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Glutamate - Adenosine Interactions And Drug-seeking
Funder
National Health and Medical Research Council
Funding Amount
$558,046.00
Summary
Substance abuse is a significant social and economic burdern upon Australian societies and on societies around the world. Treatment remains problematic due to the multi-layer nature of the disease, difficulties with treatment compliance and less than ideal treatment regimes. The present study aims to improve treatments for alcohol and drug abuse using a polypharmacy or multiple therapy approach, using pre-clinical models to determine the utility of this approach.
The Role Of Glutamate Receptor Mediated Excititoxicity In Neurodegeneration And Huntington's Disease
Funder
National Health and Medical Research Council
Funding Amount
$467,310.00
Summary
Glutamate, the principal excitatory neurotransmitter in the brain, acts on three subtypes of ionotropic glutamate receptors (iGluRs), AMPA, kainate and NMDA receptors. Evidence suggests that aberrant NMDA receptor mediated calcium influx into neurons leads to excitotoxic cell death. Calcium influx through AMPA and kainate receptors has also been implicated in excitotoxic neurodegeneration. It is widely thought that excitotoxicity contributes to chronic neurodegenerative disease. We will test thi ....Glutamate, the principal excitatory neurotransmitter in the brain, acts on three subtypes of ionotropic glutamate receptors (iGluRs), AMPA, kainate and NMDA receptors. Evidence suggests that aberrant NMDA receptor mediated calcium influx into neurons leads to excitotoxic cell death. Calcium influx through AMPA and kainate receptors has also been implicated in excitotoxic neurodegeneration. It is widely thought that excitotoxicity contributes to chronic neurodegenerative disease. We will test this hypothesis by investigating degeneration in mutant mice with altered iGluR mediated calcium flux alone and combined with mutant genes known to cause Huntington s disease by: knocking-out the NMDA receptor in select brain regions of mice and determining if that protects against neurodegenerative pathology in those brain regions. generating mutant mice with kainate or AMPA-Rs that flux abnormally high amounts of calcium and determine if that predisposes the mouse brains to neurodegenerative pathology. These experiments will provide valuable animal models enabling a deeper understanding of neurodegenerative processes. The models will also provide invaluable resources for developing therapies to protect against neurodegeneration.Read moreRead less
Ethanol abuse, alcoholism and the medical complications of excessive drinking are now major health problems worldwide. The alcohol dependence syndrome is characterised by tolerance and physical dependence ( the presence of a withdrawal syndrome). Ethanol withdrawal, in addition, to being a health hazard in itself, can act as a negative reinforcer to promote continued ethanol consumption. Alcohol dependence can be considered to result from adaptive changes produced by the chronic presence of etha ....Ethanol abuse, alcoholism and the medical complications of excessive drinking are now major health problems worldwide. The alcohol dependence syndrome is characterised by tolerance and physical dependence ( the presence of a withdrawal syndrome). Ethanol withdrawal, in addition, to being a health hazard in itself, can act as a negative reinforcer to promote continued ethanol consumption. Alcohol dependence can be considered to result from adaptive changes produced by the chronic presence of ethanol in the brain. In this research programme we will learn more about the adaptive changes in the NMDA receptors, the major excitatory receptors in the brain. Current psychopharmacologic management of human alcoholism is limited and suboptimal. We will explore the efficacy of drugs to control behaviours and withdrawal-induced brain cell death. Effective treatment of the syndrome is crucial since withdrawal induces changes, which increases the severity of subsequent withdrawal episodes and its associated brain damage. The outcomes of this research will be a better understand of the underlying changes involved in ethanol dependence and better therapies to ameliorate the withdrawal syndrome.Read moreRead less
Studying The Interaction Of Reelin Deficiency And Environmental Factors In The Development Of Schizophrenia Using Animal Behavioural Models
Funder
National Health and Medical Research Council
Funding Amount
$438,695.00
Summary
Schizophrenia is caused by an interaction of genetic predisposition and environmental risk factors such as stress or drug abuse. Reelin is a protein involved in the normal development of the brain but its levels are markedly reduced in schizophrenia. We will use mice with low levels of reelin in their brain and assess the effect of environmental stress and drugs of abuse. These studies could elucidate gene-environment interaction in schizophrenia and lead to new treatment strategies.
Mechanisms Of Glutamate Receptor Maturation In Chicken Brain
Funder
National Health and Medical Research Council
Funding Amount
$418,980.00
Summary
In the brain, many key proteins involved in signalling change during development as part of the fine tuning of the network of connections between nerve cells. Disorders of this fine tuning are thought to result in a number of neurological or psychiatric conditions such as epilepsy and schizophrenia. This project will investigate the maturation of signalling molecules in the brain (receptors for the neurotransmitter glutamate, key enzymes called protein kinases and protein phosphatases that contr ....In the brain, many key proteins involved in signalling change during development as part of the fine tuning of the network of connections between nerve cells. Disorders of this fine tuning are thought to result in a number of neurological or psychiatric conditions such as epilepsy and schizophrenia. This project will investigate the maturation of signalling molecules in the brain (receptors for the neurotransmitter glutamate, key enzymes called protein kinases and protein phosphatases that control the activity of receptors and scaffolding proteins that bind the whole lot into a signalling complex). The project uses chickens as a novel animal model because chicken brain has a slow maturation that occurs well after the initial wiring of the brain is complete. This enables the maturation changes to be clearly identified and experimentally modified. The project combines investigations at the molecular, physiological and behavioural levels. The effects of hormones and drugs on maturation will be investigated. Because brain maturation in humans is also slow an understanding of the way in which this maturation is controlled may provide insights into what causes some neurological-psychiatric disorders in children and adolescents and how to treat or prevent them.Read moreRead less
Brain damage resulting from long-term alcohol abuse is localized to discrete regions of the brain and selectively impairs key neuropsychological functions. Alcohol misuse affects processes that control excitability in the brain, leading to the over-stimulation of brain cells. When this continues for long periods the cells are likely to die and most alcoholics misuse alcohol for most of their adult lives. We will study the human brain s capacity to use and respond to glutamate, its major natural ....Brain damage resulting from long-term alcohol abuse is localized to discrete regions of the brain and selectively impairs key neuropsychological functions. Alcohol misuse affects processes that control excitability in the brain, leading to the over-stimulation of brain cells. When this continues for long periods the cells are likely to die and most alcoholics misuse alcohol for most of their adult lives. We will study the human brain s capacity to use and respond to glutamate, its major natural excitant, in the regions that are selectively damaged by alcoholism. How these capacities are affected by heredity, and by diseases commonly associated with alcoholism such as cirrhosis of the liver, will also be explored. If we can understand how selective brain damage occurs in alcoholics we will be better able to devise new drug therapies to combat and prevent it. As well, localized brain damage is a feature of many neurological diseases, so the study will provide a general model of disease mechanisms.Read moreRead less
Modulating Retinal Glutamate Transport In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$256,527.00
Summary
Damage can occur to nervous tissues like the retina and brain when there is a reduction in the blood supply. This can occur as a result of a blood clot, stroke or the eye disease, glaucoma. These conditions often result in blindness. Much of the neuronal damage is due to the release of an excess of glutamate. Glutamate is a chemical (neurotransmitter) that nerves use to communicate with each other, but it is toxic to nerves when present at high concentrations. This project will investigate the m ....Damage can occur to nervous tissues like the retina and brain when there is a reduction in the blood supply. This can occur as a result of a blood clot, stroke or the eye disease, glaucoma. These conditions often result in blindness. Much of the neuronal damage is due to the release of an excess of glutamate. Glutamate is a chemical (neurotransmitter) that nerves use to communicate with each other, but it is toxic to nerves when present at high concentrations. This project will investigate the mechanisms that regulate the concentration of glutamate in the retina. If these mechanisms could be made to work more efficiently, they may prevent the build-up of the glutamate and therefore prevent damage to the nerve cells. Understanding these mechanisms will aid in the development of an effective treatment to prevent blindness when there is a blockage of the blood supply to the retina.Read moreRead less