Addiction is often described as “a reward process spinning out of control.” For decades, researchers (as well as physicians, legislators and judges) have struggled to understand just how and why drugs like cocaine, heroin and nicotine alter critical brain pathways and lead to addictive behaviors. Wolfram Schultz, a pioneering researcher in the field of addiction, says that while we know that addiction results in changes to the brain’s dopamine system, the details have remained fuzzy.
“Ultimately, we know, those high levels of dopamine lead to plasticity in the brain, to changes in the reward processing system that result in no longer being able to make sense of the dopamine signals or how they may relate to the outside world in the proper way,” he says. “But it is very complicated.”
New research out of Johns Hopkins University has painstakingly detailed the molecular processes linking the brain’s glutaminergic learning circuitry to the dopamine-fueled motivation system, demonstrating how cocaine harnesses the brain’s plasticity, strengthens specific learning circuits, and leads to addiction.
Shining a light on the pathway
While most of the work in addiction has focused on dopamine, researchers have recently turned their microscopes to glutamate, an excitatory neurotransmitter that is critical to learning and memory that is also found in the brain’s risk and reward processing centers.
“Virtually all drugs of abuse decrease the ability of the nucleus accumbens, which is part of the striatum, to eliminate glutamate,” says Peter Kalivas, a neuroscientist studying glutamate’s role in addiction at the Medical University of South Carolina. “So when the signal comes down from the cortex to engage a behavior, like a relapse behavior in response to a cue, glutamate is released and it’s not eliminated as fast and that induces all sorts of synaptic plasticity that eventually makes that drug-seeking behavior obligatory.”
More than ten years ago, researchers at pharmaceutical company GlaxoSmithKline reported that deleting a single glutaminergic receptor, mGluR5, made mice unresponsive to cocaine. This finding intrigued Paul Worley, a researcher at Johns Hopkins who studied the mGluR class of proteins in relation to immediate early genes, proteins critical to learning and development. “That’s how we got interested in addiction. The big question was how and why this receptor would be involved in cocaine addiction,” Worley says. “The standard thinking was always that you took cocaine, you release dopamine, and you activate D1 and D2 receptors, leading to addiction. There didn’t seem to be a role for this mGluR5 receptor—but you delete it and animals no longer showed responses to the drug.”
The idea that brain’s motivation and learning systems would have to sync up in some manner to lead to an addiction made sense, though, so for more than ten years, Worley and his colleagues searched for the missing molecular link between the two. In the August 1 issue of the journal Cell, the group elucidates the complex cross-talk and interplay between D1, mGluR5, and NMDA receptors, as well as other important proteins, which underlie synaptic plasticity after cocaine administration. By using multiple techniques, the group illustrated that cocaine activates D1, a dopamine receptor, which then activates a microtubule-associated protein kinase (MAPK), which then phosphorylates mGluR5. This phosphorylation activates mGluR5 but only when an immediate early gene protein, Homer1a, is present, which then sends an excitatory signal to an NMDA receptor, ultimately strengthening the signaling between cells and helping to foster the process of addiction.
“This study adds another degree of complexity to the whole study of our understanding of addiction and the role of mGluR5 and NMDA receptors, “says Karen Szumlinski, a neuroscientist at the University of California Santa Barbara. “The big take-home picture for me is that you have this intracellular signaling pathway that gets activated by all sorts of receptors, including mGluR5. It is really, really complicated.”
New avenues for treatment
Worley believes that this work can help identify new targets to treat cocaine addiction. “This receptor is very targetable. So it’s possible that we can utilize what we’ve learned about this pathway and find ways to reverse the adaptations that occur as a consequence of cocaine and, presumably, reverse certain aspects of addiction,” he says.
But not necessarily for all types of addiction. While Worley’s current study focused on cocaine addiction, mGluR5 has been previously linked to other addictions, including binge drinking. In 2009, Szumlinski and colleagues demonstrated that mGluR5 likely plays an important role in alcoholism—but in a manner opposite to that of cocaine addiction.
“When we look within the nucleus accumbens, where most folks study addiction because of its role in motivation, we see the drugs causing opposite changes,” she says. “So we see receptors like mGluR5 go down with cocaine in the nucleus accumbens. But with alcohol, intriguingly, we see them go up in the same area. Methamphetamine also makes mGluR5 go up. So here we have different drugs, with different mechanisms of action, but they increase dopamine, serotonin, and epinephrine. So we can’t make the generalization that a deficit in glutamate is what leads to addiction. There’s more to it than that.”
Yet Szumlinski also sees promise in targeting glutamate receptors for some future addiction treatments. “It doesn’t look like there’s going to be some magic glutamate bullet that can treat all addictions but I do believe there is a potential glutamate bullet for each addiction,” she says. “It’s just going to depend on the particular drug of abuse and how that drug impacts the glutamate system. Which means there’s still a lot of work we need to do so we can understand how each of these drugs works on this pathway, how these different receptors cross-talk, and where there may be opportunities to create compounds that my clinical colleagues could actually one day put into humans.”