Serotonin and Behavior

Link to article (must register, but it's free) Neurotransmitter of the '90s - serotonin production When a stray thought niggles your brain, reminding you to stop biting your nails, you'll stop because you want to and because you can--your brain's cells have no trouble communicating the message to your body. But many people aren't so lucky. Their brain produces too much or too little serotonin, one of several chemicals that transmit impulses between nerve cells, or neurons. Accumulating evidence reveals that serotonin is unlike other neurotransmitters. It does not have receptors localized in a few specific areas of the brain. Instead, nerve cells tipped with serotonin-sensitive binding sites cluster deep within the brain stem and send neuronal tentacles snorkeling out through the gray matter. Hence, their uptake and release of serotonin ultimately affects much of our mental life. Take the case of suicidality. Brain tissue from the frontal cortex of suicide victims has fewer serotonin-releasing neurons than normal brains--but more that suck up the transmitter, suggesting an attempt to compensate for serotonin lack by upping receptor sensitivity. Still, low serotonin producers suffer from suicidal thoughts during acute stress. Some may be born with "suicidal" brains. Measurements of serotonin debris in spinal fluid may identify those at risk. * Serotonin imbalance seems to underlie obsessive-compulsive disorder (OCD), an anxiety-related condition marked by intrusive thoughts and repetitive behaviors such as hand-washing. Neurotransmitter activity may be abnormal in the frontal cortex, caudate, and cingulate gyrus, all rich with serotonin neurons. * Surging serotonin elsewhere may bring on bliss. People who take the illegal drug MDMA, or Ecstasy, get a "serotonin high" as MDMA-responsive cells release large amounts of the neurotransmitter, stimulating receptors in middle layers of the cerebral cortex. In high doses, Ecstasy destroys serotonin nerve fibers. A less toxic form of MDMA might help those with illnesses like AIDS face death more calmly. * Serotonin may interact with sex hormones to orchestrate sexual behavior, animal studies show. In female rats, serotonin usually inhibits sexual behavior. But as estrogen and progesterone make their cyclic rise, they dampen serotonin neurons in the hypothalamus, and the females go into heat. In males, serotonin does the opposite, promoting sexual activity in the presence of testosterone. Serotonin may yield better ways to control sexual dysfunction in men and ovulation in women. * Serotonin aids and abets learning and memory formation. As serotonin is released in response to a stimulus, it attaches to the receptors of the next cell down the line, raising its excitability level and increasing the chance it will become part of a circuit that encodes memory. Serotonin also enhances the neuron's electrical impulse, creating enduring memory. These responses turn on at different stages of development and underlie two distinct types of learning--sensitization and dishabituation. As scientists finally get a handle on the complexities of serotonin, they also implicate it in schizophrenia, depression, alcohol abuse, chronic pain, pre-menstrual syndrome, eating disorders, and panic attacks. "Serotonin is only one of the molecules in the orchestra," says Yale neuropsychologist Thomas J. Carew. "But rather than being the trumpet or the cello player, it's the band leader who choreographs the output of the brain." COPYRIGHT 1992 Sussex Publishers, Inc. COPYRIGHT 2004 Gale Group

Cushioning Hard Memories

Harvard Magazine

The more you love a memory," Vladimir Nabokov once declared, "the stronger and stranger it is." Certainly we never forget the details of our beloved moments: first kisses, college graduations, our children's births. "That kind of thing," said Nabokov, "is absolutely permanent, immortal." But some ineradicable memories are of things we desperately want to forget.

For those who suffer from post-traumatic stress disorder (PTSD), vivid recollections of the horrific events they survived or witnessed — wars, rapes, accidents, injuries, concentration camp internments — often return relentlessly for years, evoking the same fear, helplessness, horror, and consequent anguish that accompanied the initial experience. This creates a disabling cycle that can be difficult, if not impossible, to break.

But encouraging new research suggests that the beta-blocker drug propranolol, by inhibiting the release of certain stress-related hormones, may stop such unwanted memories from being reinforced in our brains. Unlike the creepy device that erases undesirable recalls just like files on a computer in the recent film Eternal Sunshine of the Spotless Mind, propranolol won't cause PTSD sufferers to forget their ghastly memories, "but it can take out the sting," says professor of psychiatry Roger K. Pitman.

For a double-blind pilot study published in Biological Psychiatry, Pitman recruited 41 emergency-room patients who had just survived a traumatic event (most were car crashes). Eighteen patients received a 10-day course of oral propranolol; the rest received a placebo. When the patients returned one and three months later for psychometric assessments (like measuring their heart rates while they listened to previously tape-recorded descriptions of the initial event), those who had received propranolol were less likely to show signs of PTSD.

The results are promising for PTSD prevention, which has traditionally been limited to psychological debriefing, a method increasingly regarded as ineffective. And although Pitman is excited about the results, he readily admits propranolol is imperfect, particularly because it exacerbates asthma. (Propranolol, a hypertension drug, is widely marketed as Inderal. It is far from winning approval from the Food and Drug Administration for easing stressful memories.)

The biological reason why we never forget significant experiences involves the amygdala, an almond-shaped portion of the temporal lobe. Highly emotional events stimulate the amygdala to release so-called stress hormones, such as adrenaline, into our hippocampus. These hormones strengthen the recollections, gruesome or lovely, of the events that prompted their release. In PTSD, graphic memories — frequently including flashbacks and nightmares — not only remain intense over time, but are self-perpetuating. Each time a sufferer relives the traumatic experiences, the amygdala re-releases stress hormones into the brain, and consequently reinforces already unwanted memories. But propranolol interferes with the amygdala's receptors and "takes it off-line," Pitman says. "It blocks the consolidation of memory."

Since the amygdala doesn't release stress hormones in response to ordinary situations, it's not surprising we forget where we placed our keys or parked our car. "You are likely to remember in fair detail what you were doing on the morning of September 11, 2001," says Pitman. "But do you remember what you were doing on the morning of September 10?" This reaction, he maintains, is firmly based in natural selection. "If a primitive hominid decided to take a new route to a watering hole and on her way encountered a crocodile," he says, "should she fail to remember in the future that a crocodile inhabited that route, she would be more likely to take it again and be eliminated from the gene pool."

As a society, we place tremendous value on recollection — from court testimonies to cherished reminiscences of childhood — so a drug capable of affecting memory may raise thorny legal and ethical concerns. If, for example, a woman takes propranolol following an assault, is she jeopardizing the validity of future testimony because her memory has been altered? Pitman agrees propranolol could threaten successful prosecutions, but "Medical concerns trump legal concerns," he says. "Would you withhold morphine, which can affect memory, from a mugging victim with broken bones?" He emphasizes that propranolol does not eliminate memories, but allows victims "to maintain a level of memory similar to that of a bystander."

But if propranolol, or drugs like it, become an emergency-room staple, will we soon be tinkering with memories of those experiences that, while painful, serve to define who we are, and teach us valuable lessons? "This is a legitimate ethical concern," says Pitman. "But it is speculative and I wouldn't let speculation block the ability to help someone. Most people who have PTSD are so debilitated, they would prefer to have their memories tinkered with."

If tinkering is to be done, then it must be done quickly. Propranolol must reach the amygdala before a memory has had time to settle in; even 24 hours following trauma may be too late. Pitman has yet to determine the size of "the window of opportunity," but it will almost certainly be too short for emergency-room doctors to evaluate a patient's likelihood of developing PTSD (some people, such as those with smaller hippocampi, may be predisposed to the disorder). In other words, if propranolol begins to be routinely prescribed, some percentage of those who receive it may not really need it. "You will have to decide," Pitman says, "if the damage is worse than the benefit."

~Catherine Dupree

Roger K. Pitman e-mail address: roger_pitman@hms.harvard.edu