New insights into dopamine release could mean better weapons against addiction

Neurons were previously thought to transfer dopamine to each other slowly and across large areas of the brain. New research shows that it is a much faster, more specific process. (Colin Behrens)

Dopamine, the “feel-good” chemical, is known to play a role in addiction, but until now, there has only been limited research into how it is released in the healthy brain. A team from Harvard Medical School has pinpointed how neurons secrete the neurotransmitter, which could inform better, more targeted treatments for addiction.

They homed in on dopamine-producing neurons in the midbrain, looking for active zones, or specialized sites at synapses where neurotransmitters are released. Marked by specific proteins, these active zones suggest that a neuron may transfer a neurotransmitter to another neuron within milliseconds—an idea that runs counter to current understanding.

"I think that our findings will change how we think about dopamine," said senior author Pascal Kaeser, an assistant professor of neurobiology at Harvard Medical School, in a statement. "Our data suggest that dopamine is released in very specific locations, with incredible spatial precision and speed, whereas before it was thought that dopamine was slowly and promiscuously secreted."

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The team also found that removing the active zone protein RIM, which is linked to certain brain disorders, nearly halted all dopamine release in mice. But this doesn’t hold for all proteins. Deleting the protein ELKS, for example, had “little to no effect” on dopamine secretion.

"We showed that active zones and RIM, which is associated with diseases such as schizophrenia and autism spectrum disorders in human genetic studies, are key for dopamine signaling," said Changlian Liu, first author and a fellow in Kaeser’s lab. "These newly identified mechanisms may be related to these disorders and may lead to new therapeutic strategies in the future."

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Other approaches to quelling addiction include an anti-opioid vaccine that produces antibodies to prevent opioids from crossing the blood-brain barrier, thus blocking their euphoric effects and helping people overcome addiction. And making opioids themselves more selective—i.e. designing drugs that bind to one opioid receptor rather than several—could ward off side effects of using the painkillers, such as nausea, dependence and overdose.

The Harvard scientists hope that improved understanding of dopamine production and how this might go awry in brain disorders will lead to improved addiction treatments for use in the opioid epidemic, as well as for other brain disorders.

“Right now, most treatments supply the brain with dopamine in excess, which comes with many side effects because it activates processes that shouldn't be active," Kaeser said. "Our long-term hope is to identify proteins that only mediate dopamine secretion. One can imagine that by manipulating the release of dopamine, we may be better able to reconstruct normal signaling in the brain."