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“Relapse is a part of recovery”: That’s a common refrain among professionals who treat substance use disorders. Many people who have completed treatment programs return to substance use and reenter treatment multiple times, after days, weeks or even years of sobriety.
Marina Wolf, a behavioral neuroscientist at the Oregon Health & Science University, studies how cells in the brain respond to drug exposure in ways that can lead people to develop powerful cravings even months after they stop using drugs such as cocaine, opioids or alcohol. Specifically, she has focused on an aspect of this problem called cue-induced craving, in which people’s brains come to associate a cue — such as seeing a certain location where they previously used drugs — with the desire to use that drug. These learned associations, as she described in the 2025 Annual Review of Pharmacology and Toxicology, are caused by structural changes to the brain — neuroplasticity — as a result of drug use, including the strengthening of connections, called synapses, between specific nerve cells.
These changes don’t disappear as soon as a person, or animal, stops using a drug. Cravings, in fact, can strengthen after abstinence, leaving a person vulnerable to resume using.
Wolf talked with Knowable Magazine about drug-induced neuroplasticity and its implications for treatment. This conversation has been edited for length and clarity.
How did you become interested in neuroplasticity and addiction?
I never had any formal training in synaptic plasticity or addiction. As a graduate student and then a postdoctoral fellow, I worked on how neurons are regulated by the neurotransmitter dopamine, but we studied dopamine’s role in antipsychotic drug effects, not addiction. But when I was setting up my own lab in the early 1990s, I had a friend from graduate school who was involved in groundbreaking studies to work out synaptic plasticity mechanisms in the brain’s hippocampus, a region of the brain responsible for encoding memories. This was fascinating work that helped demonstrate a critical role for a neurotransmitter called glutamate in synaptic plasticity, so I followed it closely.
At the same time, I was in a department where there were a lot of people who were using animal models of addiction. Most addiction work at that time focused on dopamine, which everyone’s probably heard of as the neurotransmitter associated with reward and addiction.
But I thought that dopamine adaptations alone were unlikely to be sufficient to lead to addiction and that there had to be an important role for glutamate and synaptic plasticity. The brain is obviously changing during addiction — people sometimes describe that as maladaptive learning — and synaptic plasticity is the way that experience changes the brain.
And there are glutamate synapses throughout the circuits that connect different brain regions that are important for addiction.
So I started doing experiments to test the role of glutamate in a super-simple rat model of addiction called behavioral sensitization. I was very excited when we got positive results, so I just kept going with this line of work, incorporating better and better animal models and more sophisticated techniques as time went on.