Studies On The Expression Of Muscarinic Receptors: Implications For The Pathology Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$498,791.00
Summary
Schizophrenia is a severe psychiatric disorder that affects approximately 1% of the population. This project will help define changes in the molecules in the brain of subjects with schizophrenia which are likely to be involved in two symptoms of the disorder, the psychoses and cognitive deficits. Understanding the cause of the cognitive deficits of schizophrenia is a high priority because they are the most disabilitating symptom of the disorder and do not respond to current drug treatments.
Brain Control Of The Thermoregulatory Cutaneous Circulation: A Window To The Mind, And To The Neurobiology Of Clozapine
Funder
National Health and Medical Research Council
Funding Amount
$561,396.00
Summary
Patients suffering from schizophrenia benefit from medication. Discovering the brain mechanisms whereby the medications work is most important. Action of many important drugs have been established in experimental animals. This is a difficult task for anti-schizophrenia drugs because it is difficult to establish what animals are thinking or feeling, and it is doubtful whether animals ever suffer from schizophrenia. Thus it would be very advantageous to discover a physiological response, measurabl ....Patients suffering from schizophrenia benefit from medication. Discovering the brain mechanisms whereby the medications work is most important. Action of many important drugs have been established in experimental animals. This is a difficult task for anti-schizophrenia drugs because it is difficult to establish what animals are thinking or feeling, and it is doubtful whether animals ever suffer from schizophrenia. Thus it would be very advantageous to discover a physiological response, measurable in, for example, rats, that can serve as a marker of the animal s emotional responses to situations that would normally prove anxiety-provoking. The present grant is based on the discovery, in my laboratory, that stressful stimuli cause sudden falls in blood flow to the tail in rats. My laboratory is the first in the world to measure pulsatile blood flow to the tail in conscious rats, and this is why we made our discovery. My laboratory also discovered that clozapine, a drug of major theoretical and practical importance for the treatment of schizophrenia inhibits fright-induced constriction of the tail artery. Clozapine interacts with many potential neurotransmitters in the brain. Some very complex combinations of these interactions are presumably responsible for the drug s unique psychotherapeutic action in schizophrenia. Our discovery that clozapine inhibits fright-induced constriction of the tail artery means that we will be able to investigate clozapine s mechanisms of action. Results of our findings are genuinely likely to increase our understanding of how clozapine works in schizophrenia. This information should also provide clues as to the nature of the presently mysterious brain malfunctions that result in schizophrenia.Read moreRead less
Investigating The Action Of Clozapine On The Epidermal Growth Factor System: Implications For Antipsychotic Drug Action
Funder
National Health and Medical Research Council
Funding Amount
$364,535.00
Summary
Current treatments for schizophrenia are ineffective for up to half of sufferers leaving the toxic drug clozapine as the only resort. This project aims to investigate if the unique effectiveness of clozapine is due to a novel action in brain cells that we have identified. The project will delineate this mechanism and from this may lead to the development of a new way of treating schizophrenia and insights into the causes of this disorder.
The Amygdala And Emotionally-mediated Sudden Cutaneous Vasoconstriction In Rats
Funder
National Health and Medical Research Council
Funding Amount
$461,788.00
Summary
Discovering how the brain organizes our emotional life is important for understanding mental illness. In rats, blood flow to the skin falls when the animal detects a possibly dangerous event. Rats go pale with fright , just as humans do. The falls in blood flow are inhibited by drugs used to treat people with schizophrenia. The grant investigates whether the amygdala is an important brain centre controlling the skin blood vessels, and whether anti-schizophrenia drugs act in the amygdala.
A Prospective Study Investigating Implications Of Bioactive Lipids For Diagnosis And Treatment Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$324,480.00
Summary
This study will investigate the role of fatty acids (lipids) in schizophrenia. Studies in blood cells and in the brains of patients with schizophrenia have shown that these lipids and related products are altered in schizophrenia. We are now able to measure separate lipid metabolites in the living human brain using a technique called magnetic resonance spectroscopy. Until recently it was only possible to assess lipid metabolites as a group, limiting interpretation. Thanks to a newly available im ....This study will investigate the role of fatty acids (lipids) in schizophrenia. Studies in blood cells and in the brains of patients with schizophrenia have shown that these lipids and related products are altered in schizophrenia. We are now able to measure separate lipid metabolites in the living human brain using a technique called magnetic resonance spectroscopy. Until recently it was only possible to assess lipid metabolites as a group, limiting interpretation. Thanks to a newly available imaging system at the Brain Imaging Research Institute and a new analysis technique, we will be able to measure single lipid metabolites in the living human brain. Simultaneously we will also measure lipids and related enzymes in red blood cells that are responsible for the regulation of these lipids. Preliminary data has shown that there is a strong correlation between these two measures. Furthermore we will investigate the genes that are responsible for the production of these enzymes. By repeating the same tests after 12 weeks we hope to understand how the newer antipsychotic drugs act. Two easy clinical tests (a skin and breath test) will help us to implement the findings in daily clinical practice (diagnostic markers for patients at risk) . With such a multi-level approach we hope to contribute to a new understanding of the origins of schizophrenia going beyond the traditional concepts. The findings might also have direct implications for treatment. Preliminary results are very promising but also contradictory. Therefore it is even more important to carefully investigate the role of these lipids in schizophrenia.Read moreRead less
Attentional Effects On Prepulse Inhibition Of The Acoustic Startle Reflex In Patients With Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$278,625.00
Summary
People suffering from schizophrenia exhibit differences from healthy people in the startle reflex, which is a blink of the eyes when a sudden loud sound occurs. Normally, this reflex is reduced in size when a quiet sound occurs a few milliseconds before the startling sound, but this prepulse inhibition of the startle reflex or PPI does not occur to the same degree in people with schizophrenia. The underlying causes of this reduction in PPI in patients with schizophrenia is not known. The most co ....People suffering from schizophrenia exhibit differences from healthy people in the startle reflex, which is a blink of the eyes when a sudden loud sound occurs. Normally, this reflex is reduced in size when a quiet sound occurs a few milliseconds before the startling sound, but this prepulse inhibition of the startle reflex or PPI does not occur to the same degree in people with schizophrenia. The underlying causes of this reduction in PPI in patients with schizophrenia is not known. The most commonly accepted theory is that it reflects a deficit in a basic sensorimotor gating function which could underlie a variety of attentional abnormalities observed in schizophrenia. However, our data indicate that patients exhibit more PPI when they ignore the prepulse stimuli. We wish to test the hypothesis that alterations in PPI in schizophrenic patients are secondary to abnormalities in attention. This is significant because the theory can point to a specific cognitive deficit associated with schizophrenia. We have also found that patients treated with some kinds of antipsychotic medications (the newer atypical antipsychotic medications) do not show reductions in PPI, but patients treated with older types of antipsychotic drug do show reductions in PPI. We intend to investigate the effects of different types of antipsychotics on attentional modulation of PPI. This is significant because it may indicate that patients with a specific kind of cognitive impairment may show improvement with a specific type of medicine. Our data suggests that chronic cannabis use may associated with differences in the startle reflex and in PPI. Understanding how such cannabis use alters PPI may provide insights into why so many people with schizophrenia regularly abuse cannabis.Read moreRead less
Identifying EQTLs And Endophenotyping Known CNVs In A Large Australian Schizophrenia Sample
Funder
National Health and Medical Research Council
Funding Amount
$902,472.00
Summary
This study hopes to identify genetic code variations associated with an increased risk of schizophrenia . We will study variation in gene expression levels in patients and healthy controls to identify underlying changes in the genetic code responsible. In a subset of patients with schizophrenia and known rare copy number variations (CNVs) in the genetic code we will conduct brain scans and psychological tests to characterize the effect of CNVs on brain structure and function in schizophrenia.