Serotonin is most commonly known for its role in mood regulation and its disruption’s link to depression. A class of anti-depressants (selective serotonin re-uptake inhibitors or SSRIs), is used to treat depression. But serotonin also plays a role in addiction.

It was originally thought cocaine caused a high only by interfering with dopamine mop-up, resulting in a boost of dopamine and a drug high. However, subsequent studies convincingly questioned the completeness of this understanding. Two such studies used “knockout mouse technology,” which investigates a single gene by removing it from a mouse embryo and growing the mouse to maturity to compare it to others who have the gene. Researchers at Duke University produced mice that “knocked out” the gene engineering dopamine. Since the mice couldn’t produce dopamine, they could not produce a high, it was thought, and they shouldn’t find drugs rewarding. Yet, they did.1

The rats kept taking cocaine, indicating they were receiving some reward independent of the dopamine system. Dr. Rene Hen, the lead researcher, suggests the reward might be related to serotonin. “We know that serotonin and dopamine cross-talk,” Dr. Hen said. “If you touch one system, you will see repercussions in the other.”2

A Columbia University study investigating the link between cocaine and serotonin knocked out the gene engineering the serotonin B1 receptor. Mice born without the B1 receptor were found to have adapted to compensate. Researchers found much higher levels of a protein called Delta Fos-B, a “transcription factor” that turns genes on and off, including dopamine-related genes. Repeated use of cocaine triggers a build-up of Delta Fos-B and is suspected to activate genes that intensify craving by increasing the activity of glutamates, general stimulatory neurotransmitters. “It’s almost like a molecular switch,” commented Eric Nestler, the lead researcher. “Once it’s flipped on, it stays on, and doesn’t go away easily.”3

Mice bred to lack B1 receptors are naturally born with high Delta FosB levels, indicating that the B-1 receptor is involved in the neurological changes resulting from heavy cocaine use. Dr. Hen calls them born addicts.” When given an opportunity to administer intravenous of cocaine by pressing a lever, they not only did so, they continued to even as the task was made more difficult. To get the first shot they had to press the lever once, while for each subsequent shot they had to press more times. Normal mice press the bar up to eight times before giving up. The B1-knockout mice pressed the lever as many as 25-30 times. They also self-administered large amounts of alcohol when given the opportunity, which indicates they are susceptible to addiction from numerous drugs, not just cocaine.4

Serotonin also plays a prominent role in the way hallucinogens act on the brain, greatly increasing serotonin levels in certain brain cells. Hallucinogens are serotonin “agonists,” which means they are molecularly similar enough to serotonin to dock with serotonin receptors.5 Large increases in serotonin levels have also been measured in users of ecstasy.6 Ecstasy appears to push the serotonin system into overdrive by interfering with serotonin mop-up transporters, similar to the way cocaine affects dopamine. Elevated serotonin causes short-term euphoria but depletes it in the longer-term. Chronic ecstacy users, for example, were found to have 50%-80% lower concentrations of serotonin.8(Evidence shows ecstasy is more potent in women, who metabolize it and a related drug, amphetamine, differently than men because of the varying concentrations of estrogen and testosterone.9)

Like just about everything, too much serotonin can be dangerous, leading to a sometimes fatal condition known as “serotonin syndrome.” In addition to illegal drugs such as LSD and ecstasy, there are many legal sources of serotonin, including anti-depressants, over-the-counter cough and cold remedies, tryptophan, St. John’s wort, ginseng, and prescription painkillers like fentanyl. Because there are a variety of sources, some people aren’t aware of how much serotonin they’re taking and overdose. In 2002, there were 7,349 cases of serotonin syndrome reported, including 93 deaths. In 2005, there were 118 deaths. In addition, between 1998 and 2007 there were more than a thousand reports of dogs who accidentally ingested antidepressants being sickened. Still, 85% of doctors surveyed weren’t aware of “serotonin syndrome.”10

For the next article in the Non-Dopamine Neurotransmitters series click here.

To go back to the Addiction Science Menu click here.

1. Broader Treatment May Aid Drug Addicts; San Francisco Chronicle, Oct. 19, 1998.
2. Two Studies Shed New Light on Cocaine’sEffect on Brain; New York Times, May 14, 1998.
3. Brain Buildup Causes Addiction, Associated Press, September 15, 1999.
4. Two Studies Shed New Light on Cocaine’sEffect on Brain; New York Times, May 14, 1998.
5. Scientists Test Hallucinogens For Mental Ills, New York Times, March 13, 2001.
6. Studies in Primates Shows Brain Damage From Doses of Ecstasy, New York Times, September 27, 2002.
7. Party Drug Might Harm Women More, Associated Press, November 29, 2001.
8. Clues to Ecstasy’s Effects on Addicts, New York Times, August 1, 2000.
9. Party Drug Might Harm Women More, Associated Press, November 29, 2001.
10. A Mix of Medicines That Can Be Lethal, New York Times, February 27, 2007.


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