At the base of the midbrain lies the ventral tegmental area, or VTA. It is a dark, melanin-pigmented structure that is connected in a feedback loop of wiring with many other far-flung chunks of brain. It projects to and receives projections from the celebrated prefrontal cortex, the memory-forming hippocampus, and most importantly for this story, the pleasure-processing nucleus accumbens. Although the specific numbers are debated, over half of the neurons that live there release the neurotransmitter dopamine. And these neurons get excited by delta-9-THC, the cannabinoid present in marijuana.
This is the reward circuitry of the brain, and it provides motivation for many behaviors. Every major drug of abuse – cocaine, nicotine, alcohol, heroin, etc. – causes an increase in the activity of the dopaminergic neurons in the VTA and the nucleus accumbens. But the firing of these neurons also increases for natural pleasurable stimuli like food and sex. Because of the broad activity of the neurons, it is difficult to find effective treatments for addiction to specific drugs by intervening at this level.
But Justinova and colleagues have found another possible way to intervene in marijuana addiction – at least in preliminary experiments on squirrel monkeys and rats. Prior studies have suggested that the effects of THC are mediated by a different type of receptor altogether: an acetylcholine receptor known as 𝛼7nAChR.
Most receptors in the brian have a primary molecule to which they respond, known as a ligand. But receptor efficiency can be changed by other secondary molecules, known as allosteric modulators. Allosteric modulators can work in two directions: positive allosteric modulators increase the efficiency of the receptor, whereas negative allosteric modulators decrease it.
Kynurenic acid is a naturally-occuring negative allosteric modulator of the 𝛼7nACh Receptor. Justinova et. al used a molecule called Ro 61-8048 to increase the levels of kynurenic acid produced in the brain. By doings this, they reduced the efficiency of the 𝛼7nACh Receptor. This caused there to be less dopamine secreted in the VTA and the nucleus accumbens when THC was present, reducing activation of the reward circuitry in response to marijuana.
The researchers gave Ro 61-8048 to a group of squirrel monkeys that had been allowed to self-administer injections of THC. Giving the monkeys Ro 61-8048 reduced marijuana seeking behavior – i.e., the monkeys pressed the lever to get high fewer times after Ro 61-8048 than they did before. This is neat because monkey self-administration of THC is probably the best animal model we have of voluntary marijuana use in humans.
Importantly, the Ro 61-8048 did not affect the food-seeking behavior of the monkeys – so the pleasure-reducing effects of the drug were specific to THC, not to pleasurable stimuli in general.
The researchers also studied an animal model of marijuana relapse. In formerly addicted, now abstinate squirrel monkeys, exposure to specific cues that signal the availability of THC can cause an increase in drug-seeking behaviors. But Ro 61-8048 administration reduced this effect. After treatment with Ro 61-8048, the animals were better able to resist temptations to relapse.
So what does this mean for interventions in human drug abuse? The authors are guardedly optimistic. Although the drugs show promise in rats and squirrel monkeys, every species has slightly different biology. Preliminary translational studies on humans will have to be done before we know whether the benefit of the drug outweighs any potential risks.
Z. Justinova, P. Mascia, H. Wu, M.E. Secci, G.H. Redhi, L.V. Panlilio, M. Scherma, C. Barnes, A. Parashos, T. Zara, W. Fratta, M. Solinas, M. Pistis, J. Bergman, B.D. Kangas, S. Ferre, G. Tanda, R. Schwarcz, S.R. Goldberg. (2013) Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid. Nature Neuroscience.