Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap

Pratt, Judith A.; Winchester, Catherine; Dawson, Neil; Morris, Brian J.

doi:10.1038/nrd3649

Cited by 162 publications

(170 citation statements)

References 180 publications

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“…25 This is in line with the fact that administration of sub-anesthetic doses of NMDA receptor antagonists, such as ketamine, phencyclidine (''angel dust''), and dizocilpine (also known as MK801), exerts psychotomimetic activity and impairs cognitive processes. 5,24 These effects resemble the positive and negative symptoms of schizophrenia, respectively. In addition, acute treatment with these drugs increases Therefore, an impaired glutamatergic transmission can be involved in pathophysiology of schizophrenia.…”

Section: Glutamatergic Modelsmentioning

confidence: 91%

“…[3][4][5] The main mechanism accounting for their clinical efficacy is an attenuation in dopamine-mediated neurotransmission, through either antagonism or partial agonism at the D2 dopamine receptor. 6 Unfortunately, the efficacy of these drugs is limited to certain symptoms of schizophrenia and their use is associated with serious side effects.…”

Section: Introductionmentioning

confidence: 99%

“…5,10 Animal models must, however, fulfill some criteria of validity, of which those considered to be the most important are construct, face, and predictive validities. [11][12][13] Construct validity refers to how the model mimics the neurobiological mechanism of the disorder.…”

Section: Introductionmentioning

confidence: 99%

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Animal models for predicting the efficacy and side effects of antipsychotic drugs

Gobira

Röpke

Aguiar

et al. 2013

Rev. Bras. Psiquiatr.

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The use of antipsychotic drugs represents an important approach for the treatment of schizophrenia. However, their efficacy is limited to certain symptoms of this disorder, and they induce serious side effects. As a result, there is a strong demand for the development of new drugs, which depends on reliable animal models for pharmacological characterization. The present review discusses the face, construct, and predictive validity of classical animal models for studying the efficacy and side effects of compounds for the treatment of schizophrenia. These models are based on the properties of antipsychotics to impair the conditioned avoidance response and reverse certain behavioral changes induced by psychotomimetic drugs, such as stereotypies, hyperlocomotion, and deficit in prepulse inhibition of the startle response. Other tests, which are not specific to schizophrenia, may predict drug effects on negative and cognitive symptoms, such as deficits in social interaction and memory impairment. Regarding motor side effects, the catalepsy test predicts the liability of a drug to induce Parkinson-like syndrome, whereas vacuous chewing movements predict the liability to induce dyskinesia after chronic treatment. Despite certain limitations, these models may contribute to the development of more safe and efficacious antipsychotic drugs.

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Section: Glutamatergic Modelsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Animal models for predicting the efficacy and side effects of antipsychotic drugs

Gobira

Röpke

Aguiar

et al. 2013

Rev. Bras. Psiquiatr.

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Section: Per Group) In the Latent Inhibition (Li) Paradigm (E) LI Wmentioning

confidence: 99%

“…*Po0.05, **po0.01, ***po0.001, ****po0.0001 significantly different from Htr 2B +/+ mice following unpaired t-test or two-way ANOVA; # po0.05 significantly different from NPE in two-way ANOVA; full statistical analysis is presented in Supplementary Table S1. well as psychomotor agitation (ie, novelty-induced hyperlocomotion) and psychostimulant hypersensitivity (ie, enhanced locomotor response to psychostimulants), all phenotypes that have been related to the positive symptoms of schizophrenia (Gunduz-Bruce, 2009;Meyer et al, 2005;Pratt et al, 2012). Moreover, 5-HT 2B receptor gene ablation impaired social interaction behavior with conspecifics, a trait used commonly to model negative symptoms of schizophrenia in rodents (Arguello and Gogos, 2006;Pratt et al, 2012). Most importantly, Htr 2B − / − mice present with selective attention deficits (ie, lack of LI establishment) and learning and memory impairments (ie, poor NOR and fear conditioning performance and social memory deficit) that closely resemble the cognitive deficits observed in Figure 3 In Htr 2B − / − mice across 24 h, the total amount of wakefulness is increased while that of NREM sleep is decreased (a), as is the latency to REM sleep, calculated as the time elapsing from sleep onset after the animal had been awakened to the first episode of REM sleep (b) (N = 4-5 per group).…”

Section: Per Group) In the Latent Inhibition (Li) Paradigm (E) LI Wmentioning

confidence: 99%

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

Pitychoutis

Belmer

Moutkine

et al. 2015

Neuropsychopharmacol

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Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a populationspecific serotonin 2B (5-HT 2B ) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT 2B mutant (Htr 2B − / − ) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT 2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT 2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr 2B − / − mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr 2B − / − mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT 2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophreniclike phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT 2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT 2B receptors in the neurobiology of psychotic disorders.

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Animal Models in Translational Research

Bolker¹

2019

Encyclopedia of Life Sciences

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Animal models are a central tool in translational research – that is either basic or targeted biological research designed to generate knowledge that will enhance human health. Basic research generally focuses on gaining insight into disease mechanisms; more targeted studies are used to create and test potential therapies and other clinical applications. While a few core species (especially rodents) dominate translational research, the rapid development of molecular and other tools is providing access to a wide array of new models that can complement traditional species and approaches. Model choice should be guided by a combination of biological, epistemological, and practical considerations, including evaluation of likely predictive validity in the context of a particular research program. Key Concepts Animal models serve as proxies for humans in much biomedical research. To support translation, models must have both internal and predictive validity. Effective models balance representation of the target with tractability for research. Rodent models dominate translational research, but emerging tools are increasing access to and interest in a wide range of additional species. Model choice should be guided by both biological and epistemological considerations, in the context of a particular research program. Model choice and interpretation must be informed by knowledge of the unique biology of both the model and the target species, especially their evolutionary history. Challenges in model‐based translational research include limited knowledge of targets and overreliance on a few dominant model species. Emerging technologies for ex vivo models based on human cells will complement, but probably not replace, the use of animal models in translational research.

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Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap

Cited by 162 publications

References 180 publications

Animal models for predicting the efficacy and side effects of antipsychotic drugs

Animal models for predicting the efficacy and side effects of antipsychotic drugs

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

Animal Models in Translational Research

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