Pitt Neuroscientists Find Clues to Reward Paradox in the Brain

PITTSBURGH—Drug addiction researchers have long been puzzled by how the brain’s “reward” center encodes conditioned reward. That is, how a specific environment repeatedly paired with a drug of abuse can alone trigger an affective state, which often leads to relapse. A recent study led by University of Pittsburgh neuroscience researchers may have solved that puzzle.

Nicholas Graziane, a postdoctoral associate in the Translational Neuroscience Program at Pitt, along with his colleagues at Pitt, the Icahn School of Medicine at Mount Sinai, and the Centre for Brain Health at the University of British Columbia, found that withdrawal from cocaine or morphine increased the excitatory drive on one type of neurons (D1R MSNs) relative to another type of neurons (D2R MSNs) in the nucleus accumbens.

“The nucleus accumbens is a key hub for encoding reward and reward-related associations in the brain,” said Graziane. “The activation of the specific types of neurons in this brain region can dictate responses to reward; activation of D1R MSNs enhances reward, while activation of D2R MSNs inhibits reward.”

The authors discovered that preventing this shift in excitatory drive on D1R MSNs relative to D2R MSNs blocked the conditioned reward of morphine. Specifically, these studies in rodents found that the situation or location previously associated with morphine was no longer preferred compared to the neutral context.

“This shift in excitatory input is important because it may highlight a cellular mechanism whereby drugs become associated with places or situations,” said Graziane. “We found that at the cellular level in the accumbens, long-term withdrawal from either cocaine or morphine increased the excitatory input on D1R MSNs vs. D2R MSNs. In other words, a street corner or pub alone, in absence of the drug, is capable of eliciting the drug’s affective state, often leading to relapse.”

“Potentially, by blocking the D1R MSNs vs. D2R MSNs shift, we could prevent the affective-state produced by the drug-paired environmental stimuli in patients suffering from context-induced forms of relapse,” said Graziane. “With the knowledge from this paper, future addiction-related research can further test the importance of the shift in excitatory input on D1R MSNs vs. D2R MSNs,” Graziane said.

Still needed are tests to determine whether blocking the increase in D1R MSN to D2R MSN excitatory input in cocaine-treated animals would have the same effect. If so, that would mean that the D1R MSN/D2R MSN balance is a key mediator in the long-term retention of pathologically rewarding associations.

The study, “Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses,” was published online by Nature Neuroscience on May 30 and was funded by the National Institute on Drug Abuse and the Pennsylvania Department of Health.

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