Cognitive Impairment in Schizophrenia: a Review of Developmental and Genetic Models, and Pro-cognitive Profile of the Optimised D3 > D2 Antagonist, S33138

doi:10.2515/therapie:2008041

Therapies

Volume 63, Issue 3, May–June 2008, Pages 187-229

https://doi.org/10.2515/therapie:2008041 Get rights and content

Abstract

In vivo animal models are indispensable both for clarifying the pathological bases of schizophrenia, and for evaluating the potential benefits and disadvantages of novel therapy. Procedures that model mnemonic impairment are of particular interest since currently-available drugs do little to improve cognitive symptoms: this is hardly surprising, in fact, since most of them potently antagonise histamine H₁, muscarinic, and/or α₁-adrenergic receptors. Further, their blockade of D₂ receptors likewise compromises cognitive performance. By contrast, D₃ receptor antagonism improves certain cognitive domains, suggesting that preferential antagonism of D₃ vs. D₂ receptors may permit enhanced effectiveness against cognitive dysfunction. The novel agent, S33138, possesses such an “optimised” profile and shows a unique and broad-based pattern of pro-cognitive properties in rodents and primates, in the absence of extrapyramidal and metabolic side-effects. The present article surveys the preclinical pharmacology of S33138. It also reviews developmental and genetic risk factors for schizophrenia and their experimental modeling in rodents, with a particular emphasis on sensorimotor gating and cognitive deficits.

Résumé – Déficits cognitifs de la schizophrénie : revue des modèles développementaux et génétiques, et profil procognitif de l’antagoniste optimisé D₃ > D₂, S33138

Les modèles animaux in vivo sont indispensables pour comprendre les bases physiopathologiques de la schizophrénie et pour évaluer les bénéfices et inconvénients potentiels de nouvelles thérapies. Les procédures qui modélisent les déficits de mémoire sont d’un intérêt particulier, car les médicaments disponibles actuellement améliorent peu les symptômes cognitifs de cette maladie : leur manque d’activité n’est pas surprenant puisque la plupart sont des antagonistes des récepteurs histaminergiques H₁, muscariniques et/ou α₁-adrénergiques. De plus, leur activité antagoniste sur les récepteurs D₂ nuit également aux performances cognitives. Par contre, un blocage des récepteurs D₃ améliore certains domaines cognitifs, d’où l’hypothèse qu’un antagonisme préférentiel des récepteurs D₃ vs. D₂ pourrait aboutir à une plus grande efficacité vis-à-vis des troubles cognitifs. Le nouvel agent, S33138, possède un tel profil « optimisé » et présente une gamme étendue de propriétés pro-cognitives, chez les rongeurs et chez les primates, en l’absence d’effets indésirables extrapyramidaux et métaboliques. Le présent article décrit la pharmacologie préclinique du S33138. Il décrit aussi les facteurs de risque développementaux et génétiques de la schizophrénie et les modèles correspondants chez les rongeurs, en évoquant surtout les déficits de filtrage sensorimoteur et cognitifs.

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Patients with schizophrenia suffer from widespread cognitive impairment, which correlates with their functional outcome (e.g., community outcome, daily activities and social problem solving) [1,2]. Recent preclinical studies have shown that the dopamine D3 receptor may be an attractive therapeutic target for treatment of cognitive impairment associated with schizophrenia [3–6]. Whereas the dopamine D3 receptor-preferring agonists (+)-PD-128907 and 7-OH-DPAT disrupt several domains of cognitive function [3,4,7], the dopamine D3 receptor antagonists SB277011, NGB2904, S33138 and S33084 are known to produce procognitive effect in several rodent behavioral tasks [3–5,8,9].
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Experimental PharmacologyCognitive Impairment in Schizophrenia: a Review of Developmental and Genetic Models, and Pro-cognitive Profile of the Optimised D3 > D2 Antagonist, S33138

Abstract

Résumé – Déficits cognitifs de la schizophrénie : revue des modèles développementaux et génétiques, et profil procognitif de l’antagoniste optimisé D3 > D2, S33138

Pharmacol Ther

NeuroRx

Neurosci Biobehav Rev

Biol Psychiatry

Biol Psychiatry

Lancet

Neurochem Int

Schizophr Res

Pathol Biol

Biol Psychiatry

Behav Brain Res

Biol Psychiatry

Trends Cogn Sci

Trends Pharmacol Sci

Int Rev Neurobiol

Genet Med

Schizophr Res

Biol Psychiatry

Biol Psychiatry

Schizophr Res

Biol Psychiatry

Neuron

Neuron

Pharmacol Ther

Pharmacol Ther

Am J Hum Genet

Biochem Biophys Res Commun

Prog Neuropsychopharmacol Biol Psychiatry

Drug Discov Today: Ther Stategies

Cognitive factors in schizophrenia: causes, impact, and treatment

CNS Spectr

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Schizophrenia: a common disease caused by multiple rare alleles

Br J Psychiatry

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Mol Psychiatry

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J Psychiatry Neurosci

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Mol Psychiatry

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Psychol Med

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Med Genet

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Science

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Mol Psychiatry

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Mol Psychiatry

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J Physiol

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Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels

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Experimental Pharmacology
Cognitive Impairment in Schizophrenia: a Review of Developmental and Genetic Models, and Pro-cognitive Profile of the Optimised D₃ > D₂ Antagonist, S33138

Résumé – Déficits cognitifs de la schizophrénie : revue des modèles développementaux et génétiques, et profil procognitif de l’antagoniste optimisé D₃ > D₂, S33138