Understanding a disease such as alcoholism, like many other diseases, involves years of research dedicated to ‘teasing out’ its multiple and interactive components. Scientists now know that alcoholism is influenced by both environmental and genetic factors. A study in the June issue of Alcoholism: Clinical & Experimental Research looks closely at how genetic differences in the intracellular signaling capacity of a neurochemical messenger called adenosine 3’:5’-cyclic monophosphate (cAMP) may relate to alcohol sensitivity and the later development of alcoholism.
"There are different theories as to the cause of alcoholism," said Shelli Kirstein, a graduate student in pharmacology, and Boris Tabakoff, chair of the Department of Pharmacology at the University of Colorado School of Medicine. Tabakoff is the senior author and Kirstein is the co-author of the paper. "One possibility involves differences in sensitivity. Less sensitive individuals may drink more because they do not receive the same cues of impending intoxication as individuals with a high sensitivity. Another possibility is that some individuals have the capacity to develop greater or more rapid tolerance and hence can drink more. Both low sensitivity and alcohol tolerance can lead an individual to drink more and become dependent on alcohol. It is not known how these two pre-existing conditions are related genetically and if being genetically programmed in one direction or the other is sufficient by itself to cause an individual to become alcoholic."
Alcohol can affect several different neurotransmitter receptors, causing them to couple to or activate intracellular signaling systems, such as adenylyl cyclases, which produces cAMP as a messenger. Signaling pathways can ‘set the tone’ for alcohol’s effects by either inhibiting (turning off) or potentiating (turning on) certain pathways. This study used different strains of specifically bred mice to examine what role cAMP signaling might play in ‘setting the tone’ for alcohol sensitivity and tolerance. Sensitivity was measured as the ability to balance on a dowel following alcohol injections. This procedure mimics the "incoordinating" or disharmonizing effects that alcohol can have for some individuals. Tolerance was measured as the difference between sensitivity after the initial dose of alcohol and sensitivity after a subsequent dosing with alcohol.
"One key finding," said Tabakoff, "is that there is a genetic correlation between cAMP signaling in the cerebellum and initial sensitivity on the dowel test for ataxia." Ataxia is the inability to coordinate voluntary bodily movements; for example, a staggering drunk would appear ataxic. "Also, there is a lack of correlation between initial sensitivity and tolerance, and there is a lack of genetic correlation between tolerance and cAMP signaling in the cerebellum or any brain region tested. Results from testing different strains of mice under similar environmental conditions reflect a genetic influence on the behavioral or biochemical phenotype investigated. Simply stated," he added, "this means that a common gene or genes influence both initial sensitivity and cAMP signaling. Next, we would like to try to identify those gene or genes."
"The cAMP signaling system is much like the traffic controller at a large airport," explained Richard Deitrich, professor pharmacology at the at the University of Colorado School of Medicine. "It controls which systems are turned on or off in a given situation. That is, which planes or systems are allowed to take off or land, and which planes or systems are put into a holding pattern or not allowed to function. Alcohol, by its ability to affect these systems, is analogous to a malfunctioning radar system. Airport operations are slowed by a marginally malfunctioning system, or a low dose of alcohol, or completely disrupted by an acutely malfunctioning radar system, or a large dose of alcohol. In such cases, the airport has to be shut down, or the individual loses fundamental brain functions. In this study, the dose of alcohol was low and so the function of the animals was only partially disrupted. That is, they could still stagger around and were not unconscious."
"Our results suggest those areas of the brain important for balance and coordination can be genetically programmed for sensitivity to alcohol’s ‘incoordinating’ effects," said both Tabakoff and Kirstein. "While the genes that influence this sensitivity are by no means the only genes that may predispose someone to alcoholism, they may influence sensitivity to certain effects of alcohol. This could make it easier to identify individuals at risk for alcoholism, as well as serve as an easily measured characteristic that contributes to the risk but does not explain the entire disorder."
"This study is very relevant to understanding the underlying differences between those individuals who drink and do not become alcoholic, and those who drink and do become alcoholic," said Deitrich. "The research shows that a combination of behavior, pharmacology, neurochemistry and genetics can be a powerful tool in investigating the basic mechanisms by which alcohol brings about its effects. Only by understanding these basic mechanisms can we design rational measures for the prevention or treatment of human alcoholism."