Schizophrenia: Prevention And Treatment Of Atypical Antipsychotic Drug-induced Obesity
Funder
National Health and Medical Research Council
Funding Amount
$413,862.00
Summary
Atypical antipsychotic drugs such as olanzapine, clozapine and risperidone are commonly used to treat mental illness. While these drugs are effective, their side effects of obesity and metabolic disorders are a major hurdle leading to a serious lack of compliance in taking medication. This project will define the mechanism leading to these side effects and will help to identify pharmaceutical targets for the better treatment of mentally ill patients.
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.
Estrogen - A Potential New Treatment For Women & Men With Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$227,545.00
Summary
Estrogen - the major female hormone, has been shown in animal studies to decrease the two main brain chemicals (dopamine and serotonin) that are implicated in causing schizophrenia. The effect of estrogen in the brain is similar to current antipsychotic drugs. We have carried out a study that showed that when we gave 12 young women with schizophrenia 100 micrograms of estrogen in a skin patch form plus standard antipsychotic drug treament they recovered more quickly than 12 young women who recei ....Estrogen - the major female hormone, has been shown in animal studies to decrease the two main brain chemicals (dopamine and serotonin) that are implicated in causing schizophrenia. The effect of estrogen in the brain is similar to current antipsychotic drugs. We have carried out a study that showed that when we gave 12 young women with schizophrenia 100 micrograms of estrogen in a skin patch form plus standard antipsychotic drug treament they recovered more quickly than 12 young women who received standard antipsychotic drug treatment only. 100mcg is a safe dose of estrogen. In this proposal we want to expand and clarify the pilot study resutls by conducting a 28 day trial in a total of 60 women with schizophrenia. 30 women would receive 100 mcg skin patch estrogen plus antipsychotic medication and 30 women would receive antipsychotic medicationly only. We also tested the value of adding a very small dose of oral estrogen to antipsychotic drug treatment in five men with schizophrenia and found that they made a better recovery compared to five men who received standard antipsychotic drugs only. We trialled the use of estrogen for seven days in men, but this may not have been long enough to examine the real impact of estrogen treatment in men. In this proposal we want to conduct a 14 day trial in a total of 60 men with schizophrenia. 30 men would receive 2mg of oral estrogen plus antipsychotic drug treatment and their results would be compared with 30 men who received standard antipsychotic drug treatment plus a placebo tablet identical in appearance to estrogen. For 14 days, this low dose of estrogen is very safe. Potentially estrogen may be a useful addition to the current standard treatment of schizophrenia. It may decrease the duration of acute illness and in women it may have a role in preventing relapses of schizophrenia as well as improving the general health of women with schizophrenia.Read moreRead less
Structural And Functional Studies On Glutamate Decarboxylase.
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
This proposal aims to determine the molecular structure of the two known isoforms of Glutamate Decarboxylase (GAD65 and GAD67). GAD in an essential human enzyme that is responsible for synthesising the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA functions in the human Central Nervous System (CNS) to dampen down excitatory signals. Proper control of GABA synthesis is important and perturbations in GABA levels lies behind human diseases such as intractable epilepsy, de ....This proposal aims to determine the molecular structure of the two known isoforms of Glutamate Decarboxylase (GAD65 and GAD67). GAD in an essential human enzyme that is responsible for synthesising the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA functions in the human Central Nervous System (CNS) to dampen down excitatory signals. Proper control of GABA synthesis is important and perturbations in GABA levels lies behind human diseases such as intractable epilepsy, depression and schizophrenia. As a result of this role, numerous common therapeutics (for example benzodiazepines) target proteins involved in the GABA neurotransmitter system. The goal of this proposal is to use the molecular structures of GAD to understand how to achieve fine control of GABA production. In addition to its role in the CNS, GAD is an important human autoantigen. Antibodies to one isoform of GAD, GAD65, are found in most patients with type I diabetes as well as certain patients with the movement disorder stiff person syndrome and related diseases of the CNS. It is suggested that the development of auto-antibodies may play a key role in the pathophysiology of these conditions. Despite sharing >80% sequence similarity with GAD65, autoantibodies to the other isoform of GAD, GAD67, are rarely found in patients with disease. The aim of this grant is to characterise the region of GAD that is targetted by autoantibodes. These data will allow us to understand why certain autoantibodes are able to inhibit GAD enzyme activity and why GAD65, but not GAD67 is recognised by autoantibodes.Read moreRead less
Brain And Skin Blood Flow: New Animal Model For Understanding Psychiatric Disorders And Evaluating Psychotropic Agents
Funder
National Health and Medical Research Council
Funding Amount
$874,840.00
Summary
We suddenly become pale when we get a fright; cutaneous blood vessels are linked to psychological function. The skin vessel constriction response occurs because special neurochemical pathways in the brain send messages to the spinal cord, and from there messages traverse peripheral sympathetic nerves to constrict the blood vessels in the skin. By measuring skin blood flow in the rabbit ear and the rat tail we have been able to discover the major brain pathway by which the constrict-the-skin-bloo ....We suddenly become pale when we get a fright; cutaneous blood vessels are linked to psychological function. The skin vessel constriction response occurs because special neurochemical pathways in the brain send messages to the spinal cord, and from there messages traverse peripheral sympathetic nerves to constrict the blood vessels in the skin. By measuring skin blood flow in the rabbit ear and the rat tail we have been able to discover the major brain pathway by which the constrict-the-skin-blood-vessels message reaches the spinal cord. The pathway involves the amygdala, a forebrain region important in emotional expression and the raphe nuclei in the medulla oblongata. Drugs which affect psychological function also effect skin blood flow. Ecstasy, the street drug used to induce euphoria also constricts the skin vessels, and, sadly, the body temperature may increase so much that death ensues. Ecstasy vigorously constricts the skin blood vessels in rabbits, and temperature increases. Ecstasy is thought to act on serotonin-containing nerve cells in the brain, releasing serotonin (5-HT) onto special 5-HT2A receptors. Activation of these receptors affects both psychological function and skin blood flow. Modern drugs used to treat schizophrenia, so called atypical antipsychotics like clozapine and olanzapine, are thought to act as antagonists at 5-HT2A receptors in the brain. We were thus very excited when we discovered in our rabbit model that clozapine reverses the skin vasoconstriction induced by ecstasy. This means that we have specific hypotheses concerning the actual brain pathways and neurotransmitters whereby ecstasy and clozapine exert their effects on skin blood flow. Elucidating these pathways in rabbits and rats will provide solid knowledge concerning the mechanism of action of the atypical antipsychotics, and it may well prove possible to use our animal model to predict whether proposed new antipsychotic agents will be therapeutically effective.Read moreRead less
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.
TEMPERATURE AS MODIFIER OF MAMMALIAN SKELETAL MUSCLE FUNCTION AND OF MUSCLE RESPONSIVENESS TO PHYSIOLOGICAL FACTORS
Funder
National Health and Medical Research Council
Funding Amount
$256,018.00
Summary
Contracting muscles are a major source of heat production in the body. Heat produced by contracting muscles can cause muscle damage if muscle temperature increases above 44oC. Also, overheating from external sources can cause an increase in muscle temperature in the upper physiological range of temperature (37-44oC) which can so readily happen to humans and animals caught in blistering sun or in closed cars parked in the sun. However, very little is known about what happens to the ability of the ....Contracting muscles are a major source of heat production in the body. Heat produced by contracting muscles can cause muscle damage if muscle temperature increases above 44oC. Also, overheating from external sources can cause an increase in muscle temperature in the upper physiological range of temperature (37-44oC) which can so readily happen to humans and animals caught in blistering sun or in closed cars parked in the sun. However, very little is known about what happens to the ability of the skeletal muscle to contract when the temperature increases in this upper physiological range of temperature. This project seeks to fill in this important gap in our knowledge and increase our understanding about the existence of protective mechanisms in muscle to prevent heat-induced damage to the muscle. Such mechanisms would allow the body to operate very close to the lethal range of temperature and may be mainly responsible for the severe muscle weakness in overheated individuals. Results obtained from the project can have far reaching implications for human physiology in general and muscle and exercise physiology in particular and for developing new strategies in the treatment of collapse from body overheating. The project will also produce new knowledge regarding the mechanism of action of drugs used in the treatment of certain mental disorders but which can trigger, in susceptible individuals, uncontrolled contraction of muscles and overheating.Read moreRead less
The Human Cardiac Transient Outward Potassium Channel,Kv4.3:A Study Of Its Pharmacology And Modulation By Disease States
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
The contraction of the heart is triggered by electrical activity.For every heart beat,electrical activity known as an action potential,occurs.This involves a rapid change in voltage inside the heart cells which must then be quickly restored to the normal resting level or sudden death ensues. Both the initial rapid change (known as depolarisation), and its restoration to normal, (repolarisation), are produced by electrical currents flowing through the cell membrane.The currents responsible for re ....The contraction of the heart is triggered by electrical activity.For every heart beat,electrical activity known as an action potential,occurs.This involves a rapid change in voltage inside the heart cells which must then be quickly restored to the normal resting level or sudden death ensues. Both the initial rapid change (known as depolarisation), and its restoration to normal, (repolarisation), are produced by electrical currents flowing through the cell membrane.The currents responsible for repolarisation are mainly carried by potassium ions.A number of these outward potassium channels exist and the present study is concerned with one of the most important of them, known as the transient outward current. The transient outward current has recently been found to be modulated by disease states,such as thickening of the heart muscle and heart failure.It is also known to be blocked by a number of drugs,some of which are used to treat abnormal heart rhythms.It is therefore of particular interest to clinical cardiologists This channel has been difficult to study in the past because it is usually mixed with several other currents in experiments on living heart cells.The gene which codes for it was identified in 1996 and we now have a cell-line in tissue culture in our laboratory which has only this particular channel,allowing us to study it systematically in isolation from other currents.This study forms the basis of our application.Read moreRead less