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New psychopharmacological treatments are needed for affective and nonaffective psychoses, especially for the associated negative and cognitive symptoms. Earlier developments mostly failed, probably partly because of limitations in behavioral models used for validation. Now, deeper understanding of the genetics underlying disease pathogenesis and progress in genetic engineering will generate many rodent models with increased construct validity. To improve these models' translational value, we need complementary data from nonhuman primates. We also have to improve and streamline behavioral test systems to cope with increased demand. Here, we propose a comprehensive neurocognitive test battery that should overcome the disadvantages of single tests and yield cognitive/behavioral profiles for modeling subsets of patient symptoms. Further, we delineate a concept for classifying disease-relevant cognitive endophenotypes to balance between face and construct validity and clinical diagnostics. In summary, this review discusses new concepts and the limitations and future potential of translational research on cognition in psychiatry. .Se requiere de nuevos tratamientos psicofarmacológicos para las psicosis afectivas y no afectivas, especialmente para los síntomas negativos y cognitivos asociados. La mayoría de los desarrollos anteriores fallaron; en parte debido, probablemente, a las limitaciones en los modelos conductuales empleados para la validación. Ahora, una comprensión más profunda de la genética subyacente a la patogénesis de la enfermedad y el progreso en la ingeniería genética generará muchos modelos de roedores con una mayor validez de constructo. Para mejorar el valor de estos modelos translacionales se requiere de datos complementarios de primates no humanos. También hay que mejorar y racionalizar los sistemas de pruebas conductuales para hacer frente a una mayor demanda. En este artículo se propone una batería completa de pruebas neurocognitivas que debería superar las desventajas de las pruebas individuales y generar perfiles cognitivo-conductuales para modelar subconjuntos de síntomas del paciente. Además, se plantea un concepto para clasificar los endofenotipos cognitivos relevantes para la enfermedad a fin de equilibrar la validez aparente y de constructo con el diagnóstico clínico. En resumen, esta revisión analiza nuevos conceptos, y las limitaciones y el potencial futuro de la investigación translacional sobre la cognición en psiquiatría.De nouveaux traitements psychopharmacologiques sont nécessaires pour les psychoses dysthymiques ou non, surtout pour les symptômes associés négatifs et cognitifs. Par le passé, la plupart des développements ont échoué, probablement en partie en raison des limites des modèles comportementaux utilisés pour la validation. Aujourd’hui, une meilleure compréhension de la génétique de la pathogenèse de la maladie et les progrès du génie génétique vont produire de nombreux modèles de rongeurs mieux construits. Des données supplémentaires issues de primates non humains sont nécessaires pour améliorer la valeur traductive de ces modèles. Afin de satisfaire une demande croissante, nous devons aussi améliorer et rationaliser les systèmes de tests comportementaux. Nous proposons ici une batterie complète de tests neurocognitifs susceptible de palier les inconvénients des tests isolés et de fournir des profils cognitifs/comportementaux pour des sous-groupes de modélisation des symptômes des patients. En outre, nous définissons un concept pour classer les endophénotypes cognitifs pertinents pour la maladie afin de trouver un équilibre entre une validité de façade et de construit et les diagnostics cliniques. En résumé, cet article analyse de nouveaux concepts ainsi que les limites et les futures possibilités de la recherche translationnelle sur la cognition en psychiatrie.

Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HT1AR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HT1AR agonists N-[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate (rac-1) and N-((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1H-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate (rac-2) in vitro and in vivo. The role of chirality in the interaction with 5-HT1AR was evaluated by molecular docking. The activity of the rac-1 was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). Rac-1 was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HT1AR antagonist, WAY-100635. The eutomer (S)-1, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, (S)-1 evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than rac-1. The eutomer (S)-1 showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, (S)-1 may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.

Diagnosis of psychiatric disorders in humans is based on comparing individuals to the normal population. However, many animal models analyze averaged group effects, thus compromising their translational power. This discrepancy is particularly relevant in posttraumatic stress disorder (PTSD), where only a minority develop the disorder following a traumatic experience. In our PTSD rat model, we utilize a novel behavioral profiling approach that allows the classification of affected and unaffected individuals in a trauma-exposed population. Rats were exposed to underwater trauma (UWT) and four weeks later their individual performances in the open field and elevated plus maze were compared to those of the control group, allowing the identification of affected and resilient UWT-exposed rats. Behavioral profiling revealed that only a subset of the UWT-exposed rats developed long-lasting behavioral symptoms. The proportion of affected rats was further enhanced by pre-exposure to juvenile stress, a well-described risk factor of PTSD. For a biochemical proof of concept we analyzed the expression levels of the GABAA receptor subunits α1 and α2 in the ventral, dorsal hippocampus and basolateral amygdala. Increased expression, mainly of α1, was observed in ventral but not dorsal hippocampus of exposed animals, which would traditionally be interpreted as being associated with the exposure-resultant psychopathology. However, behavioral profiling revealed that this increased expression was confined to exposed-unaffected individuals, suggesting a resilience-associated expression regulation. The results provide evidence for the importance of employing behavioral profiling in animal models of PTSD, in order to better understand the neural basis of stress vulnerability and resilience.