The brain’s reward and stress systems are closely interconnected, both anatomically and functionally. For example, the euphoric response to alcohol that most people experience is related to the release of stress hormones, whereas a dysfunctional stress response may be associated with alcoholism. A study in the May issue of Alcoholism: Clinical & Experimental Research has made two important findings related to this association. One, some recovering alcoholics with a lengthy abstinence may have a chronically subdued stress system. Two, their systems are hypersensitive to a neurotransmitter called serotonin, which is a key player in the body’s stress response. The implication is that some alcoholics will respond differently than non-alcoholics to stressful situations that involve the brain’s serotonin system.
Serotonin is an important neurotransmitter that influences most functions, including general motor activity, learning and memory, reproduction, the stress response, sleep, and food intake. Disturbances in serotonergic activity have been linked with numerous behavioral disorders, including alcoholism, drug abuse and depression. Fenfluramine is a drug formerly used to treat appetite disorders by increasing serotonin activity in the brain. In this study, fenfluramine was given to recovering alcoholics in order to cause an acute increase of serotonin activity. This, in turn, is believed to cause increased activity in the limbic-hypothalamic-pituitary-adrenal (LHPA) axis - an inter-connected system of brain structures and hormone-producing organs that becomes especially active when an individual is stressed - leading to the secretion of a steroid called cortisol from the adrenal glands.
"Our major finding," said Robert M. Anthenelli, associate professor of psychiatry in the College of Medicine at the University of Cincinnati, director of substance dependence programs at the Cincinnati Veterans Affairs Medical Center, and lead author of the study, "was that alcoholics who’d been abstinent for an average of more than four months had a two-fold greater cortisol response compared with non-alcoholics following administration of fenfluramine. This result was surprising because all other published studies of alcoholics with shorter lengths of abstinence found they had a blunted or unchanged stress response following serotonergic stimulation. We also found that the stress hormone response in recovering alcoholics did not return to baseline levels as quickly as it did in age- and race-matched non-alcoholic comparison subjects. In other words, it appears that some of our recovering alcoholic subjects had difficulty turning off the fenfluramine-induced stress response."
When an individual either perceives (psychological stress) or is faced with an actual threat (physical stress), the brain sets into action a cascade of signals intended to help respond to the threat. The end product of that cascade is the release of the stress hormone, cortisol, which produces numerous effects throughout the body and brain. These effects include mobilizing more glucose for the body to use as energy to respond to the threat, raising blood pressure, and suppressing the immune system. The stress response also triggers the sympathetic nervous system to increase heart rate and dilate the pupils (known as the fight-or-flight response). After mobilizing resources to meet the challenge, a reversed order of the process returns the body to a level of homeostasis (or non-stressed levels). Although stress response is important for survival, chronic stress or alterations in this response may contribute to various diseases.
"When stressors are short-lived," explained Stephen Woods, professor of psychiatry and of neuroscience at the University of Cincinnati, "the LHPA axis is very effective at ensuring that the body functions optimally until the situation changes for the better. When stress is more chronic, continued stimulation of the LHPA axis can have detrimental effects throughout the body." This study, he said, clearly showed that abstinent alcoholics stimulated with fenfluramine (mimicking a stress-related increase of serotonin) had high blood cortisol levels for a significantly longer period of time than other individuals.
"While the Anthenelli report does not speculate on what some of the specific consequences of this might be," said Woods, "it is reasonable to speculate that there are physical consequences. Whether this change in the LHPA axis response to a serotonin challenge is related to brain damage, or alteration resulting from former consumption of large amounts of alcohol, is not known. An interesting clue, however, is the authors’ recognition that the elevated cortisol response is reminiscent of what has been observed in individuals who have never before experienced alcohol, but who are considered high risk for developing alcoholism. One possibility, therefore, is that the prolonged elevation of cortisol following fenfluramine is characteristic of certain alcoholism-prone individuals and can be observed either before they ever drink or after a prolonged period of abstinence."
The similar finding of a hypersensitive cortisol response to fenfluramine that Woods referred to was in a group of non-drinking prepubertal boys considered high risk for developing alcoholism simply by virtue of a family history positive for the disorder.
"Since this hypersensitive stress hormone response to a serotonergic stressor appears to be present in some individuals with the alcoholism trait both before the onset of the disorder," said Anthenelli, "and persists after several months of abstinence, we propose that this may represent a trait marker of alcoholism. Trait markers of alcoholism refer to biochemical characteristics, or markers, that could distinguish subgroups of alcohol-dependent people or those who have a predisposition for alcoholism from people who do not."
Anthenelli’s study also looked at the possible confounding influence of cigarette smoking or certain personality characteristics on stress response. Approximately 85% of alcoholics (recovering or actively drinking) are current cigarette smokers. Smoking is known to affect serotonin function, and both smoking and nicotine withdrawal have been associated with changes in LHPA axis function. Similarly, approximately 15 to 20 percent of alcoholics have antisocial personality disorder (ASPD), defined as a life-long pattern of impulsiveness, aggression, and a general disregard for the rights of others. ASPD has been associated with changes in LHPA axis and serotonergic function. Yet, despite the strong association with alcoholism, neither nicotine dependence nor ASPD affected hormonal responses to fenfluramine.
"Based upon these findings," said Woods, "one could go out on a limb and speculate that one reason some individuals have a tendency to imbibe more and more when exposed to alcohol, and eventually become alcoholic, is that a ‘defect’ in their LHPA response to serotonin is ‘corrected’ by alcohol. Remember that a prolonged cortisol response has undesirable consequences in the brain or throughout the body. Individuals who have such a prolonged response might find that it is remedied in the presence of alcohol. If this were the case, alcohol would provide a greater degree of reward value for them than for individuals who do not have the same ‘defect.’"