SSRIs perform their antidepressant function by increasing the concentration of serotonin in the signaling junctions, called synapses, between neurons. This increase alleviates the deficiency of serotonin that causes depression.
As their name indicates, SSRIs prevent uptake of the serotonin after it has performed its task as a chemical messenger that enables one neuron to trigger a nerve impulse in a neighbor. SSRIs prevent this uptake by inhibiting the action of the molecular cargo carriers called transporters that recycle serotonin back to the neuronal storage sacs called vesicles.
Now, however, Fu-Ming Zhou (presently at the University of Tennessee) and colleagues at Baylor College of Medicine have revealed that SSRIs can have more complex effects on neurotransmitter traffic in the brain than just altering serotonin levels. They found that higher serotonin concentrations caused by SSRIs can "trick" transporters of another key neurotransmitter, dopamine, into retrieving serotonin into dopamine vesicles. Dopamine transporters have a low affinity for serotonin, but the higher serotonin levels result in its uptake by the dopamine transporters, found the scientists.
As a result, the normal dopamine-triggered firing from such neurons, in essence, launches two different types of neuronal ammunition, causing "cosignaling."
The researchers were led to study the role of dopamine signaling in SSRI action by previous evidence that dopamine was involved in depression and in the function of antidepressants in the brain. They studied the nature and machinery of serotonin and dopamine signaling by treating mouse brain slices with fluoxetine (Prozac) and other chemicals, and analyzing the effects on the dopamine-signaling machinery.
The relatively inefficient, slow process of "hijacking" of dopamine transporters by serotonin during SSRI treatment could explain why it takes many days of treatment before antianxiety effects are seen, suggested the researchers.
Also, they wrote that their findings may explain why treatment of children with fluoxetine can induce depressive symptoms in adulthood. The researchers wrote that, since serotonin plays a vital role in neuronal development, disruption by fluoxetine of the normal serotonin levels during development could be responsible for such behavioral abnormalities.
They also theorized that such corelease of dopamine and serotonin caused by SSRIs could explain cases of a "potentially life-threatening serotonin syndrome" caused by such situations as dietary overload of serotonin precursors in people taking SSRIs.
The researchers wrote that the relationship between dopamine and serotonin signaling "is likely vital for normal behavior and for the pathology that can be treated with SSRIs." The brain area involved, the ventral striatum, "is critically involved in the neuronal processes of reward and emotional functions." Thus, they wrote, enhanced participation of the striatal dopamine system in serotonin signaling during treatment with SSRIs "may contribute to the therapeutic efficacy of SSRIs."
Fu-Ming Zhou, Yong Liang, Ramiro Salas, Lifen Zhang, Mariella De Biasi, and John A. Dani: "Corelease of Dopamine and Serotonin from Striatal Dopamine Terminals"
Publishing in Neuron, Volume 46, Number 1, April 7, 2005, pages 65–74. http://www.neuron.org
The researchers include Fu-Ming Zhou of Baylor College of Medicine (presently at the University of Tennessee) and Yong Liang, Ramiro Salas, Lifen Zhang, Mariella De Biasi, and John A. Dani of Baylor College of Medicine. This work was supported by the National Institute on Drug Abuse, the National Institute of Neurological Disorders and Stroke, and grants from the National Alliance for Research on Schizophrenia and Depression (FMZ) and from the National Institutes of Health. John A. Dani consults for In Silico Biosciences to support drug discovery and analysis.
Journal
Neuron