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May 24, 2018
The ultimate solution to the opioid crisis is answering the question of what causes addiction and whether it is possible to treat it more effectively or even prevent it. That’s the challenge Elena H. Chartoff, PhD, is taking on in her laboratory.
As director of the Neurobiology of Motivated Behavior Laboratory at McLean Hospital, she is exploring the mechanisms that connect depression and anxiety with drug addiction. The work aims to help with understanding basic brain functions that control mood and motivated behavior.
“We’re trying to understand the opiate withdrawal syndrome,” she said. “After stopping opioid use, a withdrawal syndrome emerges, comprising physical and psychological signs. Although physical withdrawal signs subside in 48 to 72 hours, the psychological effects, including anxiety, dysphoria, and irritability, can last weeks or months and can be exacerbated by drug-associated stimuli. That’s what makes it so hard to quit.”
Chartoff and her team have been able to show that the nucleus accumbens (NAc), a key part of the brain’s reward circuitry, is an area necessary for psychological withdrawal from opioids. The reaction involves dopamine, a brain chemical that affects sensations of pleasure and emotional pain, and glutamate, a brain chemical necessary for basic neuron-to-neuron communication throughout the brain.
When portions of the NAc are excited, this can trigger depressive behavior. Receptors for dopamine and glutamate could be targets for treatment, which currently relies on methadone or buprenorphine, which are also opioids.
Working in conjunction with clinical research by R. Kathryn McHugh, PhD, a psychologist in the Substance Use Disorders Division, Chartoff’s lab is looking to “back-translate” in rats McHugh’s research efforts demonstrating the importance of distress intolerance (DI) to opioid misuse in humans, using techniques such as how long a person can hold their hand in ice water.
“The higher the DI score in someone with chronic pain using opioids, the higher the likelihood for abuse,” said Chartoff, whose team measures the response in rats to an acoustic startle, a quick sound that induces a reflexive movement.
“The more of a reaction, the more anxious the subject could be,” she explained. The rats are then implanted with an intravenous catheter and self-administer oxycodone by pressing a lever to allow drug delivery through the catheter. By measuring a rat’s DI level before drug use, Chartoff’s group has evidence that this can strongly predict how much oxycodone it will take.
The research focuses on glutamate receptors, which are important in how the brain works in many ways, including seizures. “They work to reduce excitability, and that could be an effective treatment,” similar to the impact of many anti-anxiety drugs that work by enhancing inhibition in the brain, said Chartoff.
The lab includes both females and males in their studies because there is striking evidence, both clinically and preclinically, for sex differences in every facet of the addiction cycle.
“We don’t know the particular influences of society, environment, and biology on addiction, which is why it’s important to use rodent models to tease out the biological contributions,” she said.