In rats, disrupting memories associated with substance abuse use reduces drug seeking behaviors, thereby opening a potential avenue for developing more effective therapies to prevent relapse, found new research from the University of Pittsburgh School of Medicine. Forty to 60 percent of all people treated for substance use disorders relapse, presenting a major challenge to treatment success.
Since Pavlov discovered classical conditioning in dogs in the 1890s, it has long been recognized that the brain associates specific cues with behaviors, like the smell of freshly brewed coffee making you want to drink a cup, or the sight of a snake inducing a heightened fear response. Breaking the links between cues and memories is a well-known strategy in treating phobias, addiction and PTSD.
But this method - commonly known as 'exposure therapy' - is not very effective at treating addiction. The reason? Context matters. While exposure therapy might have some effect in a controlled setting such as a doctor's or therapist's office, the moment a person suffering from addiction is faced with the cue in the outside world, the brain fires off the same neurons connected to drug-seeking behavior.
In the study, the scientists used a rat model of cue-associated relapse. When rats pressed a lever, they received an infusion of cocaine, accompanied by a tone and a light. With training, the rats learned to associate the audiovisual cue with the cocaine high, and exhibited drug-seeking behavior analogous to craving, repeatedly pressing the lever.
The researchers also simulated exposure therapy in the rats, showing that repeatedly playing the tone and light without providing the cocaine infusion eventually reduced drug-seeking behavior. But much like in humans, exposure therapy in the rats did not work well if they were placed in a different environment.
Using electrical recordings from rat brain tissue, Torregrossa and her team first showed that connections between the medial geniculate nucleus - the brain's switchboard for sound - and the lateral amygdala are important for forming memories that associate the cocaine high with external cues.
"It made sense to us because the amygdala is where emotional memories are formed," said Matthew Rich, a graduate student in Torregrossa's lab and the first author of the study. "It receives sensory input and associates that input with what we feel when the cues are presented to us."
To show a causal connection between these cue-associated memories and drug-seeking behavior, the researchers used a technique known as optogenetics, where light pulses are used to control genetically modified cells, to control the neurons from the previous experiment. Rats that had the cocaine-cue memories optogenetically erased pressed the lever significantly fewer times when the light and tone cue were played.
Importantly, the reduced relapse behavior persisted even when the rats were placed in a different environment, suggesting that eliminating cue-associated memories overcomes the relapse-inducing effects of a new environment.