Animal Models of Psychiatric Disorders and Their Relevance to Alcoholism

Alcohol Research & Health,  Fall, 2000  by Robert Hitzemann

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Animal models are important tools in the study of psychiatric disorders, including alcoholism,1 because they allow the use of research methods that cannot be used for ethical reasons in humans. Consequently, scientists have developed numerous approaches to evaluate the validity and reliability of animal models for studying human behavior and human disorders. Researchers have developed animal models of schizophrenia, fear and anxiety, depression, and alcoholism all of which are being used to study the relationship between alcoholism and co-occurring psychiatric disorders. These models may help researchers and clinicians determine how best to treat patients with alcoholism and co-occurring psychiatric disorders. KEY WORDS: animal model; behavioral and mental disorder; AOD (alcohol or other drug) dependence; comorbidity; validity (research methods); reliability (research methods); schizophrenia; emotional and psychiatric depression; fear; anxiety; animal strains

Scientists are increasingly being asked both to develop and to defend the use of animal models for studying psychiatric disorders that appear to be uniquely human, such as alcohol and other substance abuse, schizophrenia, depression, and anxiety These disorders either are not observed in animals or cannot be directly measured (i.e., the animals cannot verbally indicate what they think or feel). This review examines some of the animal models used to study these disorders, with a special emphasis on the use of these models in the search for genes that contribute to the disorders.

The general argument for using animal models in behavioral research is that such models allow researchers to test specific hypotheses under highly controlled conditions using methods that are either impossible or unethical to use in humans. For example, researchers can create generically altered mice (e.g., mice with a foreign gene added to their genetic makeup) to examine the influence of specific gene products on behavior. Recent advances in genetic engineering allow investigators to activate or inactivate specific genes in specific regions of the brain. Other research techniques that scientists can only use in animals include injecting materials directly into the brain and implanting brain electrodes.

Critics of animal models in behavioral research have argued that these studies could be conducted using animals with simpler systems, such as worms, or computer simulations. This argument is based on the theory that the basic processes that increase or decrease the strength of communication between and among cells (i.e., the synaptic connections), and therefore influence behavior, are probably similar in organisms as "simple" as the worm and as "complex" as the human. In higher vertebrates, however, these basic processes combine into highly sophisticated and complex arrays that no computer system has yet been able to duplicate. Thus, throughout the foreseeable future, researchers investigating complex behavioral traits and characteristics (i.e., phenotypes) of humans will continue to be forced to use animals with well-developed central nervous systems rather than simpler organisms or computer models. Although rodents are not as appropriate as are primates for modeling all aspects of a specific human behavior , rodents will carry the main workload of animal research for some time to come.

This article describes animal models of schizophrenia, fear and anxiety, and depression. It also discusses the use of animal models in studying alcoholism and co-occurring psychiatric disorders. First, however, validity and reliability--the criteria used to evaluate animal models--are defined.

CRITERIA FOR ANIMAL MODELS OF HUMAN BEHAVIOR

Validity and reliability are the main criteria for evaluating animal models (for a review, see Geyer and Markou 1995). This article first examines the four aspects of validity--face, predictive, etiological, and genetic--and then focuses on the issue of reliability.

Face validity refers to the similarity between the animal model and the specific human behavior of interest. Superficially, it would seem that the animal behavior should mimic the related human behavior as much as possible. For example, mouse and man display similar responses to a loud noise (i.e., startle responses). Both respond with an eye-blink, a rapid change in heart rate, and some form of whole body movement (e.g., a mouse jumps, a person jerks). However, when studying the regulation of the startle response, the observed response need not be obviously similar. For investigative purposes, the results would be just as informative if the mouse yawned or curled its tail, providing that these phenotypes could be reliably measured and had predictive, etiological, and genetic validity (described later in this article).

Researchers studying animal models of human psychiatric disorders are increasingly examining intermediate phenotypes or endophenotypes (i.e., markers that may indicate a susceptibility to a disorder). Endophenotypes generally are not immediately visible, but they may contribute to the susceptibility to develop a particular behavior or syndrome. The use of endophenotypes is helpful in that the underlying neurobiology (i.e., the mechanisms or mechanism by which the endophenotype increases susceptibility) is frequently known and thus researchers have the advantage (i.e., in the case of genetic studies) of linking specific gene(s) that may influence the behavior with specific brain mechanisms. A disadvantage of endophenotypes, however, is their lack of specificity. For example, prepulse inhibition of the acoustic startle response (ASR) [2] serves as an operational measure, or endophenotype, for the deficits in the mechanisms that allow normal individuals to filter or block most of the sensory and cognitive stimu li that they receive (i.e., sensory gating abnormalities). Such abnormalities are often seen in schizophrenia (see table 1). However, whereas schizophrenics show poor prepulse inhibition, deficits also are seen in Tourette's syndrome, bedwetting incidents, and during the menstrual cycle.