Preclinical models of antipsychotic drug action

Moreno, José L.; González-Maeso, Javier

doi:10.1017/s1461145713000606

Cited by 27 publications

(30 citation statements)

References 181 publications

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“…Although there exists wide evidence relating schizophrenia and dopamine function, as discussed in different sections of the present work and in part of the cited literature, an outstanding example of a combined genetic, neurobehavioral and pharmacological approach leading to the discovery of new neurochemical mechanisms with great potential relevance for schizophrenia is provided by recent work from Gonzalez-Maeso's group and others (e.g. [5]- [7] [13]). These authors have demonstrated that 5-HT2A and mGluR2 cortical (prefrontal) receptors form a physical functional complex (named 5HT2AR/mGluR2 complex), which is related to several schizophrenic symptoms in mice (they have used 5-HT2A and mGluR2 knockout mice), to hallucinogenic drug effects and to atypical antipsychotic drug therapeutic actions.…”

Section: The Roman High-avoidance (Rha) and Low-avoidance (Rla) Rat Lmentioning

confidence: 88%

“…While behavioral tests/models, drug-and lesion-induced models, developmental models and mouse genetic models have been thoroughly discussed in recent reviews (e.g. [1]- [3] [9] [10] [13] [17] [19]), genetically-based rat models have received very little attention. Thus, the aim of the present review is to discuss the most relevant aspects of some genetic approaches that have used selective breeding of rats to model schizophrenia-relevant features, as well as to describe other approaches based on existing rat strains (either selectively bred or not) which present behavioral and/or neurobiological profiles relevant to the disorder.…”

Section: Genetic Rat Models Of Schizophreniamentioning

confidence: 99%

“…cellular responses when targeted by hallucinogenic drugs, and activation of the mGluR2 abolishes hallucinogen-specific signaling and behavioral responses (e.g. [5]- [7] [13]). Moreover, in line with results with these knockout mice, post-mortem analysis of the brains of untreated schizophrenics revealed increased expression of 5HT2As and decreased expression of mGluR2s.…”

Section: The Roman High-avoidance (Rha) and Low-avoidance (Rla) Rat Lmentioning

confidence: 99%

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Genetic Rat Models of Schizophrenia-Relevant Symptoms

Río¹,

Oliveras²,

Cañete³

et al. 2014

WJNS

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It is recognized that developing valid animal models is essential for the research on the neurobiological mechanisms of (and treatments for) psychiatric disorders, even when these are as complex as schizophrenia. To be considered a valid analogue of the disorder, a given model should present good face validity (i.e. similarity of symptoms), good predictive validity (i.e. similarity of treatment effects and potential for discovering novel treatments) and enough construct validity (i.e. the model should help discover neurobiological mechanisms underlying the disorder or some relevant symptoms). The complexity of symptoms (positive, negative and cognitive) of schizophrenia makes it a very difficult task for a model to mimic all the main features of the disorder, but some rodent (mouse and rat) models have behavioural and even neurobiological phenotype characteristics resembling positive-like symptoms, cognitive symptoms and some neurochemical features of schizophrenia. As several recent works have already reviewed the main behavioural and developmental models, as well as the most used drug-induced, lesion-induced and genetic mouse models, the present review focuses on describing the most relevant genetically-based rat models of schizophrenia-relevant symptoms. Thus, we discuss several selective breeding programs leading to rat lines/strains which present impaired prepulse inhibition (PPI) of the acoustic startle response and (in some cases) latent inhibition deficits (both of which may be considered as endophenotypes of schizophrenia related with pre-attentive processes and attention, respectively), as well as other schizophrenia-relevant symptoms (e.g. learning deficits). Evidence is presented for the effects of genetic background on PPI (and other symptoms/phenotypes), as well as for environmental influences on genetic predisposition to enhanced apomorphine (mixed dopamine receptor agonist) effects. Some of the described rat models appear to present face validity and, to a certain extent, construct validity. While efforts should be made to evaluate the predictive validity of these genetic rat models, we propose that they have the advantage (over mouse knockouts, for example) of better representing "normal" genetic, neurobiological and phenotype variation, * Corresponding author.C. del Río et al. 262thus allowing the study of associations among them by means of genetic mapping or gene expression studies.

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Section: The Roman High-avoidance (Rha) and Low-avoidance (Rla) Rat Lmentioning

confidence: 88%

Section: Genetic Rat Models Of Schizophreniamentioning

confidence: 99%

Section: The Roman High-avoidance (Rha) and Low-avoidance (Rla) Rat Lmentioning

confidence: 99%

See 1 more Smart Citation

Genetic Rat Models of Schizophrenia-Relevant Symptoms

Río¹,

Oliveras²,

Cañete³

et al. 2014

WJNS

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“…Based on the in vitro pharmacological profiles, compound 3 and these 6 analogs were then subjected to in vivo behavioral studies to verify their effects on schizophrenia Antipsychotic efficacy is usually assessed by the phencyclidine (PCP)-induced hyperactivity model [49][50] . PCP, an N-methyl-D-aspartic acid receptor (NMDAR) antagonist, has been found to simulate schizophrenia 51 , and in rodents, this effect can be reversed by antipsychotic drugs 52 . Then the antipsychotic activities of the above 7 compounds were studied in the PCP-induced locomotor hyperactivity test in ICR mice ( Figure S6).…”

Section: In Vivo Behavioral Evaluation Of the Selected Compoundsmentioning

confidence: 99%

Automated design and optimization of multitarget schizophrenia drug candidates by deep learning

Tan

Jiang

Yang

et al. 2020

Preprint

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Complex neuropsychiatric diseases such as schizophrenia require drugs that can target multiple G protein-coupled receptors (GPCRs) to modulate complex neuropsychiatric functions. Here, we report an automated system comprising a deep recurrent neural network (RNN) and a multitask deep neural network (MTDNN) to design and optimize multitargeted antipsychotic drugs. The system successfully generates novel molecule structures with desired multiple target activities, among which high-ranking compound 3 was synthesized, and demonstrated potent activities against dopamine D2, serotonin 5-HT1A and 5-HT2A receptors. Hit expansion based on the MTDNN was performed, 6 analogs of compound 3 were evaluated experimentally, among which compound 8 not only exhibited specific polypharmacology profiles but also showed antipsychotic effect in animal models with low potential for sedation and catalepsy, 2 highlighting their suitability for further preclinical studies. The approach can be an efficient tool for designing lead compounds with multitarget profiles to achieve the desired efficacy in the treatment of complex neuropsychiatric diseases. KEY WORDSSchizophrenia; Multitargeted antipsychotic drugs; Recurrent neural network; Multitask deep neural network; Automated drug design Abbreviations: GPCRs, G protein-coupled receptors; RNN, deep recurrent neural network; MTDNN, multitask deep neural network; D2R, D2 receptors; 5-HT2AR, 5-HT2A receptors; 5-HT1AR, 5-HT1A receptors; EPS, Parkinson-like extrapyramidal symptoms; TD, tardive dyskinesia; HTS, high-throughput screening; AI, artificial intelligence; QSAR, quantitative structure-activity relationship; AEs, autoencoders; GANs, generative adversarial networks; RL, reinforcement learning; MW, molecular weight; logP, Wildman-Crippen partition coefficient; TPSA, total polar surface area; DNNs, deep neural networks; LSTM, long short-term memory; t-SNE, t-distributed stochastic neighbor embedding; ECFP4, extended connectivity fingerprint 4; SA, synthetic accessibility; QED, quantitative estimate of drug-likeness; R 2 , correlation coefficient; MAE, mean absolute error; RO5, Lipinski's rule of five; CNS, central nervous system; PCP, phencyclidine; NMDAR, N-methyl-D-aspartic acid receptor; SAR, structural-activity relationships; BPTT, backpropagation through time; ReLU, rectified linear unit; MSE, mean squared error

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“…2) Are PSD transcripts' expression differently affected in Ddo −/− vs. Ddo +/+ mice after administration of phencyclidine (PCP), a widely used model of aberrant glutamate transmission considered to mimic several aspects of schizophrenia (Moreno and Gonzalez-Maeso, 2013)? In this latter model, we also studied modifications in ataxia, a well known effect of NMDAR blockade by PCP (Enomoto et al, 2007), which may resemble discrete schizophrenia-like manifestations at the behavioral level.…”

Section: Introductionmentioning

confidence: 99%