Browsing by Author "Newell, KA"

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    Alterations of muscarinic and GABA receptor binding in the posterior cingulate cortex in schizophrenia
    (Elsevier, 2007-01-30) Newell, KA; Zavitsanou, K; Jew, SK; Huang, XF
    The posterior cingulate cortex (PCC), a key component of the limbic system, has been implicated in the pathology of schizophrenia because of its sensitivity to NMDA receptor antagonists. Recent studies have shown that the PCC is dysfunctional in schizophrenia, and it is now suspected to be critically involved in the pathogenesis of schizophrenia. Studies also suggest that there are abnormalities in muscarinic and GABAergic neurotransmission in schizophrenia. Therefore, in the present study we used quantitative autoradiography to investigate the binding of [3H]pirenzepine, [3H]AF-DX 384 and [3H]muscimol, which respectively label M1/4 and M2/4 muscarinic and GABAA receptors, in the PCC of schizophrenia and control subjects matched for age and post-mortem interval. The present study found that [3H]pirenzepine binding was significantly decreased in the superficial (− 24%, p = 0.002) and deep (− 35%, p < 0.001) layers of the PCC in the schizophrenia group as compared with the control group. In contrast, a dramatic increase in [3H]muscimol binding was observed in the superficial (+ 112%, p = 0.001) and deep layers (+ 100%, p = 0.017) of the PCC in the schizophrenia group. No difference was observed for [3H]AF-DX 384 binding between the schizophrenia and control groups. The authors found a significant inverse correlation between [3H]pirenzepine binding in the deep cortical layers and [3H]muscimol binding in the superficial layers (rho = − 0.732, p = 0.003). In addition, negative correlations were also found between age and [3H]pirenzepine binding in both superficial and deep cortical layers (rho = − 0.669 p = 0.049 and rho = − 0.778, p = 0.014), and between age of schizophrenia onset and [3H]AF-DX 384 binding (rho = − 0.798, p = 0.018). These results for the first time demonstrated the status of M1/M4, M2/M4 and GABAA receptors in the PCC in schizophrenia. Whilst the exact mechanism causing these alterations is not yet known, a possible increased acetylcholine and down regulated GABA stimulation in the PCC of schizophrenia is suggested. © 2007, Elsevier
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    Opposing short- and long-term effects on muscarinic M1/4 receptor binding following chronic phencyclidine treatment
    (Wiley-Liss, 2007-05-01) Newell, KA; Zavitsanou, K; Huang, XF
    Phencyclidine (PCP) is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Several studies have demonstrated that chronic NMDA receptor antagonist treatment in humans and animals can cause long-term behavioral changes that are reminiscent of negative and cognitive schizophrenia-like symptoms. The muscarinic cholinergic system, which is associated with cognitive functions, has been hypothesized to contribute to PCP's mechanism of action. No study, however, has examined the status of M1/4 receptors in the PCP model of schizophrenia. The aim of the present study was to investigate the effects of chronic (14 day) PCP treatment on mouse brain M1/4 receptors in the short term (1 hr and 24 hr) and long term (14 days) after last PCP administration. [3H]pirenzepine was used to target M1/4 receptors. In the short term following chronic PCP treatment, M1/4 binding was significantly increased in regions of the limbic system, caudate-putamen, cortex, and thalamus (ranging from 56% to 368%), compared with saline-treated mice. There were no differences in binding between mice treated with PCP for 14 days and sacrificed 1 hr or 24 hr after the final PCP treatment. In the long term following chronic PCP treatment, M1/4 binding was significantly decreased in all of the above-mentioned brain regions (ranging from 31% to 72%), except in the thalamus, which showed no change. These findings in the long-term group are similar to those reported in post-mortem studies of patients suffering from schizophrenia. © 2007, John Wiley & Sons, Inc.
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    Rapid cortico-limbic alterations in AMPA receptor densities after administration of PCP: implications for schizophrenia
    (Elsevier, 2008-10) Zavitsanou, K; Nguyen, VH; Newell, KA; Ballantyne, P; Huang, XF
    Phencyclidine (PCP), a non-competitive NMDA/glutamate receptor antagonist, is a psychotomimetic drug that produces a syndrome in normal humans that resembles schizophrenia. The present study investigated the mechanisms of PCP actions by examining the density of glutamate and muscarinic receptors in the rat brain 4 h after a single injection of PCP. We used receptor autoradiography and [H-3]MK801, [H-3]AMPA, [H-3]pirenzepine and [H-3]AFDX384 to target glutamate NMDA, glutamate AMPA and muscarinic M1 and M2 receptors, respectively. The major outcome from the present study was an overall decrease in levels of the glutamate AMPA receptor density (F= 14.5, d.f. = 1, p < 0.001) in the PCP treated rats. More specifically, PCP-treated animals displayed decreased AMPA receptor density in hippocampus CA1 (-16%), hippocampus CA2 (-25%), dentate gyrus (-27%), parietal cortex layers III-VI (-19%), central nucleus of the amygdala (-40%), and basolateral amygdala (-19%). Other brain regions examined were unaffected. PCP administration did not significantly affect glutamate NMDA, muscarinic M1 and M2 receptor density. The present study demonstrates the limbic system as the anatomical locus of alterations in AMPA receptor density after acute administration of PCP and may have implications for models of schizophrenia that focus on glutamatergic dysfunction in limbic cortical regions. © 2008, Elsevier Ltd.
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    Short and long term changes in NMDA receptor binding in mouse brain following chronic phencyclidine treatment
    (Springer Wien, 2007-08-01) Newell, KA; Zavitsanou, K; Huang, XF
    Phencyclidine (PCP) is an antagonist of the NMDA subtype of glutamate receptor. PCP treatment induces psychosis in normal humans, which provides a valuable model of schizophrenia. PCP administration also models some of the symptoms of schizophrenia in experimental animals. NMDA hypofunction has been hypothesized to explain these schizophrenia-like symptoms. Acute or chronic administration of the NMDA receptor antagonist PCP has been shown to induce several short or long-term effects in both humans and experimental animals. In an attempt to clarify the neurochemical substrates of these effects in the present study, we used quantitative autoradiography to examine the effects of chronic (14 days) PCP treatment on NMDA receptor binding in mouse brain following both a short- (1 and 24 h) and long-term (14 days) delay after the last PCP treatment. NMDA receptors were targeted using [3H]MK801. Chronic PCP treatment increased [3H]MK801 binding consistently in the hippocampus in the short-term (p < 0.01). Conversely in the long-term, there were widespread reductions in NMDA receptor binding and this effect was most evident in the hippocampus where a 35% reduction of binding was found (p < 0.001). These results suggest that the hippocampus has a strong involvement in both the short and long-term effects of PCP treatment and that reduced NMDA receptor function might be one of the neurochemical substrates of the long lasting actions of PCP or PCP-induced psychosis. Importantly, this study shows that the long-term delay following chronic PCP treatment more accurately represents a state of NMDA hypofunction than the short-term PCP model. © 2007, Springer.