Researchers face a conceptual challenge in attempting to achieve consilience between human and animal drinking phenotypes. Discussion of human drinking phenotypes has an assumed endpoint, namely drinking related to a clinical alcohol use disorder. The clinical construct of alcoholism (as opposed to simple physical dependence, addressed in a companion paper), is based on criteria that attempt to capture a maladaptive pattern of alcohol use. Thresholds for heavy drinking that constitute such a pattern in humans - "too much too fast" or "too much too often" – will often lead to adverse social or medical consequences. There is clearly no equivalent to adverse social or medical consequences in experimental animals, thus it may seem difficult to establish what constitutes "excessive" or "heavy" drinking in animal models.
A potentially useful tool to achieve consilience, or translation, despite these limitations, is offered by pharmacology. Translational research involving the opiate antagonist naltrexone has already informed this issue to some extent (see O’Malley & Froehlich, 2003
). Naltrexone, a drug that reduces acute positive reinforcement by alcohol (McCaul et al., 2000
), would be predicted to primarily limit drinking phenotypes related to the “too much too fast” construct, irrespective of whether the subject is alcohol dependent (King et al., 1997
). Emergence of additional pharmacological probes with well defined pharmacodynamic modes of action, such as kappa-opioid (e.g., nor-binaltorphimine, Walker and Koob, 2008
) or CRH1 receptor antagonists (Seymour et al., 2003
), will facilitate translation between human and animal models. It should be noted though that the use of animal models to test pharmacological probes is not without limitations. According to Egli (2005
, p. 309), “it is not clear at present whether any single paradigm or combination of paradigms differentiates clinically effective from clinically limited compounds.” In his review, Egli cites examples of “false positives”—medications that have been found to alter drinking behavior in animal models, but have not demonstrated clinical efficacy.
In addition to conducting more translational research involving pharmacological probes, a second overarching suggestion for enhancing consilience concerns the role of individual differences. In animal models, greater effort to evaluate the effects of individual differences that are important to drinking (or abstinence) in humans (e.g., sex, nicotine dependence) would help to enhance consilience in the study of all of the consumption phenotypes discussed here.
Several specific steps could also be taken by researchers in order to improve consilience between common human and animal alcohol consumption phenotypes. In , we present a short list of consumption phenotypes for which consilience could be enhanced and some ideas for future research that may help to accomplish this goal.
Suggestions for the further development of consumption phenotypes in a manner that enhances consilience
Several steps could be taken to adapt human ad libitum consumption paradigms in order to obtain information relevant to abstinence from alcohol, an important phenotype frequently measured in clinical and epidemiological studies. At a minimum, investigators could report the number of subjects who opt not to drink after a priming drink or cue exposure. A further developmental step would be to provide participants with different incentives to not drink and then to observe the effects of these measures on the decision to drink or abstain. For example, a reward (e.g., earning money) or punishment (e.g., loss of payment) could be provided to those who abstain or drink during the session. With these modifications, researchers could then test the effects of various manipulations and individual differences on the decision to drink or abstain.
In animals, a potentially useful measure of the decision to stop drinking is provided by instrumental schedules in which both ethanol and an alternative reinforcer are available. Gisburg and Lamb (2008) proposed a model in which sucrose and ethanol are both available. In one condition, signaled by an environmental cue, a particular response gives access to ethanol on a relatively dense schedule, while an alternative response gives access to sucrose on a lean schedule. In the alternative condition, signaled by a different cue, sucrose is available on a denser schedule. With adequate training, rats learn to switch responding between ethanol-appropriate responses and sucrose-appropriate responses, according to the schedule currently signaled. Thus, the environmental cue that signals increased sucrose availability could be considered as triggering a decision to “abstain” from ethanol. This schedule seems to offer an approach that could be adapted for use in both animal and human research.
The conventional, two-bottle choice paradigm could also be modified, such that if an animal chooses ethanol, the alternate reinforcer (e.g., sucrose-treated water) would become unavailable for a certain period of time. This modification would enable researchers to determine the animals’ willingness to trade another resource for ethanol. This would enhance consilience with human behavioral economic ad libitum
paradigms in which participants consume alcohol in exchange for reductions in their pay for participating in the study. The repeated choice of alcohol over alternate reinforcers (e.g., spending time with family or at hobbies) is an important aspect of alcohol use disorders (APA, 1994
) and therefore, this is an important area of further research.
Another issue that is both relevant to the decision to drink or abstain and a key component of alcohol use disorders is consumption in the face of negative consequences (APA, 1994
). While this phenomenon is a clear focus of clinical and epidemiologic/survey research in humans, it has not been modeled well in the lab on either the human or the animal side. The closest thing to a negative consequence in human laboratory studies is the loss of a small portion of one’s monetary payment due to the decision to drink in behavioral economic models (e.g., O’Malley et al., 2002
). To our knowledge, negative consequences have not been modeled effectively in the animal ethanol literature, although there are examples from the cocaine literature (see Deroche-Gamonet et al., 2004
and Vanderschuren and Everitt, 2004
). In designing such models, investigators should keep in mind the uncertain nature of negative consequences, namely that negative consequences do not occur on every drinking occasion.
Heavy or binge drinking
Consilience among survey, clinical and human laboratory studies would be improved if researchers make two modifications to their research practices. One, in surveys and clinical trials, estimated BACs should be calculated to parallel the direct measurement of BAC in the laboratory. Two, in human laboratory studies, the number of participants who consumed enough alcohol to exceed heavy drinking cut-offs should be reported to parallel measures in survey and clinical research. In animal studies, researchers should report blood/breath alcohol concentrations (estimated or actual) and develop for all species cut-offs for excessive consumption based on measures of impairment similar to those used with human subjects, as Grant et al. (2008)
did for cynomolgus monkeys.
Alcohol use within 24-hour periods, several days and over the long-term
While the modeling of ethanol consumption over several days is a strength of animal research, researchers do not typically provide information regarding patterns of alcohol consumption within 24-hour periods, leading to potential problems in the interpretation of results. For example, an animal may be able to achieve what appears to be a relatively high daily g/kg ethanol intake by drinking a large number of small volume bouts, most of which fail to produce a meaningful pharmacological effect. This pattern is not as relevant to human alcohol use disorders as high levels of consumption over shorter periods of time. One solution is to observe patterns of licking using tools such as lickometers, operant chambers or other methods that allow a fine-grained temporal analysis of ethanol intake (e.g., number of drinking bouts per day, inter-bout interval, etc.; see Files et al., 1998
and Grant et al., 2008
for examples of these techniques in research with rats and primates, respectively). Similar measures of patterns of consumption are common in human laboratory research, thus increased use of these techniques in animal research would enhance consilience.
Human laboratory models in which drinking occurs over several days are rarely used. Instead, researchers usually study alcohol consumption over a period lasting no longer than several hours. Adding additional sessions would permit examination of whether drinking increases in subsequent days in a given model, along with what experimental manipulations and/or individual differences predict drinking over several days.
In addition, the inclusion of prospective follow-up studies to examine how drinking topography predicts drinking in the long-term and the development of dependence provides another opportunity for achieving consilience between human laboratory research and animal models. Schuckit’s study documenting that a low subjective response to a fixed dose of alcohol administered in the laboratory predicts alcoholism 10 years later (Schuckit, 2004) highlights the potential of this approach in human subjects. Grant and colleagues’ (2008)
study is an excellent example of this approach using nonhuman primates.
BAC and other biomarker phenotypes
Further research on biomarkers is needed in both human and animal research. Noninvasive methods for monitoring BAC in animals and sensors that unobtrusively monitor BACs continuously in the field for clinical and survey research would represent important advances. Metabolites of alcohol, such as Ethyl Glucuronide (EtG), are promising, relatively new biomarkers (Peterson, 2004
), however further research is needed (Peterson, 2004
; SAMHSA, 2006