1. ¹Yoshitomi Research Institute of Neuroscience in Glasgow (YRING), University of Glasgow, UK
2. ²Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow, UK
3. ³Institute of Biomedical and Life Sciences, University of Glasgow, UK

Correspondence: Dr S Cochran, Yoshitomi Research Institute of Neuroscience in Glasgow (YRING), University of Glasgow, G12 8QQ, UK, Tel: +44 141 330 5153, Fax: +44 141 330 5659, E-mail: yring@bio.gla.ac.uk

⁴Present address: Department of Pharmacology, Division of Neuroscience, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

⁵Present address: Hoffman-La Roche Ltd, Grenzacher Strasse, CH-4070 Basel, Switzerland.

Received 28 February 2002; Revised 1 July 2002; Accepted 8 July 2002.

Abstract

Numerous human imaging studies have revealed an absolute or relative metabolic hypofunction within the prefrontal cortex, thalamus and temporal lobes of schizophrenic patients. The former deficit correlates with cognitive deficits and negative symptoms, whereas the latter correlates with positive symptomologies. There is also general consensus that schizophrenia is associated with decreased parvalbumin expression in the prefrontal cortex. Since the drug phencyclidine can induce a psychosis resembling schizophrenia in humans, we have examined whether repeated phencyclidine (PCP) treatment to rats could produce similar metabolic and neurochemical deficits to those occurring in schizophrenia and whether these deficits could be modulated by antipsychotic drugs. We demonstrate here that chronic intermittent exposure to PCP (2.58 mg kg^-1 i.p.) elicits a metabolic hypofunction, as demonstrated by reductions in the rates of glucose utilization, within the prefrontal cortex, reticular nucleus of thalamus and auditory system, key structures displaying similar changes in schizophrenia. Moreover, chronic PCP treatment according to this regime also decreases parvalbumin mRNA expression in the rat prefrontal cortex and reticular nucleus of the thalamus. Chronic coadministration of haloperidol (1 mg kg^-1 day^-1) or clozapine (20 mg kg^-1 day^-1) with PCP did not modulate PCP-induced reductions in metabolic activity in the rat prefrontal cortex, but reversed deficits in the structures of the auditory system. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, whereas both drugs reversed the deficits in the reticular nucleus of the thalamus. These data provide important new information, which strengthen the validity of chronic PCP as a useful animal model of schizophrenia, when administered according to this protocol. Furthermore, we propose that reversal of PCP-induced reductions in parvalbumin expression in the prefrontal cortex may be a potential marker of atypical antipsychotic activity in relation to amelioration of cognitive deficits and negative symptoms of schizophrenia.