RATIONALE: Schizophrenia is a complex psychiatric disorder comprised of three main classes of symptoms: positive, negative and cognitive symptoms. Currently, no approved treatment exists for the cognitive symptoms. There is thus a great need for research aiming at identifying novel targets for treatment of this indication. Several neurotransmitter systems are affected in schizophrenia patients, including the γ-amino butyric acid (GABAergic) system, demonstrated by reduced parvalbumin-containing interneurons, glutamate decarboxylase (GAD) and the GABA transporter GAT-1. Furthermore, gene expression of several GABA(A) receptor sub-units, such as α1, α4 and δ is reduced in the dorsolateral prefrontal cortex of schizophrenia patients. OBJECTIVES: The psychotomimetic NMDA receptor antagonist phencyclidine (PCP) is frequently employed to model schizophrenia in animal disease models. Sub-chronic PCP treatment of female hooded Lister rats has repeatedly been shown to induce impairments in object recognition memory, and this model was therefore chosen for the examination of the potential of positive modulation of extrasynaptic GABA(A) receptors in alleviating the PCP-induced deficit. RESULTS: Rats treated sub-chronically with PCP showed significant impairments in recognition memory. This deficit was reversed by positive modulation of extrasynaptic GABA(A) receptors. CONCLUSION: The present study shows that extrasynaptic GABA(A) receptors may present a novel target for the development of therapeutics aimed at improving cognitive deficits in schizophrenia.
RATIONALE: Schizophrenia is a complex psychiatric disorder comprised of three main classes of symptoms: positive, negative and cognitive symptoms. Currently, no approved treatment exists for the cognitive symptoms. There is thus a great need for research aiming at identifying novel targets for treatment of this indication. Several neurotransmitter systems are affected in schizophreniapatients, including the γ-amino butyric acid (GABAergic) system, demonstrated by reduced parvalbumin-containing interneurons, glutamate decarboxylase (GAD) and the GABA transporter GAT-1. Furthermore, gene expression of several GABA(A) receptor sub-units, such as α1, α4 and δ is reduced in the dorsolateral prefrontal cortex of schizophreniapatients. OBJECTIVES: The psychotomimetic NMDA receptor antagonist phencyclidine (PCP) is frequently employed to model schizophrenia in animal disease models. Sub-chronic PCP treatment of female hooded Lister rats has repeatedly been shown to induce impairments in object recognition memory, and this model was therefore chosen for the examination of the potential of positive modulation of extrasynaptic GABA(A) receptors in alleviating the PCP-induced deficit. RESULTS:Rats treated sub-chronically with PCP showed significant impairments in recognition memory. This deficit was reversed by positive modulation of extrasynaptic GABA(A) receptors. CONCLUSION: The present study shows that extrasynaptic GABA(A) receptors may present a novel target for the development of therapeutics aimed at improving cognitive deficits in schizophrenia.
Authors: David A Lewis; Raymond Y Cho; Cameron S Carter; Kevin Eklund; Sarah Forster; Mary Ann Kelly; Debra Montrose Journal: Am J Psychiatry Date: 2008-10-15 Impact factor: 18.112
Authors: Nagi Idris; Jo Neill; Ben Grayson; Benny Bang-Andersen; Louise M Witten; Lise Tøttrup Brennum; Jørn Arnt Journal: Psychopharmacology (Berl) Date: 2009-10-23 Impact factor: 4.530
Authors: Xia Wu; Zheng Wu; Gang Ning; Yao Guo; Rashid Ali; Robert L Macdonald; Angel L De Blas; Bernhard Luscher; Gong Chen Journal: J Biol Chem Date: 2012-06-18 Impact factor: 5.157