Cognitive deficits in schizophrenia are associ- ated with prefrontal cortex (PFC) abnormali- ties. Schizophrenic patients show a reduced performance in tasks engaging the PFC and a reduction of markers of cellular integrity and function. Non-competitive N-methyl- D- aspartate (NMDA) receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to exacerbate schizophrenia symptoms in patients and to elicit psychotomimetic actions in healthy volun- teers. Also, these drugs evoke behavioral alter- ations in experimental animals that resemble schizophrenia symptoms. The PFC seems to be a key target area for these agents. However, the cellular and network elements involved are poorly known. Cognitive deficits are of particu- lar interest since an early antipsychotic-induced improvement in cognitive performance predicts a better long-term clinical outcome. Here we report that the non-competitive NMDA receptor antagonist phencyclidine (PCP) induces a marked disruption of the activity of PFC. PCP administration increased the activity of a substantial proportion of pyramidal neu- rons, as evidenced by an increase in discharge rate and in c-fos expression. Examination of the effects of PCP on other brain areas revealed an increased c-fos expression in a number of corti- cal and subcortical areas, but notably in thal- amic nuclei projecting to the PFC. The adminis- tration of classical (haloperidol) and/or atypical (clozapine) antipsychotic drugs reversed PCP effects. These results indicate that PCP induces a marked disruption of the network activity in PFC and that antipsychotic drugs may partly exert their therapeutic effect by normalizing hyperactive cortico-thalamocortical circuits. Keywords: Antipsychotics; GABAergic interneurons; Glutamate; NMDA receptors; Prefrontal cortex; Pyramidal neurons; Oscillations; Thalamus INTRODUCTION Schizophrenia is associated with alterations in the anatomy and function of several cortical and sub- cortical areas (Harrison, 1999; Lewis and Lieberman, 2000). Among these, the prefrontal cortex (PFC) seems to play a key role in the pathophysiology of the illness (Lewis et al., 2005). Despite the obvious F.P. Graham Publishing Co. NMDA Antagonist and Antipsychotic Actions in Cortico-subcortical Circuits LUCILA KARGIEMAN a , NOEMÍ SANTANA a , GUADALUPE MENGOD b , PAU CELADA a,* and FRANCESC ARTIGAS a,* Department of Neurochemistry and Neuropharmacology, Institut d' Investigacions Biomèdiques de Barcelona (CSIC), IDIBAPS, a Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM); b Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 08036 Barcelona, Spain. fapnqi@iibb.csic.es, pcpnqi@iibb.csic.es. (Submitted 22 February 2008; Revised 4 August 2008; In final form 4 August 2008) *Corresponding author: Tel.: +3493-363 8315; FAX: +3493-363 8301; E-mail: fapnqi@iibb.csic.es, pcpnqi@iibb.csic.es ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2008 FP Graham Publishing Co., www.NeurotoxicityResearch.com Neurotoxicity Research, 2008, VOL. 14(2,3). pp. 129-140