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

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.

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.