Induction of Metabolic Hypofunction and Neurochemical Deficits after Chronic Intermittent Exposure to Phencyclidine: Differential Modulation by Antipsychotic Drugs

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 À1 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 À1 day À1 ) or clozapine (20 mg kg À1 day À1) 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.

Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics

“…Certainly, no one animal protocol can effectively model a disease as complex and heterogeneous as schizophrenia, and previous reports (Pantelis et al, 1999) suggest that individuals with schizophrenia can demonstrate impairment on multiple aspects of cognition, including some non-EDS problems, an effect not addressed by our rodent model. However, the face validity of our model is augmented by previous reports of schizophrenia-like pathology, such as decreased parvalbumin expression (Abdul-Monim et al, 2007) and cortical metabolic hypofunction (Cochran et al, 2003) following PCP administration. Future research should determine whether differential pharmacological effects are replicated in another recently developed neurodevelopmental rodent model of schizophrenia, neonatal treatment with the neurotoxin MAM (methylazoxymethanol), which has been demonstrated to produce impairments in attentional set shifting (Featherstone et al, 2007).…”

“…In addition, we employed the well-validated subchronic phencyclidine (PCP)-administration paradigm (Jentsch and Roth, 1999;Cochran et al, 2003;Egerton et al, 2005;Abdul-Monim et al, 2006, 2007 to produce enduring cognitive deficits similar to those observed in schizophrenia (Javitt and Zukin, 1991). This permitted us to examine treatment effects of classical and second-generation antipsychotics that have different profiles and activity at multiple neurotransmitter receptors, including dopamine (DA) D 2 , 5-HT 2A , and 5-HT 6 .…”

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

“…We have recently demonstrated reduced density of parvalbumin immuno reactive neurons in the hippocampus and M1 (motor area 1) region of the frontal cortex following sub-chronic PCP treatment in the rat [3]. It has also been shown that chronic intermittent administration of PCP decreases parvalbumin mRNA expression in the prefrontal cortex of rats, and that this reduction can be reversed by clozapine but not haloperidol [11].…”

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

“…Repetitive NMDA-R antagonist treatment in animals produce more persistent effects on stereotypy and locomotor activity, as well as enduring cognitive deficits and neurochemical changes that resemble more accurately the alterations observed in schizophrenia (Jentsch and Roth, 1999;Morris et al, 2005;Mouri et al, 2007). For example, the initial hypermetabolism, observed after acute NMDA-R antagonist exposure, is followed by a decrease in metabolic activity in the PFC, as well as within structures of the auditory system, and the reticular nucleus of the thalamus (Cochran et al, 2003). Repetitive PCP decreases dopamine in the dorsolateral prefrontal cortex, prelimbic cortex, and cingulate cortex, but not in supplementary motor area (Jentsch and Roth, 1999).…”