Quick Project Snapshot

Peptides and stress-induced relapse

Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for RXFP3 (relaxin family peptide 3 receptor), the cognate receptor for the neuropeptide, relaxin‐3, decreased self-administration of alcohol in a dose‐related manner and attenuated cue‐induced reinstatement following extinction. Given the established role for relaxin 3 signalling in stress responses we also examined stress-induced reinstatement of alcohol-seeking using yohimbine as a chemical stressor. The selective RXFP3 antagonist, R3(B1-22)R, prevented yohimbine-induced reinstatement of alcohol-seeking, an effect greater than that for cue-driven alcohol-seeking. By comparison, RXFP3 antagonist treatment produced no significant change in selfadministration of sucrose, suggesting a selective effect for alcohol. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity or cognition in the paradigms assessed. These data suggest relaxin‐3/RXFP3 signalling regulates alcohol intake and relapse‐like behavior, adding to current knowledge of the brain chemistry of reward-seeking.

We have extended these findings by using targeted microinjections into brain nuclei that are (i) known components of alcohol-seeking circuitry and (ii) localise dense expression of RXFP3. In this regard, we have shown that local microinjections of R3(B1-22)R into the bed nucleus of the stria terminalis reduce alcohol self-administration, and also markedly attenuate stress-induced reinstatement of alcohol-seeking. In addition, we have shown in rats that expression of relaxin-3 mRNA in the nucleus incertus correlates with alcohol intake, suggesting that high basal expression of relaxin-3 in the nucleus incertus may pre-dispose high levels of alcohol intake. We hypothesise that stress activates ascending networks containing relaxin-3 to regulate alcohol-seeking via actions at RXFP3 within the BNST and possibly other component areas of the ‘extended amygdala’.

Therefore, our aims are to determine the -

  1. Mechanism by which acute stress activates RLN3 neurons to precipitate relapse to alcohol-seeking.
  2. Nature of RXFP3-mediated modulation of neural signalling within BNST and the neurochemical phenotype of RXFP3-expressing neurons in forebrain areas implicated in regulation of stress-induced relapse to alcohol-seeking.
  3. Ability of stress and/or alcohol to regulate RLN3, CRF and orexin systems.
  4. Brain loci within the extended amygdala, in addition to the BNST, where RXFP3 signalling regulates stress-induced relapse to alcohol-seeking. This will be achieved by a combination of behavioural, anatomical and electrophysiological studies.

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 Lab

Salt, 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

Behavioural Neuroscience

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.

All Labs that operate in this Division

Addiction Neuroscience LaboratoryClinical Cognitive Neuroscience LaboratoryDevelopmental Psychobiology LaboratoryEpigenetics and Neural Plasticity LaboratoryGenes Environment and Behaviour LaboratoryInhalant Addiction LaboratoryMidbrain Dopamine Plasticity LaboratorySynapse Biology and Cognition LaboratoryVascular Neurodegeneration Research Laboratory