Molecular and physiological mechanism of GABA(A) receptor function in striatal circuits underlying addiction

Lead Research Organisation: University of Sussex
Department Name: Sch of Psychology

Abstract

Addictive drugs have in common that they influence the function of the brain?s reward pathways. A central structure in these pathways is the nucleus accumbens. We already know that the accumbens receives information about external events that indicate the availability of rewards from other parts of the brain such as the cortex and amygdala, and integrates that information with another important input, from the midbrain, that uses dopamine as its chemical messenger. The role of these systems in signalling reward has been well explored. However, the nucleus accumbens itself consists almost exclusively of nerve cells that use a quite different chemical messenger, GABA. Surprisingly little is known of how these GABAergic cells function to integrate the signals from cortex and amygdala with those from dopamine systems, yet this function lies at the heart of reward signalling. We have recently discovered that GABA signalling in reward depends upon a particular subtype of GABA receptor that is found at high densities in the accumbens. However, we have no real knowledge of how this system functions. In this project we will develop new tools that will allow us to explore the function of this particular subtype of GABA receptor, and how it interacts with other GABA receptors in determining drug-seeking behaviour. A better understanding of this process may allow us to develop new drugs to treat addictions.

Technical Summary

Understanding the neurobiological mechanisms by which drugs become addictive is essential for formulating new therapeutic approaches to combat addiction. GABAergic medium spiny neurons (MSNs) in the nucleus accumbens are a critical part of the underlying neural circuitry of addiction, integrating dopaminergic inputs from the ventral tegmental area with excitatory glutamatergic inputs from cortex, amygdala and hippocampus. The importance of GABAergic neurotransmission in the processes leading to addiction is further supported by data we have collected across species: A polymorphism in gene expressing the GABA(A) receptor alpha2 subunit in humans associates with an increased vulnerability to addiction; and studies using alpha2 knockout and knockin mice show that these receptors are both necessary and sufficient for cocaine facilitated behavioural sensitisation and conditioned reinforcement. Here we seek to further these studies through four specific aims: 1) Identifying the synaptic and extrasynaptic GABA(A)Rs in specific MSN populations; 2) Establishing by electrophysiology changes GABA(A)R function after repeated cocaine exposure; 3) Establishing the regional localization of alpha2 GABA(A)R mediated actions of cocaine by cFos immunocytochemistry; and 4) developing new tools for localized down-regulation of alpha2 GABA(A)Rs in vivo. The proposed pilot studies will provide proof of principle data for future proposals to determine the mechanisms by which GABA(A)R subtypes are involved in the progression to drug addiction. These results can be directly translated into humans where we can pinpoint ?at risk individuals? and use an informed approach to target and reverse chronic changes in the addiction neurocircuitry with selective GABAergic drugs.

Publications

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Caldarone BJ (2015) Rodent models of treatment-resistant depression. in European journal of pharmacology

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Dixon CI (2010) Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAA receptors. in Proceedings of the National Academy of Sciences of the United States of America

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Heath CJ (2010) Cortico-thalamic connectivity is vulnerable to nicotine exposure during early postnatal development through a4/ß2/a5 nicotinic acetylcholine receptors. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Maguire EP (2014) Tonic inhibition of accumbal spiny neurons by extrasynaptic a4ßd GABAA receptors modulates the actions of psychostimulants. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Royal College of Psychiatrists
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description MRC Addiction Research Strategy
Amount £999,999 (GBP)
Funding ID G1000008 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 01/2014
 
Description MRC Industrial CASE studentship
Amount £113,800 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 09/2017
 
Title Lentivirus to knockdown Gabra2 expression in mice 
Description shRNAi construct and viral particle for intracerebral injection and in vivo analysis of gene function 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Allows regions and temporal specific analysis of gene function not possible with constitutive knockout animals 
 
Description GABA(A) group 
Organisation University of Dundee
Department College of Medicine, Dentistry & Nursing
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative work on GABA(A) receptor subtyoes incliding Alpha2, Alpha4 and delta containing receptors between the Universities of Sussex and Dundee
Collaborator Contribution Collaboration facilitated by this grant
Impact PMID: 20133874 Sussex - Behaviour and molecular biology. Dundee - electrophysiology.
Start Year 2009