Anatomy and Neuroscience
Diet induced obesity: is it an addiction?
Supervisors: Dr Robyn Brown and Prof Andrew Lawrence
Location: Addiction Neuroscience Laboratory @ the Florey
Contact: Robyn Brown E: Robyn.Brown@florey.edu.au E: Andrew.Lawrence@florey.edu.au
Project description: Difficulty in managing food intake, especially highly palatable food, can result in obesity and substantial associated health liabilities. A cardinal feature of the pathological over-eating often underlying obesity is that although the individual can describe the negative consequences of their behaviour, they have great difficulty intervening and changing their behaviour. Thus, difficulty in reducing food intake has qualities of an addictive disorder. The disconnect between stated goals to reduce food consumption and actual behaviour suggests the presence of impairments in how information from the frontal cortex is integrating with basal ganglia circuitry to direct behaviour.
We have found that rats prone to diet-induced obesity display some features of ‘addiction-like’ behaviour towards palatable food. 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 the compulsive drug-taking observed in drug addiction.
Therefore we aim to:
1: Investigate the presence of addiction-like behaviour in rats prone to diet-induced obesity.
2: Conduct a preclinical trial of the glutamate homeostasis restoring drug N-acetylcysteine to reverse synaptic impairments in obesity prone rats to ameliorate aberrant feeding behaviour.
Investigating Alcohol-Related Dementia
Supervisors: Dr Christina Perry and Prof Andrew Lawrence
Location: Addiction Neuroscience Laboratory @ the Florey
Contact: Christina Perry E: Christina.Perry@florey.edu.au E: Andrew.Lawrence@florey.edu.au
Project description: Alcohol-related dementia (ARD) is one of the leading causes of secondary (preventable) dementia, and younger onset dementia (onset of symptoms prior to 65 years) in Australia. Together with the high rates of alcohol consumption in Australia, this means that ARD is becoming an increasingly urgent public health issue. The only treatment currently available for ARD is alcohol rehabilitation and abstinence. However, emerging evidence from animal models indicates that exercise may act as a protective factor against the neurotoxic effects of alcohol, and is even able to reverse some of the brain injury that occurs following alcohol exposure.
The aim of this project is to use a validated rodent model to:
1) Characterise the cognitive and neuropathological symptoms of ARD.
2) Evaluate the restorative effects of abstinence combined with voluntary exercise on these symptoms.
Context-induced relapse to alcohol-seeking after voluntary abstinence
Supervisors: Dr Erin Campbell and Prof Andrew Lawrence
Location: Addiction Neuroscience Laboratory @ the Florey
Contact: Erin Campbell E: Erin.Campbell@florey.edu.au E: Andrew.Lawrence@florey.edu.au
Project description: Substance abuse is a major health care problem. Accordingly, there is a real need to increase our fundamental understanding of the processes behind addiction, so that more targeted therapeutic strategies can follow. 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.
A limitation identified in animal models is that abstinence is achieved ‘non-voluntarily’ (experimenter-imposed). In humans, however, abstinence is typically voluntary (self-imposed), despite drug availability and often out of a desire to avoid the negative consequence associated with excessive alcohol use. A recently developed animal model addresses this limitation. In this model, the laboratory animal abstains voluntarily from alcohol use when alcohol-seeking is associated with a negative consequence. We will combine this novel animal model of relapse with an innovative procedure to manipulate neurons in defined neural circuits to determine which Nucleus Accumbens (NAc) shell output is critical for context-induced relapse to alcohol seeking.
Salt, opiates and addiction
Supervisors: Dr Craig Smith and Prof Andrew Lawrence
Location: Addiction Neuroscience Laboratory @ the Florey
Contact: Craig Smith E: Craig.Smith@florey.edu.au E: Andrew.Lawrence@florey.edu.au
Project description: We have recently used models of salt depletion / gratification in rodents to examine the central integration of this behaviour. By using gene set enrichment analysis, we found that genes regulated with sodium appetite were enriched for gene sets associated with cocaine and opiate addiction. Given the association of gene changes with salt appetite and opiate addiction, we hypothesize that the process of gratification of a salt appetite involves the release of endogenous opioids within the brain. This would be consistent with a rapid reinforcement that precedes physiological re-normalisation of plasma ionic balance. To test this hypothesis, we examined whether the opioid receptor antagonist, naltrexone (used clinically to treat heroin addicts and alcoholics), had any impact upon a salt appetite. Pretreatment of mice with naltrexone attenuated the gratification of a salt appetite. Furthermore, gratification of salt appetite is augmented in opiate-dependent mice, providing a link between instinctive behaviours and addiction.
Therefore, we aim to delineate the organisation and integration of salt (sodium) appetite in control, opiate-dependent and opiate-withdrawn mice. This will be achieved by a combination of behavioural, anatomical and electrophysiological studies.
Peptides and stress-induced relapse
Supervisors: Prof Andrew Lawrence
Location: Addiction Neuroscience Laboratory @ the Florey
Contact: Andrew Lawrence E: Andrew.Lawrence@florey.edu.au
Project description: 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 self-administration 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 (BNST) reduce alcohol self-administration, and also markedly attenuate stress-induced reinstatement of alcohol-seeking. 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 -
- Mechanism by which acute stress activates RLN3 neurons to precipitate relapse to alcohol-seeking.
- 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.
- Ability of stress and/or alcohol to regulate RLN3, CRF and orexin systems.