Who is at risk? Population characterization of alcohol self-administration in nonhuman primates helps identify pathways to dependence

Alcohol Research & Health, Winter, 2008 by Kathleen A. Grant, James Stafford, Allison Thiede, Caitlin Kiley, Misa Odagiri, Betsy Ferguson

Alcohol addiction--or alcohol Dependence--is a chronic and progressive disorder that has a significant detrimental impact on the drinker, his or her family and community, and society as a whole. Accordingly, it is important to identify the mechanisms contributing to the development of alcohol dependence as well as the factors that increase an individual's risk of becoming alcohol dependent. Only with this knowledge will researchers and clinicians be able to develop new treatment approaches and effective interventions to reduce or prevent the development of alcohol problems in people at risk. One important step is to identify the neurobiological mechanisms that are affected by alcohol use and/or which drive alcohol use and the progression to dependence. Although alcohol dependence is a uniquely human disease that does not occur naturally in animals, animal models frequently are used to study various aspects of the development of alcohol dependence and its consequences because the corresponding experiments would not be feasible or ethical to conduct in humans. This is particularly true in the area of neuroscience, where direct analyses of brain pathways are limited in living individuals (e.g., measurements using imaging methods that reflect alcohol-induced changes in brain function).

Most animal models of alcohol dependence involve rodents, which are easy to obtain in sufficiently large numbers and also have short generation times, so that the effects of excessive alcohol exposure can be rapidly determined. However, the lifespan and stages of development, the neuroanatomical and physiological complexity, and the social behavior of rodents and humans differ to such an extent that not all aspects of the human condition can be adequately modeled or are sufficiently transferable to humans. Nonhuman primates, in contrast, although lacking in a number of ways, offer researchers the ability to model aspects of the human condition more closely.

Monkeys and apes (1) (i.e., nonhuman primates) have a rich history as experimental animals in the study of biomedical disease processes (http://www.primate.wisc.edu/pin/) because they are most similar to humans in that they have relatively long lifespans, go through parallel developmental stages, and share similar genetic predispositions. The value of nonhuman primate studies is particularly evident in research aimed at assessing the risk of developing behavioral disorders, because like humans, nonhuman primates experience complex social and affective processes. The basic data generated by studies of nonhuman primates then can be followed with experimental designs that address the underlying mechanisms of the disorder under investigation and can be the basis for the development of targeted prevention and therapy.

Nonhuman primates also have been used to model aspects of alcohol abuse and dependence, such as mechanisms underlying alcohol-related organ damage. In addition, a large body of research has examined the neurobiological basis for and consequences of alcohol use, including neurobiological adaptations hypothesized to mediate addictive behaviors associated with alcoholism (Barr and Goldman 2006; Grant and Bennett 2003). For example, as described later in this article, studies in nonhuman primates have helped elucidate the interactions between alcohol and various brain-signaling pathways (i.e., neurotransmitter systems).

As with rodent subjects, most studies that use nonhuman primates as subjects involve passive administration of alcohol (chemically known as ethanol) to study the consequences of heavy drinking--that is, the alcohol is administered by the experimenter. However, monkeys also have been used to model human alcohol consumption itself by using procedures that typically incorporate access conditions in which the monkeys themselves initiate alcohol intake. This is known as self-administration.

Using such procedures, it is possible to directly identify risk factors for abusive alcohol drinking. Commonly acknowledged biological factors that put an individual at risk of developing excessive ethanol intake include gender, age of onset, metabolism, response to stress, impulsivity, family history of alcoholism, and sensitivity of the brain reward pathway. These factors are independent of, but interact with, environmental risk factors, such as cost, alcohol availability, and social acceptability of drinking. Determining the risk factors for developing chronically high alcohol intake, as well as determining which risk factors predict specific subtypes of alcoholism, are critical objectives for improving public health polity, prevention, and treatment.

One important step in that direction is to determine the population distribution of ethanol drinking and to characterize the biological traits of the individuals at either end of the drinking distribution (i.e., of individuals with particularly low or particularly high levels of alcohol consumption). This article reviews the findings of studies that have assessed the drinking distribution in monkey populations and have investigated the acquisition of drinking behavior in these animals. The article also explores how information on the population distribution of drinking can help investigators identify the neurological basis for alcohol intake levels and patterns.