most reports of neuropathology in schizophrenic brains. However, the functional aspects of this treatment have not been investigated with behavioural paradigms that are relevant for the psychopathology of the symptoms of schizophrenia. In the present study, we investigated the validity of the prenatal MAM treatment as a developmental model for schizophrenia with a prepulse inhibition of the acoustic startle reflex, latent inhibition, locomotor activity, and cognition and emotionality with freezing in fear conditioning paradigms. We have conducted two studies: in Study I, MAM was injected from E09 to E12, and in Study II, MAM was administered at later stages in the embryonic development, from E12 to E15. Morphologically, the prenatal MAM treatment induced mild to severe reduction in brain weights and in the entorhinal cortex, prefrontal cortex and striatum volumes, the severity of the effects depending on the timing of administration. However, despite the morphological abnormalities induced by the MAM treatments, no behavioural deficits were observed in the MAM-treated animals when compared to Controls in prepulse inhibition, latent inhibition with the two-way active avoidance, and in the freezing paradigms. Therefore, due to the consistent lack of treatment effect observed in the present investigation, we conclude that the prenatal MAM treatment has no validity as a behavioural model for schizophrenia.

Tammy Mk Cheng - One of the best experts on this subject based on the ideXlab platform.

  • The Methylazoxymethanol Acetate (MAM-E17) Rat Model: Molecular and Functional Effects in the Hippocampus
    Neuropsychopharmacology, 2012
    Co-Authors: Eva Hradetzky, Thomas M Sanderson, Tsz M Tsang, John L Sherwood, Stephen M Fitzjohn, Viktor Lakics, Nadia Malik, Stephanie Schoeffmann, Michael J O'neill, Tammy Mk Cheng
    Abstract:

    Administration of the DNA-alkylating agent Methylazoxymethanol Acetate (MAM) on embryonic day 17 (E17) produces behavioral and anatomical brain abnormalities, which model some aspects of schizophrenia. This has lead to the premise that MAM rats are a neurodevelopmental model for schizophrenia. However, the underlying molecular pathways affected in this model have not been elucidated. In this study, we investigated the molecular phenotype of adult MAM rats by focusing on the frontal cortex and hippocampal areas, as these are known to be affected in schizophrenia. Proteomic and metabonomic analyses showed that the MAM treatment on E17 resulted primarily in deficits in hippocampal glutamatergic neurotransmission, as seen in some schizophrenia patients. Most importantly, these results were consistent with our finding of functional deficits in glutamatergic neurotransmission, as identified using electrophysiological recordings. Thus, this study provides the first molecular evidence, combined with functional validation, that the MAM-E17 rat model reproduces hippocampal deficits relevant to the pathology of schizophrenia.

  • THE Methylazoxymethanol Acetate (MAM-E17) RAT MODEL: MOLECULAR AND FUNCTIONAL EFFECTS IN THE HIPPOCAMPUS
    Neuropsychopharmacology, 2011
    Co-Authors: Eva Hradetzky, Thomas M Sanderson, John L Sherwood, Stephen M Fitzjohn, Viktor Lakics, Nadia Malik, Stephanie Schoeffmann, Tsz Tsang, Michael F. O'neill, Tammy Mk Cheng
    Abstract:

    Administration of the DNA-alkylating agent Methylazoxymethanol Acetate (MAM) on embryonic day 17 (E17) produces behavioral and anatomical brain abnormalities modeling some aspects of schizophrenia. This has lead to the premise that MAM rats are a neurodevelopmental model for schizophrenia. However, the underlying molecular pathways affected in this model have not been elucidated. In the present study, we investigated the molecular phenotype of adult MAM rats in frontal cortex and hippocampus, which are affected in schizophrenia. Proteomic and metabonomic analyses showed that the MAM-treatment resulted primarily in deficits in hippocampal glutamatergic neurotransmission, as seen in some schizophrenia patients. Most importantly, these results were consistent with our finding of functional deficits in glutamatergic neurotransmission as identified using electrophysiological recordings. Thus, this study provides the first molecular evidence, combined with functional validation, that the MAM-E17 rat model reproduces hippocampal deficits relevant to the pathology of schizophrenia.