All of us have memories that we can recall quickly if we encounter the right cue. A sea gull reminds us of the beach. A piece of chalk triggers memories of a first-grade room. But, what if the cues we encounter trigger memories so powerful that they cause us to crave a drug. Drug-associated memories are perhaps the greatest obstacle to breaking the cycle of addiction, according to Mary Torregrossa, Ph.D., assistant professor of neuroscience at the University of Pittsburgh. Torregrossa has spent the bulk of her career trying to define the biological basis of strategies to interfere with addictive behaviors. Her promising work is informing the research community about behavioral therapies and new drugs that could combat addiction seen with cocaine, cannabis, alcohol and other highly addictive substances.

Early in her career while a research professor at Yale University, she established a novel treatment for addiction in animals. She based her work on cue exposure therapy. In humans, cue exposure therapy might involve handling drug paraphernalia without taking a drug. The idea is that if you present a cue familiar with drug taking but without the drug, you build a new memory, one which essentially foils the brain’s ability to connect that cue with drug use.  Called an extinction memory, this new memory interferes with recall of old memories linking an addictive substance to a pleasurable experience. But the problem with extinction memories is that they are highly dependent on setting. Providing cue extinction therapy to a drug addict in a clinic may work, but in the real world, the sight of a syringe might trigger an addict who received that therapy to quickly return to IV drug abuse.

In what would become high impact work in her field, Torregrossa made a major finding suggesting that it’s possible to create a protective extinction memory that transfers from a clinical setting to a drug-taking context typically encountered by addicts. She worked with rats, training them to associate a light and sound cue with the availability of cocaine. Each time the animal self-administered the drug by pressing a lever, essentially taking a hit of the drug, the same light and tone were produced. Torregrossa then took these animals and put them in a new setting where she exposed the same animals to the light and sound cues but didn’t provide cocaine when the addicted animals pushed a lever. This amounted to a setting that one would find in a drug clinic. After presenting the cues a number of times, the rats learned that they weren’t associated with any cocaine availability. The rats no longer pushed the lever when they were exposed to the light and noise cue. Thus, this new experience produced an extinction memory. But Torregrossa wanted to see if she could prevent these animals from relapsing if they moved back into the old, drug-administering context. Before moving them, she injected part of their brains with the drug, D-cycloserine, which has had success in patients seeking to overcome phobias. She found that D-cycloserine helped preserve the extinction memory in rats. When they returned to their old cage, or drug-addiction setting, the audio and visual (AV) cues no longer led them to seek cocaine.

Torregrossa’s findings constituted a major milestone. However, successful memory extinction is only part of the solution, she notes. Each of us has the capability of reconsolidating memories, too. That is, every time we recall a memory, we take it out of long-term storage and chemically process it. Memory reconsolidation has important functions. Think of studying for a test, for example. Repeatedly opening a text book and re-reading material serves to reprocess memories and more strongly consolidate them. Each time you review the same material, you recall what you’ve seen, reprocess it, and store it for later retrieval. But in the case of a drug experience, an addict reprocesses the memory of experiencing a drug’s effects, and the memory of pleasurable drug experience is re-enforced. Reconsolidating essentially repackages and strengthens that drug-related memory. Ironically, medications like D-cycloserine, which boosts memory extinction, can also strengthen – rather than disrupt – memory reconsolidation. And D-cycloserine isn’t alone. Until recently, it looked like most other therapeutic agents and behavioral interventions which solved one of the problems – disrupting memory reconsolidation or promoting memory extinction – counteracted the other process. But recently (J. Neuroscience, 2016), Torregrossa reported results of a clever study that pointed to a cell event that might address both successfully, together. She examined neuronal proteins that are phosphorylated. Adding a phosphate group to a protein is a classic way that cells regulate the production of memories. What Torregrossa wanted was to find a phosphorylation event that both improved extinction but also prevented memory reconsolidation. As with earlier experiments, Torregrossa trained rats to self-administer cocaine in the presence of AV cues, and then divided them into three groups. One group of rats received multiple AV cues without the drug, thereby inducing memory extinction. In a second group of animals received a few instances of the AV cues – enough to activate memory reconsolidation but not enough to trigger extinction. A third, control group of animals received no cues.

Torregrossa then looked at these cell regulatory events in the region of the brain affected by addiction – the amygdala – using a mass spectrometry-based technology called phosphoproteomics. One protein – calcium calmodulin-dependent kinase II alpha (CaMKIIα) – stood out.  Long-known to regulate learning and memory, CaMKIIα appeared to be a perfect target for curbing addictive behavior. Torregrossa infused an inhibitor to CaMKIIα in the brains of addicted rats and found that the inhibitor could promote extinction but also inhibit memory reconsolidation. The combined enhancement of the two processes – extinction and disruption of reconsolidation – could provide a powerful, single medicine that treats addiction, according to Torregrossa. She is now pursuing additional studies to understand the activity of this promising molecule and its potential to modulate cocaine-associated memories.

Educated with bachelor of science degrees in biochemistry and psychology from the University of Maryland, Torregrossa went on to receive her doctorate in neuroscience from the University of Michigan. After completing post-graduate appointments at the Medical University of South Carolina and Yale University, she came to the University of Pittsburgh, where since 2012 she has held a faculty appointment in the department of psychiatry.  Her many honors include a Howard Hughes Undergraduate Research Fellowship, the Ruth L. Kirchstein National Research Service Award, and a NIDA-NIAA Early Career Investigator Showcase Award. Torregrossa is a member of the Society for Neuroscience and the Research Society of Alcoholism. She holds several NIH grants, and is a reviewer for more than a dozen journals.

Treating Addiction Pharmaceutically

The image below shows the importance of audiovisual (AV) cues and extinction training in a rat model of cocaine addiction. Rats that receive extinction training (far right blue bar) show half the tendency to press a lever for cocaine as those cocaine-seeking rats trained with AV cues (tall red bar). The second panel points out that inhibiting CaMKIIα has the best chance of both increasing extinction and reducing reconsolidation. Panel three shows CaMKIIα being injected into the amygdala. Panel four shows that the results of these injections are an overall reduction in drug seeking behavior, because the injection can both enhance the strength of an extinction memory and disrupt >reconsolidation -- and strengthening -- of the original memory tied to drug seeking.

While these injections showed promise in treating animals, the same kinds of injections would be impractical in humans, according to Torregrossa. CaMKIIα is widespread in the brain, so using a pill to block its effect would not work either. One way to block the effects of CAMKIIα in specific regions of addicted individuals might be to target brain regions with low-frequency transcranial magnetic stimulation (TMS). This could be achieved using a cap externally placed on the head. Such TMS could target the same memory pathway in places like the amygdala that were affected by inhibition of CaMKIIα, relieving addiction while preventing widespread damage to other important brain regions.

The amygdala, which oversees responses needed for survival, is a system not under conscious control, says Torregrossa, so targeting this area is working from the "bottom up," essentially. One could work from the "top down," too, by making the brain consciously do activities that disrupt addiction. In fact, according to Torregrossa, playing complicated puzzles strengthens such "top down," conscious control and reduces addictive cravings - even in rats! Combining "bottom up" and "top down" treatments may yield effective approaches to curbing addiction in the future, she adds.