Exploring the relationship between alcoholism and serotonin one step at a time

November 14, 2002

The brain's serotonin neurotransmitter system has been associated with a variety of psychiatric disorders, including depression, anxiety, anti-social personality disorder, and alcohol dependence. Although research has shown that alcoholics appear to have an altered and/or injured serotonin system, the specifics of those alterations remain unclear. In the November issue of Alcoholism: Clinical & Experimental Research, researchers use a selective serotonin reuptake inhibitor called citalopram, commonly used for treatment of depression and anxiety, as a pharmacological probe that binds to the serotonin transporter, the site in the serotonin system responsible for "turning off" serotonin excitation. They then examine the responses in abstinent, alcohol-dependent men of three hormones known to increase when the serotonin system is excited: adrenocorticotropin (ACTH), cortisol, and prolactin.

"When we say serotonin system," explained Gary S. Wand, professor of medicine and psychiatry at Johns Hopkins University School of Medicine and corresponding author for the study, "we are referring to a complicated neurotransmitter circuitry that includes the production of serotonin, the factors that regulate the degradation and the reuptake of serotonin, as well as the activity and number of receptors that respond to serotonin. So this means a complex system.

"What we wanted to do for this study was use a very specific probe of the serotonin system, a functional probe that would shake up and excite serotonin by binding to just a single component of the serotonin system, something called a serotonin transporter," said Wand. "We specifically chose citalopram because we wanted to see if only the serotonin transporter was deranged in alcoholics. Of all the various parts of the serotonin system, we decided to tackle this one first."

Researchers administered two separate dosing sessions of citalopram (0 and 40 mg) to two groups of male participants between 30 and 50 years of age: 12 healthy and abstinent alcohol-dependent subjects, and 14 healthy control subjects. Hormone levels were measured at numerous intervals, ranging from 30 minutes prior to and 240 minutes following dosage. In addition, all participants were interviewed in order to determine the presence or absence of a family history of alcoholism.

"Based on previous findings," said Wand, "we thought we would see a greater hormonal response to citalopram in the alcoholics when compared to the controls. We were surprised to see that citalopram did very little. In fact, this is what we would call a 'negative finding.' Our results suggest two possibilities. One, that the serotonin system may be deranged in certain forms of alcoholism but not in all forms of alcoholism. Two, perhaps the serotonin transporter, which has been the subject of much attention, is not responsible for serotonin abnormality in alcoholics."

Mary E. McCaul, a professor in the department of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, offers additional explanations for the contrast between these findings and earlier research in the field.

"Much of the earlier research has studied people who had very recently stopped drinking," said McCaul. Wand's study examined alcoholics who had been abstinent for several months up to 17 years. "If heavy alcohol consumption damages the serotonin system," she said, "it is possible that over time, the system will return to normal functioning. By studying persons who had stopped drinking months and years earlier, Dr. Wand was possibly observing subjects whose serotonin systems had recovered from the damage of earlier drinking."

Another explanation involved the absence of other psychiatric problems among the study patients. "We know that serotonin system functioning is altered in a number of psychiatric conditions," she said, "however, Dr. Wand's study very carefully screened out people who had a psychiatric condition in addition to their alcohol dependence. If earlier research included persons with other mental health problems, serotonin activity may have been altered not by the alcohol dependence but instead by the psychiatric conditions."

A third explanation offered by McCaul concerned the specificity of the Wand study. "This research used a highly specific drug probe to test the functioning of the serotonin transporter, an important site for regulation of the amount of the neurotransmitter serotonin," she said. "Earlier studies used drug probes that are less specific; that is, the test of the serotonin transporter was not as clean."

Fundamentally, noted McCaul, scientists still have much to learn about the brain and alcoholism. "We need to better understand what roles brain neurotransmitters play in the pleasant and unpleasant effects of drinking alcohol, increasing or decreasing an individual's risk of developing problems from drinking, and the likelihood of recovery from alcohol abuse and dependence," she said. "We know that the brain serotonin system is involved in a number of mental health problems. We need to better assess the unique associations between the serotonin system and alcoholism versus associations that are actually the result of the depression and anxiety that often co-exist with alcoholism. Finally, research is needed to distinguish between pre-existing alterations in brain neurotransmitter systems that increase a person's risk of developing alcohol abuse and dependence versus changes that result from prolonged toxic exposure of the brain to alcohol."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included Deidre Gotjen, Zsolt Szabo and Shing Lee of the Johns Hopkins University School of Medicine. The study was funded by the National Institutes of Health and The Kenneth Lattman Foundation, and conducted on the premises of the Johns Hopkins University General Clinical Research Center.

Alcoholism: Clinical & Experimental Research

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