Quick Project Snapshot
Alcohol & striatal adaptation
Alcohol drinking and cigarette smoking are amongst the leading worldwide causes of preventable death and disease. Moreover, alcohol and tobacco are commonly co-abused and animal studies have implicated potential overlapping mechanisms of action in the brain.
In this regard both alcohol and tobacco impact central cholinergic systems and drugs acting at nicotinic receptors can regulate both drinking and smoking. Importantly, we have recently confirmed the functional relevance of lateral striatal M5 muscarinic receptors in regulating voluntary alcohol intake.
These novel findings allow us to hypothesise that plastic adaption of cholinergic signalling occurs following chronic intermittent alcohol in the lateral striatum.
Based on these exciting results, we will:
(i) perform analogous RNA-Seq studies in human alcoholic brain compared to age-matched control brain.
(ii) characterise the molecular and electrophysiological consequences of chronic intermittent alcohol intake on cholinergic transmission in the rat striatum.
(iii) examine in rats how pharmacological manipulation of nicotinic and muscarinic M5 receptors, alone and in combination, impacts upon alcohol use / relapse.
Overall, this novel and innovative study will lead the field by characterising the molecular effects of chronic alcohol use in human caudate (medial striatum) vs putamen (lateral striatum); characterising the impact of alcohol on striatal cholinergic transmission and a parallel preclinical assessment of a potential novel therapeutic target, namely the muscarinic M5 receptor.
Addiction Neuroscience Laboratory
The Addiction Neuroscience Group studies how alcohol and other drugs change the brain’s chemistry, structure and function. For example we continue to unravel the circuitry and brain chemistry implicated in stress-induced relapse to alcohol-seeking. This project has been expanded with the recruitment of two new PhD students (Sarah Sulaiman Ch’ng and Leigh Walker). Together, these students are interrogating how and where in the brain specific peptide systems interact to regulate reward-seeking. So far we have identified a novel neural signalling system in the brain for the regulation of stress-induced relapse to alcohol-seeking. Specifically, we have shown that relaxin-3 inputs (likely from the nucleus incertus, NI) to the bed nucleus of the stria terminalis (BNST) are critical for stress-induced relapse to alcohol-seeking in rats. We are extending this innovative project which will lead the field by further delineating the circuitry and brain chemistry implicated in stress-driven relapse, the major stumbling block in the successful treatment of substance abuse clients. Given the scale and costs of substance abuse disorders, the identification of improved therapeutic approaches will have immediate and sustained impact.
Another related project involves a model of voluntary abstinence from alcohol that is precipitated by the presentation of an adverse consequence following drug use (as occurs in the human situation). Using this model we (Dr Nathan Marchant & Professor Andrew Lawrence) are characterising the circuitry that underpins context-induced relapse to alcohol-seeking following voluntary abstinence. We have identified a potentially critical neural mechanism by which alcohol associated environments promote alcohol seeking during abstinence. We will further unravel the brain mechanisms of relapse to alcohol seeking, and will identify novel brain areas and circuits that future clinical studies can target in treatment-seeking alcoholics.
There is a strong negative correlation between cognitive function and treatment outcome for addicts. An often overlooked factor is that long term alcohol abuse is strongly associated with an accelerated rate of cognitive decline and dementia. Dr Christina Perry has recently been awarded an NHMRC Dementia Fellowship to directly study this problem using validated animal models, with the translationally accepted touchscreen cognitive behavioural platform. Going forwards we will undertake the first comprehensive and systematic analysis of how long term chronic intermittent exposure to alcohol leads to precipitation of behavioural and neuropathological symptoms of dementia. Importantly, we will establish the extent to which these symptoms can be rescued with abstinence, and whether a relatively simple behavioural intervention can enhance this recovery. This study will provide the field with a road map for alcohol-induced cognitive decline. Our results will have important therapeutic applications for an aging population.
Obesity has reached pandemic proportions and is rapidly surpassing smoking as the number one killer in the industrialized world. Dr Robyn Brown (Doherty Fellow), has generated compelling evidence, based on complementary behavioural and electrophysiological approaches, which show that rats prone to diet-induced obesity display ‘addiction-like’ behaviour towards palatable food. Moreover, for the first time we provide evidence of dysregulated glutamate physiology at accumbal synapses in rats prone to obesity. This provides important preliminary evidence to support our central hypothesis that the pathological over-eating commonly observed in diet-induced obesity shares common features with compulsive drug-taking observed in drug addiction. This finding suggests that the management of obesity should incorporate “relapse-prevention” strategies in parallel to weight loss programs, as an adjunct to help reduce episodes of over-eating.
For details of these & other projects please follow the links below.
All Projects by this LabSalt, opiates and addictionMechanisms of dopamine phenotype plasticity in adult midbrain neuronsPeptides and stress-induced relapseDiet-induced obesity: is it an addiction?Context-induced relapse after voluntary abstinenceInvestigating Alcohol-Related DementiaAlcohol & striatal adaptation
The Division of Behavioural Neuroscience focuses on the use and development of models that reflect aspects of human disorders such as addiction, anxiety, depression, schizophrenia, autism and neurodegenerative conditions such as Huntington’s disease. The Cognitive Neuroscience group additionally studies cognitive disorders caused by diseases such as stroke (cerebrovascular disease), Alzheimer's disease and other dementias from a clinical perspective.