Brain circuit implicated in cocaine relapse
Thursday, May 16, 2019
An estimated 1.5 million people over the age of 12 abuse cocaine each month in the United States, which accounts for 0.6% of the population. More than 5% of school students report using cocaine during their years in high school.
Repeated use of cocaine rewires the brain and changes the brain’s reward circuitry, which leads to dependence and addiction. Behavioral therapy is the only treatment option for patients with cocaine addiction.
An initial, short-term effect — a buildup of the neurochemical dopamine — leads to euphoria and a desire to take the drug again. Researchers are seeking to understand how cocaine’s many longer-term effects produce the persistent cravings and risk of relapse.
Since scientists have identified the specific brain mechanisms that underlie the cocaine high, neurobiologists have focused on the follow-up questions: How does repeated cocaine exposure make individuals compulsively continue to take the drug even when they know it may cost them their jobs, loved ones, freedom, and maybe their lives? Why do people find it so difficult, often impossible, to quit the drug, and why do they remain vulnerable to relapse after years of abstinence?
Researcher Peter W. Kalivas, Ph.D., a university professor and chair of the Department of Neuroscience at the Medical University of South Carolina (MUSC), and colleagues have identified a type of neuron that is critical for cocaine-seeking behaviors in rodents.
These neurons, dopamine D1 receptor-expressing medium spiny projection neurons (D1-MSNs), are located in the reward system, the nucleus accumbens. The team also discovered that these neurons drive drug seeking through their projections to a specific part of the brain, the ventral pallidum (VP).
D1-MSNs co-exist in the nucleus accumbens alongside another cell-type, the D2-MSNs. Both cells play a critical role in the brain system that regulates goal-directed behavior such as getting high. D1-MSNs activity could reinforce behaviors that would lead to drug relapse, while D2-MSNs instead may help avert these behaviors.
According toJasper Heinsbroek, Ph.D., a postdoctoral scholar at MUSC working with Kalivas, increased activity of D1-MSNs after drug use leads to higher motivation to seek drugs. Exposure to drugs reduces the capacity of D2-MSNs to limit excessive motivation. This can lead to a strong drive to seek drugs over natural rewards such as food and shelter in the presence of drug cues.
To investigate how D1-MSNs drive the motivation to seek drugs, the MUSC team traced the connections of these neurons. They showed that individual neurons project to both the VP and another major area that regulates motivation, the ventral mesencephalon (VM).
To help identify whether the VP or VM projection is responsible for cocaine-seeking behavior, the researchers used a transgenic rat model, which allowed the them to inhibit the activity of D1-MSNs and their projections to the VP versus the VM.
The researchers found that cocaine seeking continued to exist when the VM projections were inhibited. However, inhibiting projections to the VP strongly diminished the motivation to seek cocaine.
These findings — discovering a circuit that is critical for relapse and identifying a specific target that could be modified — suggest the possibility of a new avenue of research and a cure for cocaine addiction.
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