Translational Studies of Alcoholism: Bridging the Gap
Zahr, Natalie M. Phd, Sullivan, Edith V. Phd, Alcohol Research
Human studies are necessary to identify and classify the brain systems predisposing individuals to develop alcohol use disorders and those modified by alcohol, while animal models of alcoholism are essential for a mechanistic understanding of how chronic voluntary alcohol consumption becomes compulsive, how brain systems become damaged, and how damage resolves. Our current knowledge of the neuroscience of alcohol dependence has evolved from the interchange of information gathered from both human alcoholics and animal models of alcoholism. Together, studies in humans and animal models have provided support for the involvement of specific brain structures over the course of alcohol addiction, including the prefrontal cortex, basal ganglia, cerebellum, amygdala, hippocampus, and the hypothalamic-pituitary-adrenal axis. KEY WORDS: Alcohol dependence; alcoholism; chronic alcohol exposure; alcohol and other drug effects and consequences; genetic factors; environmental factors; brain; neurobiology; translational studies; human studies; animal studies; animal models
What currently is known about alcohol's effects on the brain has benefited from transla-esearch-the parallel study of humans with alcohol dependence and of animal models that mimic targeted aspects of this complex disease. Human studies provide a full depiction of the consequences of chronic alcohol expo-sure, but they are limited by ethical considerations for experimentation of rigorous controls of relevant variables. Animal models, on the other hand, can distinguish components of the addiction processes but cannot fully represent the human condition.
In humans, 40 to 60 percent of the risk for alcoholism can be attributed to genetic factors. These genetic factors interact with environmental factors (e.g., early-life stress, family structure, peer pressure, or the social environ-ment; McKenzie et al. 2005) to influ-ence an individual's vulnerability to alcohol problems (Prescott and Kendler 1999). The genetic component has been modeled by breeding animal strains (predominantly rats and mice) with a high preference for alcohol (e.g., the alcohol preferring [P] and nonpreferring [NP] rats, high-alcohol- drinking [HAD] and low-alcohol- drinking [LAD] rats, the high-alcohol- preferring [HAP] mouse, and C57 black mice). The environment also has been modeled, for example, by separating young monkeys from their mothers, which reproduces early-life stress (Barr et al. 2004).
The last quarter century has seen a plethora of technologies capable of exploring the human animal in vivo, and many have been applied to alcohol-related research. Currently available noninvasive human technologies (reviewed elsewhere in this two-part series) include electroencephalogram (EEG) (Rangaswamy and Porjesz, pp. 238-242), functional magnetic reso-nance imaging (fMRI) (Nagel and Kroenke, pp. 243-246; Rosenbloom and Pfefferbaum, Part 2), magnetic resonance spectroscopy (MR spectroscopy) (Nagel and Kroenke, pp. 243-246), single-photon emission computed tomography (SPECT) (e.g., Abi-Dargham et al. 1998), and positron emission tomography (PET) (Thanos et al., pp. 233-237). Further investigation of alcohol's effects at the cellular (e.g., He and Crews 2008; Tupala and Tiihonen 2004), molecular (e.g., Alexander-Kaufman et al. 2007), and genetic (e.g., Dodd et al. 2006; Saba et al., pp. 272-274) levels is made possible by carefully screened human postmortem brain tissue (Harper et al. 2003a).
Even with these new technologies, animal models continue to have a vital role, enabling researchers to better interpret the implications of new findings. Moreover, the wide variation (or heterogeneity) of alcoholic populations examined with respect to genetic predisposition, age of onset, pattern of drinking, frequency of withdrawals, length of sobriety, nutritional, and hepatic status has hampered researchers' attempts to isolate only those specific brain regions affected by alcohol per se. …