Effects of Antipsychotics on Dentate Gyrus Stem Cell Proliferation and Survival in Animal Models: A Critical Update

Keilhoff, Gerburg; Fusar‐Poli, Paolo; Becker, Andaxel

doi:10.1155/2012/832757

Cited by 14 publications

(11 citation statements)

References 176 publications

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“…While APD are largely developed according to DA and 5HT receptor antagonism, changes in cell growth and survival may be of significance in enhancing therapeutic efficacy. Current literature regarding this issue remains inconsistent, perhaps due to discrepancies in paradigms, dosages, and assessment time points (Keilhoff et al , 2012). For example, Halim et al , 2004 found that 28 days of clozapine (CLZ) increased dentate gyrus (DG) cell proliferation in healthy animals, but not survival.…”

Section: Discussionmentioning

confidence: 99%

Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia

Chou

Jones

2015

Brain Research

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Previous work established that repeated olanzapine (OLZ) administration in normal adolescent rats induces a sensitization effect (i.e. increased behavioral responsiveness to drug re-exposure) in the conditioned avoidance response (CAR) model. However, it is unclear whether the same phenomenon can be detected in animal models of schizophrenia. The present study explored the generalizability of OLZ sensitization from healthy animals to a preclinical neuroinflammatory model of schizophrenia in the CAR. Maternal immune activation (MIA) was induced via polyinosinic:polycytidilic acid (PolyI:C) administration into pregnant dams. Behavioral assessments of offspring first identified decreased maternal separation-induced pup ultrasonic vocalizations and increased amphetamine-induced hyperlocomotion in animals prenatally exposed to PolyI:C. In addition, repeated adolescent OLZ administration confirmed the generalizability of the sensitization phenomenon. Using the CAR test, adolescent MIA animals displayed similar increase in behavioral responsiveness after repeated OLZ exposure during both the repeated drug test days as well as a subsequent challenge test. Neurobiologically, few studies examining the relationship between hippocampal cell proliferation and survival and either antipsychotic exposure or MIA have incorporated concurrent behavioral changes. Thus, the current study also sought to reveal the correlation between OLZ behavioral sensitization in the CAR and hippocampal cell proliferation and survival. 5′-bromodeoxyuridine immunohistochemistry identified a positive correlation between the magnitude of OLZ sensitization (i.e. change in avoidance suppression induced by OLZ across days) and hippocampal cell proliferation, and a negative correlation between OLZ sensitization magnitude and hippocampal short term cell survival. The implications of the relationship between behavioral and neurobiological results are discussed.

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Section: Discussionmentioning

confidence: 99%

Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia

Chou

Jones

2015

Brain Research

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“…Nevertheless, the potent prevention by risperidone of amphetamine-supersensitivity in a VHL model in rats suggests a role for its 5-HT2A antagonist properties, likewise implicated in blockade of the actions of PCP in rats 145,146,149,151,153 . In addition, 5-HT1A agonism may be involved in the effects of aripiprazole (and clozapine), ostensibly via neuroprotective/neurorestorative actions 148,151,154 .…”

Section: Antipsychotics and Their Potential Mechanisms Of Actionmentioning

confidence: 99%

“…In this sense, rapid intervention with antipsychotics might nominally be considered "course-altering" 259 . However, evidence for protective effects of SGAs against pathophysiological changes associated with psychosis is limited and of uncertain clinical relevance 154,212,[260][261][262][263][264] . Moreover, in certain patients, decreases in brain volume in patients may be aggravated by long-term exposure to high doses of antipsychotics 76,78 .…”

Section: Evaluation Of Course-altering Therapy After the First Episodementioning

confidence: 99%

Altering the course of schizophrenia: progress and perspectives

Millan¹,

Andrieux²,

Bartzokis³

et al. 2016

Nat Rev Drug Discov

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426

323

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Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to - and of - this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.

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“…Chronic treatment with the mood stabilizer lithium increases new-neuron proliferation and differentiation in animal models, and the bipolar disorder medication valproate rescues aberrant DG activity and manic-like behavior in animal models 98,99 . Furthermore, anti-psychotic drugs, such as haloperidol, risperidone or clozapine, restore neurogenesis in animal models of schizophrenia, and antipsychotics can also ameliorate anxiety and restore new-neuron proliferation in an animal model of PTSD 100,101 .…”

Section: Neuropsychiatric Disorders and Adult Dg Neurogenesismentioning

confidence: 99%

Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis

Yun

Reynolds

Masiulis

et al. 2016

Nat Med

111

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People diagnosed with neuropsychiatric disorders such as depression, anxiety, addiction or schizophrenia often have dysregulated memory, mood, pattern separation and/or reward processing. These symptoms are indicative of a disrupted function of the dentate gyrus (DG) subregion of the brain, and they improve with treatment and remission. The dysfunction of the DG is accompanied by structural maladaptations, including dysregulation of adult-generated neurons. An increasing number of studies using modern inducible approaches to manipulate new neurons show that the behavioral symptoms in animal models of neuropsychiatric disorders can be produced or exacerbated by the inhibition of DG neurogenesis. Thus, here we posit that the connection between neuropsychiatric disorders and dysregulated DG neurogenesis is beyond correlation or epiphenomenon, and that the regulation of adult-generated DG neurogenesis merits continued and focused attention in the ongoing effort to develop novel treatments for neuropsychiatric disorders.

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Effects of Antipsychotics on Dentate Gyrus Stem Cell Proliferation and Survival in Animal Models: A Critical Update

Cited by 14 publications

References 176 publications

Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia

Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia

Altering the course of schizophrenia: progress and perspectives

Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis

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