’Promiscuous’ area of brain could explain role of antidepressants

A study at Baylor College of Medicine in Houston may lead to a better understanding of how antidepressants like Prozac work – and how to make them more effective.

According to results published in today’s issue of the journal Neuron, a study in mice proposes that dopamine and serotonin neurotransmitter systems in the brain occasionally get their signals crossed, causing delays in stabilizing mood. “This study provides a new site for drug discovery in one of the biggest market for drugs – those that treat symptoms of depression,” said Dr. John Dani, professor of neuroscience at BCM and lead author of the study.

Dani’s study, funded by the National Institutes of Health, offers an alternative explanation for the delayed effect of most antidepressants. “Some scientists thought that you had to take an antidepressant for weeks because as serotonin is elevated, some of its receptors had to turn off and become desensitized rather than be stimulated,” Dani said. “That didn’t make a lot of sense to us since desensitization is usually a rapid mechanism.”

Serotonin and dopamine neurotransmitter systems, which factor heavily in regulating mood, emotional balance, and psychosis, are released and reabsorbed in the striatum, an area of the brain which affects motivation and reward-based learning. Dani’s findings indicate that these systems may be less selective and more “promiscuous” than previously believed. “There has been a fundamental principal in neuroscience that a neuron releases one neurotransmitter,” said Dani. “We have come to realize that neurotransmitters aren’t the perfect 1-to-1signalers that we assumed – they’re a little promiscuous. That is, rather than transporting one neurotransmitter, these systems may transport other neurotransmitters as well.”

A better understanding of how antidepressants work would come as welcome news to those who suffer from depressive disorders, a leading cause of disability worldwide. Over 14 million adults experience depression each year in the United States alone. “Instead of taking serotonin up as they normally would into serotonin neurons, it is taken up into the terminals for dopamine so that now when your neurons fire to send a dopamine signal, they’re actually also sending a little bit of a serotonin signal,” Dani said. “This kind of interaction among neurotransmitter systems alters the timing of how these neurotransmitter systems act, and in that way, it certainly impacts how you process information.”

Depression is commonly treated with selective serotonin reuptake inhibitors (SSRIs) like Prozac to elevate and prolong the presence of the neurotransmitter serotonin in the brain. By blocking the uptake of serotonin after its initial release, conventional antidepressants provide the brain more serotonin for a longer period of time. An alternative approach suggested by this study is to develop antidepressant treatments that help serotonin enter dopamine terminals.