Bradford Scholars -how to deposit your paper Overview Copyright check• Check if your publisher allows submission to a repository.• Use the Sherpa RoMEO database if you are not sure about your publisher's position or email openaccess@bradford.ac.uk.

No abstract

As quantitative neuroimaging continues to elucidate the gross neuropathology of schizophrenia, neurochemical and histological studies have contributed to defining this pathology in terms of neurotransmitter dysfunction. Increasingly, there is evidence implicating neurons containing the major inhibitory neurotransmitter of the brain--gamma-aminobutyric acid (GABA). Benes was the first to demonstrate deficits in some morphological subtypes of interneurons in the frontal cortex in schizophrenia. We identified that this was specific to a subgroup of GABAergic interneurons containing parvalbumin (PV), which is found in the fast-firing cells providing inhibitory control of the cortico-fugal pyramidal cells. PV is notable in being expressed late in development; the late expression of this protective calcium binding protein (CBP) may impart an early vulnerability to these neurons, indicating a possible mechanism for the developmental origins of schizophrenia. Cortical GABAergic neurons expressing the CBP calretinin (CR) are unaffected in schizophrenia, although those containing calbindin (CB) are also diminished in number. These deficits in PV and CB are notable in also being observed in bipolar disorder, indicating how the close aetiological relationship of these two psychiatric disorders is reflected in their pathology. One of the most substantial abnormalities seen in post-mortem brain tissue is the hippocampal deficit of PV-containing neurons, again in the absence of effects on CR-positive cells. This deficit occurring in a structure implicated in cognitive symptomatology may well have functional relevance, and we find it can be induced by a model of the disease, sub-chronic phencyclidine (PCP) administration, that can also produce cognitive disturbances. This PCP model, like schizophrenia, demonstrates other neurochemical changes which include indicators of glutamatergic dysfunction. The temporal and aetiological relationships between glutamatergic and GABAergic deficits remains unclear, but may well relate to an initial loss/dysfunction of GABA/PV neurons that subsequently gives rise to a glutamatergic pathology.

The glutamate/N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) has been shown to induce both positive and negative symptoms of schizophrenia, as well as cognitive deficits, thus providing a relatively valid model of psychosis. Isolation rearing from weaning in the rat has been proposed as a non-pharmacological model of psychosis. The aim of the present study was to explore the validity of a combination of these techniques to model cognitive dysfunction associated with schizophrenia. The present study evaluates the effects of the novel antipsychotic ziprasidone and the typical antipsychotic haloperidol in their ability to reverse the cognitive deficit induced by PCP in isolation reared rats and social controls. Rats housed in social isolation (n = 25) or in groups of five (n = 25) from weaning were food deprived and trained to respond for food in an operant reversal learning paradigm. PCP at 1.0 and 1.5 mg/kg (intraperitoneally, i.p.) significantly and selectively impaired reversal task performance in both groups of rats. This impairment was not significantly improved following the coadministration of haloperidol (0.05 mg/kg, i.p.). Higher haloperidol doses (0.1 and 0.25 mg/kg, i.p.) were found to impair task performance, with the social animals being more sensitive than isolation-reared animals. In contrast, ziprasidone (2.5 mg/kg, i.p.) reversed the impairment caused by PCP. This was significant in social animals, while in isolates there was a non-significant enhancement in performance of the reversal task with ziprasidone compared to PCP alone. Thus, PCP produced a selective reversal learning deficit in rats, which was ameliorated following treatment with ziprasidone but not haloperidol. Rearing conditions did not influence performance of the test or the deficit produced by PCP.