Where cocaine memories aren’t made

Researchers thought they had a good grasp on how and where in the brain powerful addiction-driving memories form, but a new study shows that the process is much more complicated than expected.

People with addictions carry memories of their encounters with a drug that are powerful enough to compel them to seek out the drug repeatedly, even when they know it is harmful. A new paper published in the EMBO Journal offers insight into the neural pathways involved with addiction and reward memories, contributing information that may guide the development of new treatment programs.

Oliver Schlüter, a neuroscientist at the University of Pittsburg, and his colleagues began their study by focusing on the nucleus accumbens—a brain region in each hemisphere that sits behind the eyebrows near the middle of the brain—because it plays a critical role in the reward circuit of the brain and therefore addiction.

Previous studies in animals have shown that when exposed to cocaine, nerve cells in the nucleus accumbens grow silent synapses—connections between neurons that don’t transmit electrochemical signals but serve as new opportunities for rewiring neural circuits. After withdrawal from the drug, the synapses mature by recruiting neurotransmitter receptors called calcium‐permeable AMPA‐type glutamate receptors (CP‐AMPARs). With these receptors, the synapses are no longer silent, and they start to transmit electrochemical messages among nerve cells.

This remodeling of neural circuits in the nucleus accumbens (NAc) is critical for many drug‐induced behaviors. However, whether the remodeled connections played a role in storing memories associated with cocaine use, such as where it was taken, was unclear.

To test the link, Schlüter and his colleagues injected mice with cocaine and put them in a specific compartment of a test box, repeating the process over several days . Then the researchers stopped giving the mice the injections to simulate withdrawal. When placed in the test box, the mice preferred the compartment they associated with receiving the drug.

Examination of brain tissue from these mice showed that silent synapses had formed in the nucleus accumbens and that the synapses had strengthened during withdrawal by recruiting CP‐AMPARs.

Next, the team studied certain proteins that play a role in the maturation of the silent synapses through CP‐AMPAR recruitment. Mice that couldn’t make these receptors still remembered, and preferred, the side of the test box they associated with getting high. This observation suggests that recruiting CP‐AMPARs into silent synapses in the NAc is not needed to make memories of the spot associated with the feelings of getting high.

“At first, the result was surprising,” Schlüter said. “That means the memory of where a drug is experienced must be created somewhere else.”

The team now plans to pinpoint where these memories are made and stored and to continue to study the NAc to improve our understanding of addiction.