Schizophrenia Research Institute SRI

Sydney, Australia

Schizophrenia Research Institute SRI

Sydney, Australia
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Matosin N.,University of Wollongong | Matosin N.,Schizophrenia Research Institute SRI | Newell K.A.,University of Wollongong | Newell K.A.,Schizophrenia Research Institute SRI
Neuroscience and Biobehavioral Reviews | Year: 2013

Metabotropic glutamate receptor 5 (mGluR5) potentiates the NMDA receptor (NMDAR) in brain regions implicated in schizophrenia, making it a viable therapeutic target for the treatment of this disorder. mGluR5 positive allosteric modulators may represent a valuable novel strategy for schizophrenia treatment, given the favourable profile of effects in preclinical paradigms. However it remains unclear whether mGluR5 also plays a causal or epiphenomenal role in NMDAR dysfunction in schizophrenia. Animal and cellular data suggest involvement of mGluR5, whilst post-mortem human studies remain inconclusive. This review will explore the molecular, animal and human data to support and refute the involvement of mGluR5 in the pathology of schizophrenia. Furthermore, this review will discuss the potential of mGluR5 modulators in the therapy of schizophrenia as well as aspects of mGluR5 that require further characterisation. © 2012 Elsevier Ltd.

du Bois T.M.,University of Wollongong | du Bois T.M.,Schizophrenia Research Institute SRI | Newell K.A.,University of Wollongong | Newell K.A.,Schizophrenia Research Institute SRI | And 2 more authors.
European Neuropsychopharmacology | Year: 2012

Schizophrenia is a complex and devastating mental disorder of unknown etiology. Hypofunction of N-methyl- d-aspartate (NMDA) receptors are implicated in the disorder, since phencyclidine (PCP) and other NMDA receptor antagonists mimic schizophrenia-like symptoms in humans and animals so well. Moreover, genetic linkage and post mortem studies strongly suggest a role for altered neuregulin 1 (Nrg1)/erbB4 signaling in schizophrenia pathology. This study investigated the relationship between the NMDA receptor and Nrg1 signaling pathways using the perinatal PCP animal model. Rats (n = 5/group) were treated with PCP (10. mg/kg) or saline on postnatal days (PN) 7, 9 and 11 and were sacrificed on PN12, 5. weeks and 20. weeks for biochemical analyses. Western blotting was used to determine total and phosphorylated levels of proteins involved in NMDA receptor/Nrg1 signaling in the prefrontal cortex and hippocampus. In the cortex, PCP treatment altered Nrg1/erbB4 expression levels throughout development, including decreased Nrg1 and erbB4 at PN12 (- 25-30%; p< 0.05); increased erbB4 and p-erbB4 (+. 18-27%; p< 0.01) at 5. weeks; and decreased erbB4 and p-erbB4 (- 16-18%; p< 0.05) along with increased Nrg1 (+. 33%; p< 0.01) at 20. weeks. In the hippocampus, levels of Nrg1/erbB4 were largely unaffected apart from a significant decrease in p-erbB4 at 20. weeks (- 13%; p< 0.001); however NMDA receptor subunits and PSD-95 showed increases at PN12 and 5. weeks (+. 20-32%; p< 0.05), and decreases at 20. weeks (- 22-29%; p< 0.05). This study shows that NMDA receptor antagonism early in development can have long term effects on Nrg1/erbB4 expression which could be important in understanding pathological processes which might be involved in schizophrenia. © 2011.

Frank E.,Schizophrenia Research Institute SRI | Frank E.,University of Wollongong | Newell K.A.,Schizophrenia Research Institute SRI | Newell K.A.,University of Wollongong | And 2 more authors.
Schizophrenia Research | Year: 2011

Metabotropic glutamate receptors 2 and 3 (mGluR2/3) have been shown as efficient targets for antipsychotic intervention. We therefore investigated the receptor density of mGluR2/3 in the dorsolateral prefrontal cortex (dlPFC; Brodman area 46) of schizophrenia/schizoaffective patients (n = 37) and matched controls (n = 37) using receptor autoradiography. No difference in mGluR2/3 density was identified in relation to schizophrenia diagnosis. Overall and in individual groups, a negative correlation of mGluR2/3 density and age at death has been found. These and previous results suggest that density of mGluR2/3 in the dlPFC is less likely to impact on the efficiency of the mGluR2/3 agonist in treating schizophrenia symptoms. © 2011.

Matosin N.,University of Wollongong | Matosin N.,Schizophrenia Research Institute SRI | Frank E.,University of Wollongong | Frank E.,Schizophrenia Research Institute SRI | And 6 more authors.
Schizophrenia Research | Year: 2013

Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [3H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia and 37 matched control subjects. Subsequently, we measured [3H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n=6/group). Subjects with schizophrenia showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. Furthermore, mGluR5 binding in the rat cortex, thalamus, hippocampus and striatum was unaltered by short-, medium- and long-term antipsychotic treatment. Our data suggests that there are no alterations in mGluR5 in schizophrenia subjects. The lack of alteration in mGluR5 binding and protein in schizophrenia is advantageous because its ability to modulate the NMDAR is potentially unhindered, thereby supporting the development of novel antipsychotic agents that work through the mGluR5/NMDAR complex. © 2013 Elsevier B.V.

Cheng L.,University of Wollongong | Yu Y.,University of Wollongong | Yu Y.,Schizophrenia Research Institute SRI | Szabo A.,University of Wollongong | And 6 more authors.
Journal of Nutritional Biochemistry | Year: 2015

The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6. J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-β, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity. © 2015 Elsevier Inc.

PubMed | University of Wollongong, Xuzhou Medical College and Schizophrenia Research Institute SRI
Type: Journal Article | Journal: Molecular nutrition & food research | Year: 2015

Oxidative stress is involved in chronic stress-induced depression and the disruption of neurotransmission and neuroplasticity. Recently, orientin, a phenolic compound abundant in some fruits, millet, and herbs, has been shown to have antioxidant properties. This study investigated the potential antidepressant effects of orientin against chronic stress and its underlying mechanisms.The chronic unpredictable mild stress (CUMS) model was used to investigate the effects of orientin on behavior and biochemical alterations in mice. After 2 weeks of the CUMS protocol, the mice were treated with orientin (20 mg/kg and 40 mg/kg, oral gavage) for 3 weeks. Administration of orientin significantly alleviated the CUMS-induced depression-like behavior, including sucrose preference reduction, locomotor activity decline, and hypomotility. Orientin treatment attenuated the oxidative stress markers and increased the concentrations of serotonin and norepinephrine in the hippocampus and prefrontal cortex of CUMS mice. Orientin treatment also increased the brain-derived neurotrophic factor and synapse-associated proteins (synaptophysin and postsynaptic density protein 95) of CUMS mice.Orientin exerts antidepressant-like effects on CUMS mice, specifically by improving central oxidative stress, neurotransmission, and neuroplasticity. Therefore, supplementation with orientin-enriched food or fruit could be beneficial as a preventive strategy for chronic stress-induced depression.

Marsh P.J.,Macquarie University | Green M.J.,Schizophrenia Research Institute SRI | Green M.J.,University of New South Wales | Green M.J.,National Alliance for Research on Schizophrenia and Depression NARSAD | And 5 more authors.
American Journal of Psychiatric Rehabilitation | Year: 2010

Impaired recognition of facial emotion in schizophrenia is associated with poor social functioning. Evidence shows that targeted emotion recognition training (ERT) can improve perception of facial emotions in schizophrenia for up to 1 week after training. This study investigated whether (a) improved recognition generalizes to novel faces, (b) training effects are durable over 1 month, and (c) baseline functioning levels predict the extent of improvement. Thirty-nine participants with schizophrenia received ERT using Ekman's Micro-Expression Training Tool (METT; 2003). Emotion recognition was assessed using METT face stimuli and other face stimuli not used in training (static faces shown at 100% and 50% intensity and dynamic stimuli). Baseline ratings of interpersonal and cognitive functioning were collected; a subgroup of 10 participants was followed up at 1 month posttraining. Post-METT training, participants showed improved perception of METT faces and novel faces. The subgroup followed over 1 month showed improved recognition of novel faces and dynamic stimuli 1 month after training, but not immediately after training. Baseline measures of interpersonal and social functioning and general face processing and working memory abilities (50% intensity expressions only) predicted improvement in facial affect recognition immediately after METT training. These findings suggest that the effectiveness of ERT in schizophrenia is influenced by pretraining levels of social functioning and that general face processing abilities and working memory may affect the ability to accurately process subtle facial expressions. Furthermore, improved recognition generalizes to novel faces but only over time, which might indicate an increasing awareness of facial emotion after ERT, at least in people with better baseline social functioning. Copyright © Taylor & Francis Group, LLC.

Golembiewski J.A.,MAAP | Golembiewski J.A.,Schizophrenia Research Institute SRI
Archives of Psychiatry and Psychotherapy | Year: 2014

It is commonly assumed that psychiatric violence is motivated by delusions, but here the concept of a reversed impetus is explored, to understand whether delusions are formed as ad-hoc or post-hoc rationalizations of behaviour or in advance of the actus reus. The reflexive violence model proposes that perceptual stimuli has motivational power and this may trigger unwanted actions and hallucinations. The model is based on the theory of ecological perception, where opportunities enabled by an object are cues to act. As an apple triggers a desire to eat, a gun triggers a desire to shoot. These affordances (as they are called) are part of the perceptual apparatus, they allow the direct recognition of objects - And in emergencies they enable the fastest possible reactions. Even under normal circumstances, the presence of a weapon will trigger inhibited violent impulses. The presence of a victim will also, but under normal circumstances, these affordances don't become violent because negative action impulses are totally inhibited, whereas in psychotic illness, negative action impulses are treated as emergencies and bypass frontal inhibitory circuits. What would have been object recognition becomes a blind automatic action. A range of mental illnesses can cause inhibition to be bypassed. At its most innocuous, this causes both simple hallucinations (where the motivational power of an object is misattributed). But ecological perception may have the power to trigger serious violence also -a kind that's devoid of motives or planning and is often shrouded in amnesia or post-rational delusions.

Karl T.,Garvan Institute of Medical Research | Karl T.,Schizophrenia Research Institute SRI | Karl T.,Prince of Wales Medical Research Institute | Chesworth R.,Garvan Institute of Medical Research | And 5 more authors.
Neuropeptides | Year: 2010

Recent research has highlighted a potential role for neuropeptide Y (NPY) and its Y1 receptor in the development of schizophrenia. Genetic as well as molecular biological studies have demonstrated reduced levels of NPY in schizophrenia patients. Importantly, Y1 receptors may mediate some of the potential effects of NPY on schizophrenia, as decreased Y1 receptor expression has been found in the lymphocytes of schizophrenia patients. To clarify NPY's role in schizophrenia, we investigated a genetic animal model for Y1 deficiency in regard to (i) acoustic startle response (ASR), (ii) habituation to ASR and (iii) sensorimotor gating [i.e. prepulse inhibition (PPI)] using two different PPI protocols. Mutant and wild type-like mice were screened for baseline behaviours and after pharmacological challenge with the psychotropic drugs dexamphetamine (DEX) and MK-801. Y1 knockout mice (Y1 -/-) showed a moderate reduction of the ASR and an impaired ASR habituation at baseline and after DEX treatment. The baseline PPI performance of Y1 mutant mice was unaltered their response to DEX and MK-801 challenge was moderately different compared to control mice, which was dependent on the PPI protocol used. MK-801 challenge had a protocol-dependent differential effect in Y1 -/- mice and DEX a more pronounced impact at the highest prepulse intensities. In conclusion, it appears that the Y1 receptor influences the acoustic startle response and its habituation but does not play a major role in sensorimotor gating. Further explorations into the effects of Y1 deficiency seem valid. © 2009 Elsevier Ltd.

Baker A.,University of Newcastle | Baker A.,Schizophrenia Research Institute SRI | Richmond R.,University of New South Wales | Lewin T.J.,University of Newcastle | And 3 more authors.
Australian and New Zealand Journal of Psychiatry | Year: 2010

Objective: Cigarette smoking is very common among people with a psychotic disorder and is often not addressed by clinicians. Additionally, few studies have evaluated smoking interventions among this group. The present study reports findings from a naturalistic follow up 4 years after a smoking intervention trial. Method: Longer-term smoking, symptomatology and functioning were examined among 247 participants (recruited in Sydney and Newcastle, Australia) who initially attended a 1 year follow up of an eight-session individually administered trial for regular smokers with a psychotic disorder. Variables profiled included continuous and point prevalence abstinence rates, smoking reduction status (no reduction, <50%, ≥50%, or abstinence) and changes in anxiety, depression and current functioning. Results: Two-thirds of those who completed the 1 year assessment were followed up at 4 years (164/247, 66.4%), of whom 79.2% reported maintenance or improvement in their smoking reduction status relative to 1 year. Abstinence at 1 year was significantly associated with 4 year point prevalence abstinence. Lengthy periods of abstinence were also evident among those reporting 4 year point prevalence abstinence or at least a 50% reduction. No baseline or intervention status variables predicted smoking status at 4 years. Symptomatology and functioning also improved between baseline and 4 years. Conclusions: Smokers with a psychotic disorder are capable of long-term change. It is recommended that clinicians address and monitor smoking during treatment of people with psychosis, emphasizing potential lifestyle and harm reduction benefits, with a view to eventual smoking cessation. © 2010 The Royal Australian and New Zealand College of Psychiatrists.

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