Research shows sugar and cocaine provoke responses from different groups of neurons

The brain is keenly attuned to rewards in the natural environment, forming neural ensembles that light up when cued to think about food, sugar or other necessities for survival. But that same process can take a dark turn when the brain learns to recognize and then seek out illicit drugs like cocaine.

A team at the Medical University of South Carolina has shown that it isn’t the same neural ensemble indiscriminately responding to either cocaine or sucrose but that different ensembles develop to respond to each of those potential rewards. And those ensembles not only light up when directly presented with the reward, but they also light up when presented with a cue that’s become associated with the reward.

“The fact that they are different networks is actually very encouraging, because it means you could specifically try to diminish the network that responds to cocaine without diminishing the network that responds to food or other natural rewards.”

Ana Clara Bobadilla, Ph.D.

Ana Clara Bobadilla, Ph.D., now an assistant professor at the University of Wyoming, conducted the research while completing her postdoctoral work in the lab of Peter Kalivas, Ph.D., Distinguished University Professor at MUSC. It was published in Molecular Psychiatry in September. She said the experiment points the way to new questions, like how specific cells are recruited into networks that respond to sucrose or to cocaine.

“If we can understand that, then we can also try to find a mechanism to prevent a cell from being recruited. So if you think about it in the long term, you could make the response to cocaine less strong because you make the network less strong,” she said.

“The fact that they are different networks is actually very encouraging,” she continued, “because it means you could specifically try to diminish the network that responds to cocaine without diminishing the network that responds to food or other natural rewards, which are very important for survival.”

Kalivas said Bobadilla’s experiment was a “technological leap,” because it looked at the two ensembles within the same animal, so she can directly compare the strength of each response and how the ensembles change when the animal competes for the natural reward cue and drug cue. In the lab, a cue for the drug or the sucrose would be a distinct tone and light.

“She’s positioned to really take a good look at the two ensembles in the same animal, which has never really been done before. And she coupled it with a model that’s been kicking around a little bit, where you give sucrose and a drug to the same animal, but she really refined that as well,” he said.

Dots of red and green fill the screen. Some of the red dots clump together and some of the green dots clump together, but the reds form bigger clumps
Medium spiny neuron in the nucleus accumbens core expressing the fluorescent proteins TdTomato (red) and Green Fluorescent Protein (GFP, green). The cells included in the cocaine ensemble are tagged in red, and the sucrose ensemble cells in green. The yellow signal indicates an overlap between TdTomato and GFP (red and green), which is interpreted as a neuron recruited in both the cocaine- and sucrose-seeking ensembles. Image provided

To extrapolate to human behavior, Kalivas said, a cue might look like a person fielding two phone calls at once – one from the spouse, urging the person to come home to his or her family, and one from a drug-using buddy, urging the person to come hang out. Each call is acting as a cue to a particular reward. Addiction researchers know from years of study that cocaine and other addictive drugs produce changes in cells that the same amount of sucrose doesn’t produce, and this drug-induced pathology means the strength of the cocaine cue becomes stronger than the natural reward cue at motivating behavior.

But no one really knows how an individual neuron ends up in a sucrose ensemble or a cocaine ensemble or if that individual neuron always remains in the same ensemble, Kalivas said. Bobadilla has developed the technology and protocols and is well-positioned to tag the ensembles over time and answer these questions, he said.

“It’s right on the ground floor of understanding this very important concept about how the brain works, which is ‘How do codes of information get held by neurons?'” he said.

“We might be able to determine what makes the cocaine ensemble so powerful in driving behavior, in competition with a sucrose ensemble,” he said.

Bobadilla said she’d also like to compare two illicit drugs – for example, cocaine and heroin. Despite sharing high probabilities of relapse, the two drugs display very different pharmacology.

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