The Many Sides of GABA

If you have a superficial level of knowledge about neuroscience, you probably won’t associate psychostimulants with gamma-aminobutyric acid (more commonly known as GABA). Just as you learn in early biology that a mitochondrion is the “powerhouse of the cell”, you learn in early neuroscience that GABA is the “primary inhibitory neurotransmitter of the brain”. And while this is often true (exceptions are being found on a regular basis), it perhaps doesn’t do justice to the diversity of roles that GABA can play.

There are, for example, many instances of GABA having an inhibitory effect on another inhibitory neuron. This can in effect stop the inhibition, potentially allowing for excitation by another neurotransmitter. Exactly this happens every time you make a voluntary movement. Neurons in the striatum release GABA that inhibits the action of neurons in the globus pallidus. These neurons normally inhibit areas of the thalamus that are necessary for movement but when they are inhibited the thalamus is essentially freed up, allowing us to move.

So, GABA-ergic actions don't necessarily mean inhibition as an end result. This is also true when it comes to the addictive properties of drugs. Dopamine (DA) neurons in the nucleus accumbens (NAc) directly modulate GABAergic connections to the ventral pallidum (VP), which itself sends GABAergic projections back to the NAc. Thus, it is easy to imagine that influencing DA transmission in the NAc, an inevitable outcome of drug use, also has an effect on GABAergic activity throughout the reward system.

Because of this, researchers like Claire Dixon and colleagues have been interested in how GABAa receptors are affected by the administration of drugs like cocaine. In a study published earlier this year in PNAS, Dixon et al. used knockout (KO) mice that had the gene for the alpha2 subunit of the GABAa receptor deleted. GABAa receptors containing these subunits are highly expressed in the NAc.

While these KO mice still demonstrated a stimulant response to cocaine (based on locomotor assays), they failed to show sensitization to the drug, i.e. their activity remained the same on repeated administrations while the wild-type (WT) mice's activity progressively increased. Additionally, cocaine's ability to facilitate conditioned reinforcement (lever pressing) was vastly reduced in the KO mice.

This indicates that GABA may have a role in mediating an addictive response to drugs. The authors hypothesize that the ability of cocaine to increase behaviors associated with environmental cues connected to the drug (lever pressing), and with conditioned activity (sensitization), may depend upon GABAa receptors. Alpha-2 subunits may allow cocaine to strengthen the association between cues and a drug, an association that underlies some of the most compulsive aspects of addiction. Thus, perhaps GABA receptors represent a potential, if not unlikely, target for treating addiction.

Dixon et al. (2010). Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAa receptors. PNAS, 107, 2289-2294.