MIT researchers reported in the November 23 issue of Nature that they have discovered a new type of receptor that responds to serotonin. This finding could help explain how drugs such as Prozac, which manipulate levels of serotonin signaling, bring about their therapeutic effects.
The article was co-authored by Professor H. Robert Horvitz of the Department of Biology and the Howard Hughes Medical Institute, biology graduate student Rajesh Ranganathan and Dr. Stephen C. Cannon of Harvard Medical School.
Dysfunction of neuronal signaling mediated by the brain chemical serotonin may be implicated in anxiety, depression, obsessive-compulsive disorder, schizophrenia, regulation of appetite and hunger, migraine, nausea and sleep. Human violence, aggression and suicide also have been tied to altered levels of serotonin signaling in the brain.
Serotonin binds to receptors that mediate either slow or fast modulatory responses. Previously, scientists knew of only one type of fast receptor for serotonin, one that leads to an excitatory response (a stimulation of neuronal signaling). In this study, the researchers report that in the roundworm Caenorhabditis elegans, the gene mod-1 encodes a new type of fast receptor -- an inhibitory receptor that blocks neuronal signaling.
"We have identified a new mechanism of signaling in the nervous system, whereby serotonin can rapidly turn off, instead of turn on, the actions of nerve cells," Professor Horvitz said.
"This finding raises the possibility that humans have a similar fast serotonin receptor that is inhibitory" Mr. Ranganathan said. "The race will now be on to find such a human receptor."
Researchers do not know which human behaviors, if any, would be affected by a human mod-1-like receptor. "This would be a brand new molecule," Mr. Ranganathan said. "We have no idea which of the basic processes modulated by serotonin such a receptor might affect."
If such a human receptor were found, there could be significant implications for new drug development targeted at this inhibitory pathway. The new information also could help researchers understand how existing serotonin-regulating drugs work, and also whether such inhibitory pathways may be involved in the myriad unwanted side effects caused by serotonin-modulating drugs, such as sexual dysfunction.
In addition, a human receptor would provide drug companies with a powerful new target for drugs designed to affect specific behaviors.
Neurons generate electrical signals that cause brief reversals in the electrical state or polarity of the membrane of the neuronal axon.
These electrical events in turn cause the release of a chemical messenger from a storage vesicle in the axon terminal. The chemical messenger, called a neurotransmitter, travels across a small gap between nerve cells to bind and activate a postsynaptic receptor protein.
The activation of the receptor protein sets in motion a series of events that change the electrical state of the responding cell. This results in one of two possible outcomes: the neuron stays in a resting state, or it generates a new electrical signal to communicate with the next neuron. Activation of some receptors excite the cell, while activation of others inhibit it. Such activation can be either fast or slow, depending on the characteristics of the receptor.
The current understanding is that serotonin activates many slow receptors that can be either excitatory or inhibitory, but it activates only one fast receptor, which is always excitatory.
"We always have thought of fast effects of serotonin as excitatory," Mr. Ranganathan said. "Now we have to think of the other side of the coin -- that they may be inhibitory."
Worms on Prozac
The identification of mod-1 was based on findings reported by the Horvitz laboratory earlier this year. A study done by former MIT graduate student Elizabeth R. Sawin, Mr. Ranganathan and Professor Horvitz showed that when well-fed Caenorhabditis elegans roundworms are situated within their food source of bacteria, they slow their movements slightly to remain in the vicinity of the food.
In contrast, when worms that have been deprived of their food for 30 minutes encounter bacteria, they slow down dramatically.
The researchers found that for these responses, the worm uses the same neurotransmitters that the human brain uses to modulate behavior. The neurotransmitter dopamine is used by well-fed worms and the neurotransmitter serotonin is used by food-deprived worms.
As expected, giving Prozac to the worms makes the reaction of food-deprived animals even more dramatic, because Prozac increases serotonin-based behavioral responses.
The researchers isolated 17 mutants which, when food-deprived, do not slow down like normal worms in response to food. The mod-1 mutant was the mutant with the strongest defect.
This work is part of a long-term project supported by the National Institutes of Health to understand the development and functioning of the nervous system of Caenorhabditis elegans.
A version of this article appeared in MIT Tech Talk on December 6, 2000.
