In preparation for his optogenetic experiment, Lüscher placed the mice on the track, timed their runs, fed them cocaine and put them back on the track. He then took slices of each mouse’s brain and measured whether it led to an increase in the amount of electricity passing between neurons in the accumbens and the prefrontal cortex. The increase in electricity — and thus the presumed sensitivity of the mouse to cocaine — lined up perfectly with the rate at which the mice ran around the track.
When Lüscher and his team repeated the experiment, they followed up the cocaine with optogenetics. They drilled tiny holes in the mouse skulls and inserted light fibers through the brain tissue until they reached the NAc, where the neurons had been genetically modified to contain light-sensitive, gated proteins. Then Lüscher and his team shined a blue light through light fibers, selectively stimulating some of the neurons. The stimulated neurons fired, releasing glutamate. But the low frequency of the firing and the amount of glutamate released wasn’t enough to cause the neighboring neurons to fire.
In other words, Lüscher’s protocol created the conditions that caused the neurons to fire apart, which made them wire apart. Doing so, he hoped, would result in a disappearance of AMPA receptors from the surface, weakening the connections.
The results were clear. When they placed the mice back in the maze and gave them cocaine, they responded as if it was a first-time injection. The addiction sensitization had disappeared.
Lüscher’s work, published in 2011 in Nature, implied for the first time that optogenetics could be used to reverse LTP, allowing researchers to manually erase learned behaviors. In a 2014 paper, Lüscher’s team demonstrated that mice taught to self-administer cocaine over a longer time period also responded. Not only did this protocol lead to the removal of the defective AMPA receptors, but when AMPA receptors returned, they were normal again.
Although there were still likely plenty of abnormalities present in his treated mice, Lüscher’s 2011 optogenetics paper was among the first indicating we may be approaching a cure, or at least an age of powerful new interventions for addiction. In 2014, Wolf and her colleagues published work in rats suggesting that relapse in cocaine addicts also could be prevented by administering a non-toxic experimental compound that leads to the removal of the calcium-permeable AMPA receptors for about a day, thus reducing the ability of cocaine-related cues to trigger powerful craving that can lead to relapse.
“These compounds would not cure addiction. They would be something a recovering addict could take to maintain abstinence prior to entering a situation full of cues that might trigger relapse,” Wolf says. “But right now, there are just no treatments for cocaine addicts, so even just a day of protection would be of great help.”
Since optogenetics is considered far too invasive for humans, Wolf’s technique had a clear advantage over Lüscher’s. But Wolf’s approach also had a downside: The injected drug traveled all over the brain, unlike Lüscher’s localized optogenetic approach, which Lüscher believes also could lead to long-lasting changes.
Lüscher knows it will likely be many years before optogenetics is modified so it could be used in humans. Instead, he is focused on mastering DBS, which uses electrodes to stimulate groups of neurons rather than individual brain cells. Although some researchers have attempted to use DBS on addicts in various parts of the brain and say they have promising anecdotal results, no large-scale studies have been conducted, Lüscher says. And none of these experimenters has done so with the intent of reversing the synaptic changes brought on by the use of cocaine or other drugs of addiction.
Researchers still aren’t sure precisely why DBS works in Parkinson’s patients. The strong burst of electrical activity somehow immobilizes the neurons that cause tremors. And this is the same protocol that others have tried to apply to different parts of the brain to treat addiction.
Lüscher’s approach is fundamentally different. He radically slows down the pace of the electrical stimulation of brain cells to match the rhythm of activations that he used to reverse addiction with optogenetics. Rather than tiring out neurons to temporarily immobilize them, as is done with Parkinson’s, Lüscher is using DBS to remodel the connections between neurons because “cells that fire out of sync, lose their link.”
DBS is far less precise than optogenetics, and the electrical field its electrodes create is larger and stimulates many more neurons than necessary. But Lüscher has discovered that if he administers a drug that temporarily blocks neurons from binding with dopamine, and then administers DBS, he is able to replicate his findings with optogenetics in mice.
“The two together still are not exactly the same as optogenetics, but it does the job,” Lüscher says of DBS and the drug. “So it’s a very pragmatic approach to try to translate and emulate what we have been successfully doing with optogenetics.”
“It’s a still long shot to go from optogenetics in mice to doing this on humans,” Lüscher said as he sat in his lab one morning. “I am not sure if that will happen in my lifetime [as a scientist]. But DBS is an intermediate step. I am optimistic.”