The first thing that scientists at the University of Pittsburgh in Pennsylvania did was to establish that synapses, or connections, in a circuit that links two particular brain areas get stronger with cocaine use.
The study, which is available in Cell Reports, explains that the circuit links the medial geniculate nucleus (MGN) in the thalamus, which processes sensory inputs, such as sounds, and the lateral amygdala (LA), which is important for reward and motivation.
This finding confirmed that strengthening the synapses in this MGN-LA circuit helps to form and reinforce memories that link the drug “highs” with environmental cues that accompany them.
The team then demonstrated how weakening MGN-LA circuit synapses erased the cocaine-cue memories and reduced relapse in rats. The animals showed much-reduced drug-seeking behavior on exposure to cues.
The researchers used two methods to erase the cocaine-cue memories. In the first, they used an exposure therapy approach. In the second, they weakened the synapses directly using optogenetics, a technology that uses light to change cell function.
Both methods disrupted the memories that the rats had formed between environmental cues, such as the sound of a bell, and the high of cocaine that ensued when they pressed a lever.
However, the method that weakened the synapses directly was more effective than exposure therapy at preventing relapse when cue exposure occurred in a different environment.
“While we’ve always known,” says senior study author Mary M. Torregrossa Ph.D., who is an associate professor of psychiatry, “that the brain forms these cue-associated memories, the specific circuits have never been clearly identified.”
Cocaine and addiction therapy
Cocaine is a “powerfully addictive stimulant” and a common drug of abuse. It takes its name from the coca plant which is native to South America and whose leaves contain the active substance.
The 2014 National Survey on Drug Use and Health found that around 913,000 people in the U.S. met clinical diagnostic criteria for abuse of or dependence on cocaine.
The basis of exposure therapy, which is a common strategy in the treatment of addiction, phobia, and post-traumatic stress disorder, is to cut the link between environmental cues and memories. In the case of addiction, the memories relate to drug use and the highs that it brings.
However, although the strategy appears sound, exposure therapy is not very effective as a treatment for addiction. Experts suggest that the reason is to do with the “context” of the cues.
The risk of relapse is low while treatment takes place in a controlled environment, such as the therapy clinic. However, once the person goes into a different environment and experiences cues in that context, the chance of relapse is much higher.
Setting up the experiments
Torregrossa and her team used an animal model of “cue-associated relapse.” They placed rats in a controlled environment that gave them an infusion of cocaine whenever the animals pressed a lever.
Receipt of the cocaine dose also coincided with two other stimuli: the ringing of a bell and the shining of a light.
After many repetitions, the rats learned to associate the bell and light with the highs that accompanied the ingestion of cocaine.
Exposure to the cues triggered drug-seeking behavior — that is the repeated use of the lever to get the drug.
The researchers then deployed a strategy similar to exposure therapy.
They repeatedly exposed the rats to the cues — they rang the bell and shone the light— but when the rats pressed the lever, there was no cocaine in the infusion.
Eventually, the rats stopped pressing the lever in response to the cues.
As with humans, though, the exposure therapy was less effective when the rats were in a different environment. There was little significant reduction in lever pressing.
Targeting synapses prevented relapse
In a separate group of rats that developed cocaine addiction, the team took a different approach. Instead of exposure therapy, they weakened the animals’ MGN-LA circuit synapses with optogenetics.
This led to much less lever pressing compared to the exposure therapy rats.
In addition, the reduction in drug-seeking behavior persisted even when the animals were in a different environment.
The synapse-weakening treatment had effectively wiped out the animals’ “cocaine-cue memories.”
“In the long-term, these findings may help us develop drugs or approaches like deep brain stimulation to specifically target these memories strengthened by substance use and improve the success of exposure therapy to prevent relapse.”
Mary M. Torregrossa Ph.D.
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