Microstructure of Ethanol Consumption in Rodent Models of Alcoholism

Scientists Creating Super Smart Mice To Study Brain Disorders
Scientists Creating Super Smart Mice To Study Brain Disorders
Comprehensive measurements of drinking behavior during episodes such as binge, abstinence, and relapse are essential to reveal the factors and mechanisms that underlie alcohol abuse and dependence.

The Centers for Disease Control and Prevention (CDC) rank alcohol-attributable mortality as the third leading cause of preventable death in the United States.1 Researchers are examining the neurocircuitry that underlies reward processing and regulation,2 and are identifying potential genetic, neural, behavioral, and environmental markers of alcohol use disorder (AUD).3

Genome-wide association studies (GWAS) in humans reveal a heritability of AUD of approximately 50%, and now it is evident that AUD is caused by a complex interplay between polygenic traits and wide-ranging environmental components.4,5 Animal models are essential in order to address the neurobiologic and behavioral basis of alcohol addiction because they allow for rigorous control of both genetic and environmental variables.6

Rats selectively bred for a high alcohol-consumption phenotype are commonly used to model AUD because of the predictive validity.7

For example, this phenotype is observed without environmental manipulations in the alcohol-preferring (P) lines of rats.8 In addition to ethanol (EtOH) preference and tolerance, excess alcohol consumption, and withdrawal- and relapse-like behavior, P rats display innate differences in various neurotransmitter and neuromodulator systems involved in reward processing, compared with the alcohol-nonpreferring (NP) lines of rats.6,8 Based on various criteria, this is an appropriate animal model of alcoholism because P rats exhibit behavioral and neurophysiologic correlates of AUD in a human population.8

The voluntary, oral ingestion of EtOH in sufficiently high quantities to satisfy the requirements for a valid rat model of alcoholism is essential for a mechanistic understanding of how chronic voluntary alcohol consumption develops and becomes compulsive.8 For example, P rats self-administer large amounts of alcohol and develop physical dependence under a long-term, free-choice access to a single concentration of EtOH and water.9,10 Moreover, following a period of alcohol deprivation, P rats transiently increase their voluntary intake above baseline drinking conditions upon re-instatement of EtOH.11

This phenomenon, called the alcohol deprivation effect (ADE), mainly depends on the genetic background of the animal and is hypothesized to model alcohol craving and relapse observed in humans.12

It is important to note that while an ADE has been demonstrated in P rats after a single deprivation period that follows a long-term, continuous access to free-choice EtOH, other rat lines selectively bred for high alcohol consumption do not exhibit an ADE after a single abstinence phase in a similar behavior paradigm.11 In addition to rats, the ADE phenomenon has been reported in humans,13 monkeys,14 and mice.12

Although a pattern of alcohol intake is not explicitly included in the DSM-5 criteria for AUD diagnosis, 2 of the criteria do relate to quantity and frequency of consumption.15 Consequently, because quantity and frequency of alcohol intake are associated with problematic, high-risk drinking, the consumption phenotypes must be examined in detail, in both humans and other animals.16

The most commonly reported measure in rodent studies is the total voluntary alcohol intake during a 24-hour 2-bottle choice test. However, it is known that this particular drinking phenotype is only moderately associated with phenotypes observed and studied in humans.16 Micro-patterns of alcohol consumption within a 24-hour period therefore must be analyzed in order to avoid potential pitfalls in the interpretation of results.9,17

To illustrate this crucial point, consider the following example. A rat may ingest relatively high amounts of EtOH throughout the day by either drinking a large number of small volume bouts or by consuming high levels over shorter periods of time. The latter example, however, is more relevant to a human AUD. The incorporation of these parameters into nonhuman animal research will help model addictive behavior to alcohol that is observed in human alcoholics and will hence contribute to face validity.16

Comprehensive measurements of drinking behavior during episodes such as binge, abstinence, and relapse are essential to reveal the factors and mechanisms that underlie alcohol abuse and dependence.

Moreover, translational models of alcoholism must provide detailed information on drinking parameters while preserving the “naturalistic” self-administration behaviors in the home cage environment.18 The free-choice paradigm, a component of the preference test wherein rodents are offered 2 or more types of fluid (eg, EtOH and water), has been an extremely useful tool for quantification of behavioral responses to assess the influence of genetic and environmental manipulations on voluntary EtOH consumption.19 The 2-bottle choice protocol involves weighing the bottles throughout the day (eg, once every 24 hours), and thus the presence of the investigator or spillage may interfere with the results.9

Although methodological improvements have been made in measuring home-cage consummatory behavior (eg, “lickometer”), the use of this apparatus still relies on periodic removal of the bottles from the home cage.9

Recently, Vengeliene and colleagues described a novel, more sophisticated drinkometer system for monitoring home-cage, long-term voluntary EtOH drinking behavior in Wistar rats. Moreover, they applied Fourier analysis to characterize the consumption patterns of EtOH during a 24-hour period, including the approximate mean of EtOH intake, the maximal peak of EtOH intake, and the number of maximal peak occurrences in 1 hour. Results of this elegant study indicate that EtOH consumption patterns during baseline follow a stable, characteristic diurnal rhythm, and that the repeated EtOH deprivation results in an increased drinking frequency and altered diurnal drinking patterns.20

Taken together, the available data indicate that a single prolonged abstinence phase can shape the motivation to self-administer EtOH upon re-instatement, thus altering the microstructure of drinking in adult rats. And, according to findings reported by Vengeliene et al., alcohol deprivation may regulate EtOH consumption by means of change in the frequency of EtOH drinking bouts but not by means of change in bout size.20

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