Susan M. Cochran

Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs

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.

Modelling prefrontal cortex deficits in schizophrenia: implications for treatment.

Current treatments of schizophrenia are compromised by their inability to treat all symptoms of the disease and their side‐effects. Whilst existing antipsychotic drugs are effective against positive symptoms, they have negligible efficacy against the prefrontal cortex (PFC)‐associated cognitive deficits and negative symptoms. New models that reproduce core pathophysiological features of schizophrenia are more likely to have improved predictive validity in identifying new treatments. We have developed a NMDA receptor antagonist model that reproduces core PFC deficits of schizophrenia and discuss this in relation to pathophysiology and treatments. Subchronic and chronic intermittent PCP (2.6 mg/kg i.p.) was administered to rats. PFC activity was assessed by 2‐deoxyglucose imaging, parvalbumin and Kv3.1 mRNA expression, and the attentional set‐shifting test (ASST) of executive function. Affymetrix gene array technology was employed to examine gene expression profile patterns. PCP treatment reduced glucose utilization in the PFC (hypofrontality). This was accompanied by a reduction in markers of GABAergic interneurones (parvalbumin and Kv3.1 mRNA expression) and deficits in the extradimensional shift dimension of the ASST. Consistent with their clinical profile, the hypofrontality was not reversed by clozapine or haloperidol. Transcriptional analysis revealed patterns of change consistent with current neurobiological theories of schizophrenia. This model mirrors core neurobiological deficits of schizophrenia; hypofrontality, altered markers of GABAergic interneurone activity and deficits in executive function. As such it is likely to be a valuable translational model for understanding the neurobiological mechanisms underlying hypofrontality and for identifying and validating novel drug targets that may restore PFC deficits in schizophrenia.

Chronic phencyclidine administration induces schizophrenia-like changes in N-acetylaspartate and N-acetylaspartylglutamate in rat brain.

Administration of phencyclidine (PCP) to both humans and animals models the symptoms of schizophrenia. Brain concentrations of N-acetylaspartate (NAA) are reduced in this disease, reflecting neuronal dysfunction. This study investigates the effects in rats of a chronic intermittent regime of PCP on NAA and its precursor N-acetylaspartylglutamate (NAAG) in rat frontal and temporal cortex, hippocampus and striatum, determined by HPLC. We found significant PCP-induced deficits of NAA and NAAG only in the temporal cortex; NAAG was significantly elevated in the hippocampus. These changes closely reflect postmortem findings reported in schizophrenia.

The novel long PDE4A10 cyclic AMP phosphodiesterase shows a pattern of expression within brain that is distinct from the long PDE4A5 and short PDE4A1 isoforms.

In situ hybridisation methods were used to map the distribution of the novel long PDE4A10 isoform in the brain. PDE4A10 distribution was compared to that of the long PDE4A5 isoform and the short PDE4A1 isoform using probes specific for unique sequences within each of these isoforms. Coronal sections of the brain, taken at the level of the olfactory bulb, prefrontal cortex, striatum, thalamus, hippocampus and cerebellum, were analysed. Strongest expression of PDE4A isoforms was found in the olfactory bulb granular layer with high signals also in the piriform cortex, the dentate gyrus and the CA1 and CA2 pyramidal cells. For the two long forms, level general staining was noted throughout the striatum, thalamus and hippocampus but no signal was evident in the cerebellum. The long PDE4A10 and PDE4A5 isoforms localised to essentially the same regions throughout the brain, although PDE4A10 was uniquely expressed in the major island of Calleja. A signal for the short PDE4A1 isoform was found in regions in which the two long isoforms were both expressed, with the exception of the medial nucleus of the amygdala where weak signals for PDE4A5 and PDE4A10 were detected but PDE4A1 was absent. Uniquely, strong signals for PDE4A1 were detected in the glomerular layer of the olfactory bulb, the CA3 pyramidal cell region and the cerebellum; areas where signals for the two long forms were not evident. PDE4A transcripts for both PDE4A5 and PDE4A10 were not apparent in the brain stem and those for PDE4A1 were low. PDE4A isoforms are present in several key areas of the brain and therefore present valid targets for therapeutic interventions. Whilst the two long PDE4A isoforms show a remarkably similar distribution, in at least three regions there is clear segregation between their pattern of expression and that of the PDE4A1 short form. This identifies differential regulation of the expression of PDE4A long and short isoforms. We suggest that specific PDE4A isoforms may have distinct functional roles in the brain, indicating that PDE4A isoform-selective inhibitors may have specific therapeutic and pharmacologic properties.

Induction of differential patterns of local cerebral glucose metabolism and immediate-early genes by acute clozapine and haloperidol

Atypical antipsychotic drugs, such as clozapine, show many differences in their actions as compared to typical antipsychotic drugs, such as haloperidol. In particular, the neuroanatomical substrates responsible for the superior therapeutic profile of clozapine are unknown. In order to identify regions of the CNS which are affected either differentially or in parallel by clozapine and haloperidol, we have used 2-deoxyglucose autoradiography to monitor local cerebral glucose utilisation (LCGU), in parallel with in situ hybridisation to monitor the expression of five immediate-early genes (c-fos, fos B, fra 1, fra 2 and zif 268). Clozapine (20 mg/kg i.p.) caused a reduction in LCGU in many areas of the psychosis-related corticolimbothalamic and Papez circuits, such as the anterior cingulate and retrosplenial cortices and the mammillary body. Haloperidol (1 mg/kg i.p.) showed less ability to modulate LCGU in these regions. Clozapine also increased immediate-early gene expression in these limbic circuits, although the pattern of induction was different for each gene, and also differed from the pattern of effects on LCGU. The only region which displayed similar effects with both antipsychotics was the anteroventral thalamus, with LCGU and c-fos mRNA expression being altered similarly by both drugs. This further supports the hypothesis of the thalamus being a common site of antipsychotic action. Since the Papez circuit has been implicated in emotive learning, and to be involved in mediating the negative symptoms associated with schizophrenia, the greater action of clozapine on regions within this circuit may also provide clues to the atypical antipsychotics superior efficacy against negative symptoms. This is one of the first studies which provides a direct comparison of regional activity as assessed by LCGU and by a panel of IEGs. The results emphasise the necessity of monitoring a number of different parameters of regional activity in order to identity the neuroanatomical substrate for actions of a drug in the CNS.

Modelling prefrontal cortex deficits in schizophrenia: implications for treatment: Modelling prefrontal cortex deficits in schizophrenia

Current treatments of schizophrenia are compromised by their inability to treat all symptoms of the disease and their side‐effects. Whilst existing antipsychotic drugs are effective against positive symptoms, they have negligible efficacy against the prefrontal cortex (PFC)‐associated cognitive deficits and negative symptoms. New models that reproduce core pathophysiological features of schizophrenia are more likely to have improved predictive validity in identifying new treatments. We have developed a NMDA receptor antagonist model that reproduces core PFC deficits of schizophrenia and discuss this in relation to pathophysiology and treatments. Subchronic and chronic intermittent PCP (2.6 mg/kg i.p.) was administered to rats. PFC activity was assessed by 2‐deoxyglucose imaging, parvalbumin and Kv3.1 mRNA expression, and the attentional set‐shifting test (ASST) of executive function. Affymetrix gene array technology was employed to examine gene expression profile patterns. PCP treatment reduced glucose utilization in the PFC (hypofrontality). This was accompanied by a reduction in markers of GABAergic interneurones (parvalbumin and Kv3.1 mRNA expression) and deficits in the extradimensional shift dimension of the ASST. Consistent with their clinical profile, the hypofrontality was not reversed by clozapine or haloperidol. Transcriptional analysis revealed patterns of change consistent with current neurobiological theories of schizophrenia. This model mirrors core neurobiological deficits of schizophrenia; hypofrontality, altered markers of GABAergic interneurone activity and deficits in executive function. As such it is likely to be a valuable translational model for understanding the neurobiological mechanisms underlying hypofrontality and for identifying and validating novel drug targets that may restore PFC deficits in schizophrenia.

Modelling prefrontal cortex deficits in schizophrenia

Current treatments of schizophrenia are compromised by their inability to treat all symptoms of the disease and their side‐effects. Whilst existing antipsychotic drugs are effective against positive symptoms, they have negligible efficacy against the prefrontal cortex (PFC)‐associated cognitive deficits and negative symptoms. New models that reproduce core pathophysiological features of schizophrenia are more likely to have improved predictive validity in identifying new treatments. We have developed a NMDA receptor antagonist model that reproduces core PFC deficits of schizophrenia and discuss this in relation to pathophysiology and treatments. Subchronic and chronic intermittent PCP (2.6 mg/kg i.p.) was administered to rats. PFC activity was assessed by 2‐deoxyglucose imaging, parvalbumin and Kv3.1 mRNA expression, and the attentional set‐shifting test (ASST) of executive function. Affymetrix gene array technology was employed to examine gene expression profile patterns. PCP treatment reduced glucose utilization in the PFC (hypofrontality). This was accompanied by a reduction in markers of GABAergic interneurones (parvalbumin and Kv3.1 mRNA expression) and deficits in the extradimensional shift dimension of the ASST. Consistent with their clinical profile, the hypofrontality was not reversed by clozapine or haloperidol. Transcriptional analysis revealed patterns of change consistent with current neurobiological theories of schizophrenia. This model mirrors core neurobiological deficits of schizophrenia; hypofrontality, altered markers of GABAergic interneurone activity and deficits in executive function. As such it is likely to be a valuable translational model for understanding the neurobiological mechanisms underlying hypofrontality and for identifying and validating novel drug targets that may restore PFC deficits in schizophrenia.