Cocaine and Glutamate, Part Two

Ten years ago, if you had asked a neuroscientist what neurotransmitter is most important to the development of an addiction, nine out of ten times they would have said “dopamine”. Ask the same question today, however, and you’ll probably be told that it is impossible to pin such a complex process on one neurotransmitter, as clearly (at least) both dopamine and glutamate are integral to the addiction process.

In hindsight, it is not surprising that glutamate be involved in addiction. Glutamate is the most abundant excitatory neurotransmitter in the brain. It is utilized in a number of cognitive processes, but essential to synaptic plasticity, and thus to learning and memory. And addiction is really just a type of learning—perhaps learning gone haywire, but learning nonetheless. It involves the association of a positive experience with the drug that was taken to induce it, resulting in a seeking of the drug to reproduce the experience. In addiction, however, unlike other learning processes, this seeking becomes obsessive and compulsive.

It is now thought that cocaine use causes glutamatergic synapses on dopamine neurons in the ventral tegmental area (VTA), a midbrain region of the reward system, to become stronger—even after just a single use. This makes the dopamine neurons there more sensitive to glutamate, causing a hyper-sensitivity to cocaine that results in addiction. It is believed the strengthening of these glutamatergic synapses involves changes in the composition of subunits of glutamate receptors.

In order to shed more light on the specifics of this subunit restructuring, a study published last week in the journal Neuron investigates the behavioral results of changes in glutamate receptor structure. The authors created genetically engineered mice that lacked one of three types of glutamate receptor subunits: GluR1, GluR2, or NR1.

As expected, they found that cocaine-induced strengthening of synapses on dopamine neurons was dependent on the functionality of glutamate receptor subunits, specifically the GluR1 and Nr1 subunits. They also, however, made two major discoveries. First, deletion of the GluR1 subunit caused the extinction of cocaine-seeking behavior to be slowed. Thus, these mice continued to seek cocaine long after cocaine had been withheld from them, when normal mice had already “forgotten” about the drug. By extension, this might mean that pharmacological stimulation of this receptor could have potential as a treatment for addiction.

Additionally, they found that the NR1 receptor subunit was necessary for the reinstatement of drug-seeking behavior after extinction. This is analogous to relapse behavior in humans. Once again, this could have pharmacological potential in addiction treatment.

Of course, these pharmacological applications, if viable, will take some time to work out. As you can imagine, it will not be easy to create a treatment that can selectively inhibit specific subunits on glutamate receptors in a particular brain region (although this can and has been done with other receptor subunits). And, with how important glutamate is to learning in general, there is potential that a treatment aimed at glutamate receptors could disrupt other cognitive processes. So, if you’re waiting for a pill to solve your cocaine problem, you may have to wait a while longer. A cocaine vaccine (see this post about vaccinations to treat drug abuse) may be available first.

ENGBLOM, D., BILBAO, A., SANCHISSEGURA, C., DAHAN, L., PERREAULENZ, S., BALLAND, B., PARKITNA, J., LUJAN, R., HALBOUT, B., MAMELI, M. (2008). Glutamate Receptors on Dopamine Neurons Control the Persistence of Cocaine Seeking. Neuron, 59 (3), 497-508. DOI:10.1016/j.neuron.2008.07.010

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