Among the mysterious aspects of selective serotonin reuptake inhibitors, the newest class of antidepressants, is that they take hours to achieve their cellular effect - increased brain levels of serotonin - but days to weeks to make patients feel better.

In the April 7, 2005, issue of Neuron, researchers from the Baylor College of Medicine in Houston reported results that could explain the reason for the antidepressants' delayed effects. They also provided evidence that the whole concept of a "dopaminergic" neuron might be overly simplistic.

"Over the years, the idea that one neuron has one transmitter has been broken down, by a number of groups, including ours," senior author John Dani told BioWorld Today. "And this paper breaks it down even further."

Given their name, it should be no surprise that selective serotonin reuptake inhibitors affect serotonin. However, in their Neuron paper, Dani, who is a professor at the Baylor College, and his colleagues showed that administration of SSRIs ultimately affects dopamine neurons, causing them to take up serotonin and co-release it with the dopamine that is their signaling mainstay.

The researchers studied brain slices of the striatum, a midbrain with rich dopaminergic and serotonergic innervation. The striatum is involved in motor and cognitive functions, including both habit- and reward-based learning, though Dani pointed out that "in principle, [the observed effects] could go on anywhere in the brain where you can elevate serotonin enough to make it visible to dopamine transporters."

Serotonin and dopamine are chemical cousins; both belong to the monoamine family of neurotransmitters, which also includes epinephrine and norepinephrine. Neurotransmitters are recycled from the synapse back into the presynaptic neuron after use and each of the transmitters has their own uptake mechanism.

"We think of these transporters as perfectly selective, but it turns out that they are probably built to be a little bit promiscuous," Dani said. "When you use selective serotonin reuptake inhibitors, by increasing the relative level of serotonin to dopamine, you are selecting for a situation where dopamine transporters can take up serotonin."

They first used staining to see whether serotonin and tyrosine hydroxylase, a key enzyme for synthesizing dopamine, existed in the same synapses. Whereas both substances were very rarely detected in the same synapses under normal conditions, after the addition of serotonin to the slice culture, a majority of tyrosine/hydroxylase-containing synapses also had serotonin in them. Inhibiting dopamine uptake terminals prevented the co-accumulation, suggesting that serotonin was hitching a ride on the cellular machinery for dopamine uptake.

The scientists next checked whether the serotonin that was taken up by the dopamine neurons was released back into the synapse when those cells were subsequently electrically active.

They measured the transmitter release by dopamine neurons in response to stimulation. While dopamine neurons normally released next to no serotonin, they released both dopamine and serotonin when slices were pretreated with serotonin to allow for its uptake. While electrical stimulation will activate a number of neurons, making it possible that the serotonin and dopamine the scientists observed came from different cells, spontaneous activity of single neurons showed the same co-release of the two transmitters.

Dani and his colleagues also conducted in vivo experiments, administering Prozac to mice either alone or in combination with dopamine transporter inhibitors. Chromatography experiments showed that antidepressants elevated serotonin levels in the brain, and that co-treatment with dopamine uptake inhibitors partially reversed that effect, again suggesting that serotonin is snapped up by dopamine neurons when it is elevated after antidepressant treatment.

Dani cautioned that "from our work, we don't know that this is the mechanism for antidepressant action. Though we can say with great confidence that this is what's happening in the cells, we can't say that's why antidepressants work." His own laboratory, as well as others, is working on this next step, and "if we or others show that this is how antidepressants work, drug companies will have a new target - producing a drug that puts serotonin into dopamine neurons. And the market for antidepressants is such that it will certainly be interesting to them."