RATIONALE: Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its nonreinforced preexposure. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia (SZ). We showed that rats and mice treated with the N-methyl-D-aspartic acid (NMDA) receptor antagonist MK801 expressed LI under conditions preventing LI expression in controls. This abnormally persistent LI was reversed by the atypical antipsychotic drug (APD) clozapine and by compounds enhancing NMDA transmission via the glycineB site, but not by the typical APD haloperidol, lending the MK801 LI model predictive validity for negative/cognitive symptoms. OBJECTIVE: To test additional representatives from the two classes of drugs and show that the model can dissociate between atypical APDs and glycinergic drugs are the objectives of the study. MATERIALS AND METHODS: LI was measured in a conditional emotional response procedure. Atypical APD risperidone, selective 5HT2A antagonist M100907, and three glycinergic drugs were administered in preexposure or conditioning. RESULTS: Rats treated with MK801 (0.05 mg/kg) exhibited LI under conditions that disrupted LI in controls. This abnormality was reversed by risperidone (0.25 and 0.067 mg/kg) and M100907 (1 mg/kg) given in preexposure. Glycine (0.8 g/kg), D-cycloserine (DCS;15 and 30 mg/kg), and glycyldodecylamide (GDA; 0.05 and 0.1 g/kg.) counteracted MK801-induced LI persistence when given in conditioning. CONCLUSIONS: These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APDs, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.
RATIONALE: Latent inhibition (LI) is the poorer conditioning to a stimulus resulting from its nonreinforced preexposure. LI indexes the ability to ignore irrelevant stimuli and is used extensively to model attentional impairments in schizophrenia (SZ). We showed that rats and mice treated with the N-methyl-D-aspartic acid (NMDA) receptor antagonist MK801 expressed LI under conditions preventing LI expression in controls. This abnormally persistent LI was reversed by the atypical antipsychotic drug (APD) clozapine and by compounds enhancing NMDA transmission via the glycineB site, but not by the typical APD haloperidol, lending the MK801 LI model predictive validity for negative/cognitive symptoms. OBJECTIVE: To test additional representatives from the two classes of drugs and show that the model can dissociate between atypical APDs and glycinergic drugs are the objectives of the study. MATERIALS AND METHODS: LI was measured in a conditional emotional response procedure. Atypical APD risperidone, selective 5HT2A antagonist M100907, and three glycinergic drugs were administered in preexposure or conditioning. RESULTS:Rats treated with MK801 (0.05 mg/kg) exhibited LI under conditions that disrupted LI in controls. This abnormality was reversed by risperidone (0.25 and 0.067 mg/kg) and M100907 (1 mg/kg) given in preexposure. Glycine (0.8 g/kg), D-cycloserine (DCS;15 and 30 mg/kg), and glycyldodecylamide (GDA; 0.05 and 0.1 g/kg.) counteracted MK801-induced LI persistence when given in conditioning. CONCLUSIONS: These results support the validity of MK801-induced persistent LI as a model of negative/cognitive symptoms in SZ and indicate that this model may have a unique capacity to discriminate between typical APDs, atypical APDs, and glycinergic compounds, and thus, foster the identification of novel treatments for SZ.
Authors: John H Krystal; D Cyril D'Souza; Daniel Mathalon; Edward Perry; Aysenil Belger; Ralph Hoffman Journal: Psychopharmacology (Berl) Date: 2003-09-02 Impact factor: 4.530
Authors: A Schotte; P F Janssen; W Gommeren; W H Luyten; P Van Gompel; A S Lesage; K De Loore; J E Leysen Journal: Psychopharmacology (Berl) Date: 1996-03 Impact factor: 4.530
Authors: Daniel Klamer; Erik Pålsson; Aron Revesz; Jörgen A Engel; Lennart Svensson Journal: Psychopharmacology (Berl) Date: 2004-06-02 Impact factor: 4.530
Authors: Mark D Black; Rachel J Stevens; Nancy Rogacki; Robert E Featherstone; Yaw Senyah; Odessa Giardino; Beth Borowsky; Jeanne Stemmelin; Caroline Cohen; Philippe Pichat; Michal Arad; Segev Barak; Amaya De Levie; Ina Weiner; Guy Griebel; Geoffrey B Varty Journal: Psychopharmacology (Berl) Date: 2010-12-22 Impact factor: 4.530
Authors: Robert E Hampson; Andrew J Sweatt; Anushka V Goonawardena; Dong Song; Rosa H M Chan; Vasilis Z Marmarelis; Theodore W Berger; Sam A Deadwyler Journal: Behav Pharmacol Date: 2011-08 Impact factor: 2.293
Authors: Mark D Black; Geoffrey B Varty; Michal Arad; Segev Barak; Amaya De Levie; Denis Boulay; Philippe Pichat; Guy Griebel; Ina Weiner Journal: Psychopharmacology (Berl) Date: 2008-08-16 Impact factor: 4.530