Professor Andrew J Lawrence
Associate Director FNI
Head, Division of Behavioural Neuroscience
EDITORIAL POSITIONS
Andrew Lawrence
Senior Editor, The British Journal of Pharmacology
Editorial board member, Addiction Biology
Associate Editor, Neurochemical Research
Editor, The Open Neuropsychopharmacology Journal
Our laboratory is investigating the neural pathways implicated in drug-seeking behaviour and additionally, the association between mood disorders, stress and drug-seeking behaviour. For example, alcohol is one of the most widely used and abused drugs in society, with an immense social, medical and financial impact. Drug self-administration and behavioural parameters are measured to assess the influence of specific receptors and emotional states such as anxiety and depression on drug-seeking behaviour. Stressors can be used to examine the relationship between psychological state and relapse to drug-seeking behaviour following a period of abstinence. These behavioural approaches are complemented with a range of neurochemical, anatomical and molecular strategies to provide a multidisciplinary strategy.
In addition, we are employing genetic approaches to investigate the neural substrates of drug-seeking, drug-induced plasticity and relapse. This latter aspect is of critical importance, as the defining feature of addictions is the chronic and relapsing nature of the disorder. Many of these research directions have a common underlying theme of neural plasticity as a key mediator of altered behaviour patterns. To facilitate these studies we have perfected the technique of intravenous self-administration of drugs of abuse in mice. Projects currently underway involve self-administration of opiates, cocaine and nicotine.
Fellows, Senior Research Officers and Research Officers
Andrew LawrenceBSc (Hons) PhD (Loughborough, UK)
Jhodie DuncanBSc (Hons) PhD (Melb)
Bianca Jupp BSc (Hons) PhD (Melb)
Robyn BrownBCom/BSci (Hons) (Melb)
Jee Hyun-Kim BPsych (Hons) PhD (UNSW)
Elena KrstewBSc (Melb)
Liz CahirBSc (Hons) (Melb)
Heather Madsen BSc (Hons) (Melb)
Rose Chesworth BPsych (Hons) (Syd)
Alec Dick BSc (Hons) (Melb)
Nicola Chen, Universityof Melbourne
CRF and orexin are neuropeptides implicated in a range of functions including arousal, stress responses and drug-seeking. We, and others, have previously demonstrated that both CRF and orexin have roles in alcohol consumption, seeking and relapse. Recently, we have developed a model of relapse to alcohol-seeking after extended periods of abstinence, demonstrating the utility of animals to study the enduring propensity to relapse that is characteristic of human addicts. Importantly, we have examined patterns of neural activation following cue-induced relapse immediately after extinction training (a rodent equivalent of rehab) compared to relapse that occurs when extinction is followed by an extended period of abstinence. Immediate reinstatement increased neural activation in a range of cortical and sub-cortical structures implicated in drug/alcohol-seeking and while delayed reinstatement showed a broadly similar pattern, these markers were further elevated in cortical structures. These data suggest that a base network of interconnected circuitry is implicated in relapse-like behaviour, although following prolonged abstinence the way the brain integrates the salience of cues that previously signalled drug availability may change. Notably, functional blockade of the orexin system essentially prevented the expression of relapse-like behaviour at both time points. This would suggest that the orexin system in the brain is involved in cue-driven reward-seeking, irrespective of a period of abstinence. By combining pharmacological blockade of the orexin system with the relapse paradigm and subsequent assessment of neural activation we have identified putative anatomic loci where the orexin system may be acting to influence reward-seeking. These target structures will be the focus of future studies to identify where in the brain this peptide system acts to modulate relapse.
Viral-based studies are also underway to examine, in discrete brain nuclei, the role of various neuropeptides / receptors in aspects of drug use and relapse to drug-seeking.
This project has evolved out of ongoing studies that have for some time been examining independently the role of glutamate and adenosine systems in drug-seeking. For example, using a combination of pharmacological and genetic approaches, we have previously linked the mGlu5 receptor to alcohol reward, motivation and sensitivity in both rats and mice. More recently, using mice with the adenosine A2a receptor deleted, we have linked this receptor to the reinforcing and motivational properties of opiates. For example, mice lacking the adenosine A2a receptor show reduced desire to intravenously self-administer opiates compared to wildtype littermates. Notably, alcohol and opiates act on similar pathways in the brain; this is why naltrexone (an opioid receptor antagonist) can be used to reduce alcohol consumption.
We therefore have provided a clear base for the involvement of glutamate and adenosine in drug-seeking behaviour. Given that mGlu5 and adenosine A2a receptors are co-localised on a discrete population of neurons implicated in the neural network that is targeted by drugs of addiction, we hypothesised that these receptors may interact in a functional manner to regulate goal-directed behaviour such as self-administration of a drug. To test this, we trained a group of rats to self-administer alcohol and then injected them with a combination
of mGlu5 and adenosine A2a receptor antagonists. Importantly, we used doses of antagonists that we had previously determined were without effect by themselves (i.e. subthreshold). When we combined subthreshold doses of the two antagonists there was a dramatic, synergistic effect whereby alcohol self-administration was reduced by almost 50%. In addition, this combination of mGlu5 and adenosine A2a receptor antagonists completely blocked relapse to alcohol-seeking in rats that had been through a rehabilitation program.
This project is now moving into human brain to study the interactions between these two receptors and we are also screening compound libraries for potential lead compounds that may interact with these two receptors. In addition, we are currently examining an interaction between mGlu5 and A2a receptors in relation to cocaine-driven behaviours.
The purposeful abuse of inhaled chemical vapors to produce self-intoxication and/or altered mental state is a significant public health concern. In Australia, sniffing the fumes of aerosol spray paint is the most popular form of inhalant abuse, while petrol sniffing remains a significant problem for indigenous communities, especially within remote settings. The typical onset of experimentation with inhalants occurs earlier than with most other drugs of abuse, in the preteen years, coinciding with the maturation of crucial cognitive and emotional brain structures. Despite long-standing awareness of the significant morbidity and mortality associated with inhalant abuse, fundamental neurobiological research has been comparatively sparse. Accordingly, we have established a paradigm whereby adolescent rodents inhale a major psychoactive component of many inhalants. Longitudinal studies are currently underway, incorporating state-of-the art Magnetic Resonance Imaging techniques, to ascertain the impact of chronic intermittent exposure to inhalants on brain pathology, in particular white matter tracts. Parallel cohorts of rodents are being examined to characterise the impact of inhalant abuse upon affect, cognition and drug use in adulthood. In addition, we are collaborating with Dr Tim Bredy at QBI to study the epigenetic consequences of adolescent toluene use in our rodent model.
Nicotine addiction, through smoking cigarettes, is a major contributor to the global burden of disease and a leading cause of preventable death. To address this issue we have established a model of nicotine self-administration in mice and are combining this with molecular genetic approaches to examine the role of specific nicotinic receptor subunits in nicotine reward, plasticity, locomotor behaviour and anxiety. Ongoing experiments have implicated individual nicotinic receptor subunits as necessary for different behavioural effects of nicotine.
Behavioural Approaches:
Molecular Approaches:
Image Analysis:
NHMRC Project Grant (508964) Genetics of Stress Responsiveness
Mark Murphy, Thomas Brodnicki, Andrew Lawrence.
NHMRC Project Grant (566736) Glutamate - adenosine interactions and drug-seeking
Professor AJ Lawrence, A/Prof P Dodd & Dr K Pfleger.
NHMRC Project Grant (628680) A novel paradigm for defining the in-vivo role of alpha4-containing neuronal nicotinic acetylcholine receptors in nicotine mediated complex behaviours.
A/Prof J Drago & Professor AJ Lawrence
Pratt / Besen Foundations: Neuropeptides, stress & drug-seeking
Professor AJ Lawrence & A/Prof A Gundlach
ARC Discovery Project (DP110100379) The long-term consequences of toluene exposure on the maturing brain
Prof AJ Lawrence, Dr TW Bredy, Dr M Gavrilescu
Prof Seong-Seng Tan
Florey Neuroscience Institutes
Genetics of drug-seeking behaviour
A/Prof John Drago
Florey Neuroscience Institutes
Genetics of drug-seeking behaviour
Dr Scott Kolbe & Professor Gary Egan
Florey Neuroscience Institutes
MRI scanning in relation to inhalant abuse
Dr Tim Bredy
Queensland Brain Institute, UQ
Epigenetic consequences of drug abuse
Dr Dan Lubman
Turning Point, Monash University
Animal models of adolescent drug use
A/Prof Iain McGregor
Psychology, University of Sydney
Long-term consequences of psychostimulant use
Dr Maarten Van den Buuse
Mental Health Research Institute
Animal models of adolescent drug use
Dr Bryce Vissel
Garvan Institute of Medical Research, Sydney
Genetics ofdrug-seeking behaviour
A/Prof Peter Dodd
Biochemistry, University of Queensland
Glutamate – adenosine receptor interactions and drug seeking
Dr Kevin Pfleger
Western Australian Institute for Medical Research
Glutamate – adenosine receptor interactions and drug seeking
Dr Clarke Raymond
Eccles Institute of Neuroscience, ANU
Synaptic plasticity
Drs Steve Petrou & Christopher Reid
Florey Neuroscience Institutes
Drug-induced plasticity
Dr Catherine Ledent
IRIBHN, Belgium
Genetics of drug-seeking behaviour
Dr Michelle Ehrlich
Mount Sinai Medical School, USA
Genetics of drug-seeking behaviour
A/Prof Jian-Hui Liang
National Institute of Drug Dependence, Beijing, PR China
Pharmacotherapies for alcoholism
Dr Amir Rezvani
Duke University, North Carolina, USA
Genetics of drug-seeking behaviour
Dr David Overstreet
UNC Chapel Hill, North Carolina, USA
Pharmacotherapies for alcoholism
Professor Rainer Spanagel & Dr Rosanna Parlato
Central Institute for Mental Health, Mannheim, Germany
Genetics of drug-seeking behaviour & Pharmacotherapies for alcoholism
Professor Ivan Diamond & Dr Maria Orolfo
Gilead, USA
Pharmacotherapies for alcoholism
Professor Masahiko Funada
National Institute of Mental Health, Tokyo, Japan
Rodent models of inhalant abuse
Drs Alon Chen & Abraham Zangen
Weizmann Institute, Israel
Neuropeptides & drug-seeking
UNC Chapel Hill, North Carolina, USA
Pharmacotherapies for alcoholism
Professor Rainer Spanagel & Dr Rosanna Parlato
Central Institute for Mental Health, Mannheim, Germany
Genetics of drug-seeking behaviour & Pharmacotherapies for alcoholism
Professor Ivan Diamond & Dr Maria Orolfo
Gilead, USA
Pharmacotherapies for alcoholism
Professor Masahiko Funada
National Institute of Mental Health, Tokyo, Japan
Rodent models of inhalant abuse
Drs Alon Chen & Abraham Zangen
Weizmann Institute, Israel
Neuropeptides & drug-seeking
“The mind loves the unknown, it loves images where meaning is unknown. Since the meaning of the mind itself is unknown.”
