Natasja M.W.J. de Bruin and Chris G Kruse Pages 3739 - 3759 ( 21 )
5-hydroxytryptamine<sub>6</sub> receptor (5-HT<sub>6</sub>R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT<sub>6</sub>R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT<sub>6</sub>R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT<sub>6</sub> antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT<sub>6</sub>R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT<sub>6</sub>R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT<sub>6</sub>R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT<sub>6</sub>R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer’s disease.
5-Hydroxytryptamine<sub>6</sub> receptor (5-HT<sub>6</sub>R), Cognition, Schizophrenia, Comorbidities, Animal models, Clinical development.
Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project Group Translational Medicine & Pharmacology (TMP), c/o Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.