Cannabis is the most widely used illicit drug in the world. Delta-9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, is known to be preferentially taken up into fat tissue where it can be stored for weeks, months and possibly years. Boy fat has the capacity to store large quantities of THC and the slow passive release of THC from fat cells into the blood accounts for why THC remains at detectable levels in the blood or urine for weeks after exposure to cannabis. Under n ....Cannabis is the most widely used illicit drug in the world. Delta-9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, is known to be preferentially taken up into fat tissue where it can be stored for weeks, months and possibly years. Boy fat has the capacity to store large quantities of THC and the slow passive release of THC from fat cells into the blood accounts for why THC remains at detectable levels in the blood or urine for weeks after exposure to cannabis. Under normal conditions the slow passive release of THC from fat cells has negligible effects on the user as the amounts involved are so small. However, we have recent preliminary evidence to show that conditions associated with increased fat metabolism (e.g. dieting, exercise or stress) cause a greatly enhanced release of THC from fat stores into the blood supply. Further, we have demonstrated that such levels attained promote significant behavioural and physiological changes The current proposal aims to further characterise this phenomenon. We aim to: (1) determine the length of time that THC can be stored in fat before being released into blood, (2) establish that the release of THC stored in fat tissue may be promoted by fat breakdown associated with food deprivation, stress or exercise, (3) characterise the physiological and behavioural effects of THC released from fat, (4) determine the mechanisms responsible for THC release from fat, and (5) determine if THC released from fat can cross from the bloodstream into saliva. This proposal has far reaching consequences for our understanding of the long-term effects on cannabis use on physical health and behaviour. Further, it may have major implications for the correct interpretation of analytical data from road-side saliva testing and forensic and criminal cases involving cannabis use.Read moreRead less
Brain Pathways Underlying Vulnerability To Drug Relapse
Funder
National Health and Medical Research Council
Funding Amount
$416,788.00
Summary
Addiction to drugs is a major health and social burden for Australian society. Once addiction is established, prevention of relapse is the most significant obstacle to successful treatment. Unfortunately, efficacious pharmaceutical options to treat relapse are lacking. By employing an animal model of relapse that accurately reflects drug taking in humans the proposed project aims to advance our understanding of the brain mechanism underlying addiction.
Increased Vulnerability To Stress During Opiate Dependence: Molecular, Anatomical, And Behavioural Correlates
Funder
National Health and Medical Research Council
Funding Amount
$272,640.00
Summary
Heroin addiction is a major health and societal problem in Australia. It is consistently associated with an adverse impact upon individual users, their families, and communities. It is a chronically relapsing condition for which few, if any effective prevention and treatment strategies exist. Moreover, why an individual initiates and maintains heroin taking remains unclear. Stress and negative emotions have a strong impact on heroin use. Stress may drive some individuals to start using heroin, s ....Heroin addiction is a major health and societal problem in Australia. It is consistently associated with an adverse impact upon individual users, their families, and communities. It is a chronically relapsing condition for which few, if any effective prevention and treatment strategies exist. Moreover, why an individual initiates and maintains heroin taking remains unclear. Stress and negative emotions have a strong impact on heroin use. Stress may drive some individuals to start using heroin, stress increases the pleasurable effects of heroin and stress increases the aversive effects of heroin withdrawal. These effects will encourage addiction and discourage addicts from seeking treatment. Stress can also cause an otherwise drug-free individual to relapse to heroin addiction despite having been drug-free for some time. In this project we will study why stress has such a large impact on heroin addicts and heroin addiction. We will test the hypothesis that heroin use actually produces profound alterations in the neural network in the brain which controls responses to stress. This project uses a simple animal model of heroin addiction whereby rats are injected with morphine to study the regulation of several genes which are important in responding to stress. We will also study how this exposure and changes in gene expression alter neurobiological, cardiovascular, and behavioural responses to stress. This project will identify parts of the brain that are altered during heroin addiction, and will also identify why heroin addicts are more vulnerable to stress than the general population. Therefore, this project will help us to identify targets for therapeutic intervention (both psychological and pharmacological) and possibly disrupt the addictive cycle.Read moreRead less
Heroin Dependence In WA: Identification Of Candidate Genes Involved In Susceptibility And Treatment Outcome
Funder
National Health and Medical Research Council
Funding Amount
$560,797.00
Summary
We will address identification of genetic factors which are important for the development of heroin addiction. In addition, we will correlate variation in genes involved in metabolism of heroin as well as the drugs used to treat heroin addiction with treatment outcome. Once these genetic factors are identified it will allow earlier intervention for treatment. In addition, it will allow identifying which treatment option might be most successful for the single individual.
MDMA (Ecstasy) has recently become one of the most popular recreational drugs in the world. A major concern with MDMA use is the mounting evidence from animal studies that even moderate doses may cause irreversible damage to nerve cells that utilize serotonin (5-HT) for neurotransmission. What is not known is how this damage might be expressed in terms of altered emotion, cognition and behaviour. Existing evidence suggests an important role for 5-HT in anxiety, depression and impulsiveness, but ....MDMA (Ecstasy) has recently become one of the most popular recreational drugs in the world. A major concern with MDMA use is the mounting evidence from animal studies that even moderate doses may cause irreversible damage to nerve cells that utilize serotonin (5-HT) for neurotransmission. What is not known is how this damage might be expressed in terms of altered emotion, cognition and behaviour. Existing evidence suggests an important role for 5-HT in anxiety, depression and impulsiveness, but whether MDMA use will increase the likelihood of such problems is uncertain. A major aim of this project is to examine the behavioural, cognitive and emotional changes in rats following exposure to MDMA. Using a variety of sophisticated tasks, we will determine the acute and the long term effects of MDMA in relation to memory, attention, impulsivity, and anxiety. A further concern is whether MDMA use may increase vulnerability to the addictive effects of other drugs of abuse . We aim to examine whether rats pre-exposed to MDMA are subsequently sensitised to the rewarding effects of cocaine and opioids. MDMA users may also suffer a temporary depression a few days after taking the drug. We will assess the possible anhedonic or depressing effects of MDMA. Finally, there is still a lot to understand about the way MDMA affects the brain. Our recent work shows that many diverse brain regions are affected by this drug. We want to extend this work to see how this pattern of brain activation is altered by fluid deprivation and high ambient temperatures - conditions experienced at rave parties. The present project will help further our understanding of MDMA and its neurotoxic effects and to highlight any potential long-term dangers to health that may exist for people who are currently using or are planning to use this drug.Read moreRead less
Molecular Cell Biology Of HNP22: Role In Alcohol Dependence
Funder
National Health and Medical Research Council
Funding Amount
$346,320.00
Summary
We used a differential screening procedure to detect changes in gene expression in the human alcoholic brain and described a novel gene, which we named hNP22, with increased expression in the superior frontal cortex of the alcoholic cases. This is the first report of a novel alcohol-responsive gene isolated from the human brain. We now propose to further explore the hNP22 gene, its product and its regulation in human brain tissue, and in a variety of experimental systems. We will determine how p ....We used a differential screening procedure to detect changes in gene expression in the human alcoholic brain and described a novel gene, which we named hNP22, with increased expression in the superior frontal cortex of the alcoholic cases. This is the first report of a novel alcohol-responsive gene isolated from the human brain. We now propose to further explore the hNP22 gene, its product and its regulation in human brain tissue, and in a variety of experimental systems. We will determine how protein expression correlates with the level of alcohol consumption. We will use animal and cell culture models to determine the response of the gene to various stimuli. We will express the recombinant protein to determine its function. It is likely that the gene product may be a component in an important signal pathway within neuronal cells and thus may represent a novel target for therapeutic intervention.Read moreRead less
Neurocognitive Studies Of Reward Sensitivity In Opiate Addiction And Its Influence On Addiction-related Behaviour
Funder
National Health and Medical Research Council
Funding Amount
$258,275.00
Summary
Drug abuse is the greatest single preventable risk factor for physical illness and death in Australians . Our understanding of the neural and cognitive mechanisms that contribute to the transition from drug use to addiction is not yet complete. The current proposal investigates cognitive control dysfunction, most notably the impulsivity for reward seen in drug addiction that is known to predict the transition from drug use to addiction and relapse during treatment.
Cortictropin Releasing Factor As A Therapeutic Target For Alcohol And Drug Abuse
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
A key problem with alcoholism, as with addiction generally, is the chronically relapsing nature of the disorder. This can be modelled in rodents and there is good general correspondence between animal studies of reinstatement and human experience of relapse. We have identified brain chemicals involved in this process. Consequently, by better understanding the biological mechanisms related to addiction and relapse, we will be in a position to counter this devastating condition.
The Risk Factors For Ecstasy And Related Drug Overdose: A Case-crossover Study
Funder
National Health and Medical Research Council
Funding Amount
$406,755.00
Summary
Our ability to respond to the emergent harms of Ecstasy and Related Drug (ERD) use is hampered by our lack of understanding of the practices users engage in that place them at risk of harm. This study will examine the risk factors for non-fatal ERD Emergency Department (ED) admission in a sample of non-fatal ERD overdose victims recruited through two hospital EDs in Melbourne. The research involves a case-crossover study of the risk factors for ERD-related ED admission, as well as a detailed cas ....Our ability to respond to the emergent harms of Ecstasy and Related Drug (ERD) use is hampered by our lack of understanding of the practices users engage in that place them at risk of harm. This study will examine the risk factors for non-fatal ERD Emergency Department (ED) admission in a sample of non-fatal ERD overdose victims recruited through two hospital EDs in Melbourne. The research involves a case-crossover study of the risk factors for ERD-related ED admission, as well as a detailed case series of ERD-related ED admissions. The case-crossover investigation will involve a comparison between behaviours occurring prior to the critical drug use episode with typical drug use behaviours and more specifically those occurring prior to a control use episode (another occasion on which ERDs were used). Data will be collected by Researchers positioned in the ED, with information collected on the specifics of the critical and control use episodes through interviews with participants following stabilisation and a return to consciousness. The case series will be established from all ERD-related ED admissions flagged as such by triage nurses. Potential risk factors under study will include the environmental conditions in which the drug was used (eg time of day, physical location), other drug taking behaviour, personal factors (eg asthma, depression) and other dose-related issues (eg amount purchased, source of purchase). Statistical analysis will establish the major differences between the critical, typical and control use episodes. The proposed research will examine risk factors for ERD-related harms within the context of an understanding of the usual practices and behaviour of users of these drugs. Identifying transient change in risk behaviours will provide a foundation for developing contextually-sensitive strategies for harm minimisation. The development of a detailed case series will impact upon the treatment and management of acute ERD-related harms.Read moreRead less
Targeting Alpha-conotoxin MII To Inhibit Neuronal Nicotinic Acetylcholine Alpha3beta2 Receptors Of The CNS
Funder
National Health and Medical Research Council
Funding Amount
$218,334.00
Summary
Nicotinic acetylcholine receptors (nAChRs) play a central role in nerve signal transmission, neurite growth and development and are the representative model of the ligand-gated ion channel superfamily. Recent studies, including those from Dr Lewis' and A-Prof Alewood's laboratories, have identified alpha-conotoxin peptides which can discriminate among the different nAChRs, apparently by binding to the specific interfaces formed by different subunit combinations. Thus alpha-conotoxins are unique ....Nicotinic acetylcholine receptors (nAChRs) play a central role in nerve signal transmission, neurite growth and development and are the representative model of the ligand-gated ion channel superfamily. Recent studies, including those from Dr Lewis' and A-Prof Alewood's laboratories, have identified alpha-conotoxin peptides which can discriminate among the different nAChRs, apparently by binding to the specific interfaces formed by different subunit combinations. Thus alpha-conotoxins are unique tools with which to identify and determine the physiological role, played by the different native neuronal nAChRs. Moreover, they are unusually stable peptides and can withstand enzyme and acid treatment. These findings have encouraged us to pursue the viability of alpha-conotoxin MII as a new and selective antagonist for the neuronal nictotinic receptor alpha3 beta2 which is involved in nicotine addiction. The challenge and major goal of this project is to deliver alpha-conotoxin MII efficiently into the brain. A-Prof Toth has developed a novel drug-delivery system for the oral administration of drugs and peptides, which in their unmodified form are poorly absorbed or biologically unstable. In this project alpha-conotoxin MII will be combined with a specifically designed lipopolysaccharide delivery system . The delivery system can be specifically tailored to transport a wide variety of peptides through the different biological barriers. The peptides can be conjugated to the delivery system in such a way as to release the peptide after it has been absorbed (prodrug), or to form a biologically stable and active novel molecule. The outcomes of this work will include the first delivery system of nicotinic antagonists to the brain and new knowledge concerning the importance of the neuronal nictotinic receptor alpha3 beta2 in nicotine addiction.Read moreRead less