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David M. Lyons: Chapter 6. Animal Models, in The American Psychiatric Publishing Textbook of Psychopharmacology, 4th

Edition. Edited by Alan F. Schatzberg, Charles B. Nemeroff. Copyright ©2009 American Psychiatric Publishing, Inc. DOI:

10.1176/appi.books.9781585623860.408558. Printed 5/10/2009 from www.psychiatryonline.com

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Chapter 6. Animal Models

ANIMAL MODELS: INTRODUCTION

Practical limitations and ethical concerns restrict opportunities for randomized, controlled trials of

potentially new drug treatments for human psychiatric disorders. Prospects for discovering the

neural mechanisms of action of established therapeutic drugs are also less prevalent in psychiatry

than other fields of medicine, because biopsies of diseased brain tissue in humans are seldom

performed. Animal models are therefore essential for screening new drugs and for understanding

how drug therapies in humans restore the neural basis of mental health. This chapter addresses the

validity, utility, and limitations of animal models in psychopharmacological research.

MODEL TYPES AND VALIDITY

Two principal types of animal models are prevalent in psychopharmacology. Assay models are used

to screen drugs with unknown therapeutic potential and need not resemble anything seen in a

psychiatric disorder. The validity of assay models is determined by their ability to predict that a

drug reliably belongs to a therapeutic class. In rats, for example, passive avoidance deficits induced

by olfactory bulbectomies are reversed by antidepressants but not by psychostimulants,

neuroleptics, or anticholinergics (Song and Leonard 2005). New drugs with unknown therapeutic

potential that reverse bulbectomy-induced deficits in rats are therefore considered to be possible

antidepressants. Assay models also satisfy additional criteria, including ease of use, high

throughput capacity, reproducibility, and economic concerns.

The second principal type of animal model simulates an aspect of interest in a psychiatric disorder.

Simulation models are used to investigate the biology of psychiatric disorders or the mechanisms of

action of psychotherapeutic drugs. In addition to the criterion of predictive validity described above

for assay models, simulation models are often evaluated for two other aspects of validity.

Face validity refers to phenomenological similarities between the animal model and the human

psychiatric condition. As originally proposed by McKinney and Bunney (1969), animal models of

human mental illness have a high degree of face validity when the following criteria are met: the

model is produced by etiological factors known to produce the human disorder, the model

resembles the behavioral manifestations and symptoms of the human disorder, the model has an

underlying physiology similar to the human disorder, and the model responds to therapeutic

treatments known to be effective in human psychiatric patients. How these criteria are evaluated

and established has been described in detail elsewhere (McKinney 2001; Weiss and Kilts 1998).

Construct validity refers to the theoretical rationale for linking a psychiatric disorder to an endpoint

measured in the animal model. To establish construct validity, a theory for understanding a

disorder is mapped or shown to be equivalent to an endpoint in the animal model (Sarter and Bruno

2002). Disease heterogeneity and related concerns that no single animal model can capture the

complexities of an entire disorder have shifted attention away from modeling disorders as a whole

(McKinney 2001; Insel 2007) to focus on psychiatric endophenotypes (Gould and Gottesman 2006).

The endophenotype strategy presupposes that each disorder comprises behavioral, physiological,

neuroanatomical, cellular, and molecular components that are more proximal to causal risk factors

than are the actual disorders defined in DSM-IV-TR (American Psychiatric Association 2000;

Arguello and Gogos 2006). Psychiatric endophenotypes are conceptualized as mediating the link

between genetic or environmental risk factors and the resulting disorder (Figure 6–1). Precise

delineation of endophenotypes also serves to highlight the fact that certain features of psychiatricPrint: Chapter 6. Animal Models

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disorders—for example, diminished verbal recall, self-conscious emotions, delusions of control,

impaired theory of mind, and suicidal ideation—are likely unique to humans. Many other

endophenotypes are, however, amenable to modeling in animal research, as will be described in the

following sections of this chapter.

FIGURE 6–1. Psychiatric endophenotypes mediate the link between causal risk factors and the

resulting psychiatric disorders defined in DSM-IV-TR.

Representative examples and nonexhaustive lists of risk factors, endophenotypes, and disorders are provided

to illustrate this theoretical framework for psychiatry neuroscience and psychopharmacological research.

Features that confer a high degree of validity for simulation models are often poorly suited for

animal assay models used in drug screening research. An example is the typical delay in response

onset for conventional antidepressants. On the other hand, simulation models that achieve all three

aspects of validity may be better suited to identify substantively new drugs that differ from those

used to establish an assay model. Excessive reliance on assay models may increase the tendency to

perpetuate the same side effects as those produced by known medications. The following sections

selectively illustrate how animal models have advanced our understanding of the

psychopharmacology and biology of depressive disorders.

LEARNED HELPLESSNESS

One of the earliest and most studied models of depression emerged from now classic studies of

learned helplessness (Overmier and Seligman 1967; Seligman and Maier 1967) and uncontrollable

stress (Weiss 1968). Animals exposed to uncontrollable stress, but not those exposed to

controllable stress, exhibit diminished reactivity to rewarding stimulation, altered sleep patterns,

social impairments, and deficits in learning appropriate avoidance–escape behavior (Maier 2001;

Vollmayr et al. 2004; Weiss and Kilts 1998). Exposure to uncontrollable stress also induces

significant changes in noradrenergic (Weiss 1991), serotonergic (Maier and Watkins 2005), and

GABAergic (Minor and Hunter 2002) brain systems hypothesized to mediate the behavioral

endpoints measured in learned helplessness models. Avoidance–escape deficits in rats are reversed

by subchronic treatment with known antidepressants, including tricyclic antidepressants (TCAs),

monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and

atypical antidepressants. Stimulants, neuroleptics, sedatives, and anxiolytics do not reverse learned

helplessness effects (Weiss and Kilts 1998).

These and related findings demonstrate that learned helplessness models have a high degree of

validity in terms of etiology (uncontrollable stress), behavioral symptoms (anhedonia, passivity,

disrupted sleep), pathophysiology (sensitization of serotonergic neurons), and response to

conventional antidepressants. In rats, however, learned helplessness persists only for several days,

whereas depression in humans may last for months. A possible explanation for this discrepancy is

that rats do not spontaneously generate perseverative memories or ruminations about theirPrint: Chapter 6. Animal Models

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experiences beyond the context in which the experiences occurred. By reminding rats of a stressful

experience through repeated exposure to contextual cues, Maier (2001) discovered that learned

helplessness manifestations in rats can be prolonged. These findings lend support to the view that

stressful perseverative thinking plays a prominent role in the maintenance of human depressive

disorders (Brosschot et al. 2006; Nolen-Hoeksema 2000).

CHRONIC STRESS

Chronic stress models in rodents prevent acclimatization by presenting a variety of stressors in an

unpredictable sequence over several weeks. Rats exposed to immobilization, immersion in cold

water, and other stressors fail to show the typical increase in open-field activity observed in rats

not exposed to chronic stress (Katz et al. 1981). A variety of antidepressants restore normal

open-field activity in rats exposed to chronic stress, whereas nonantidepressants do not reproduce

this effect (Willner 1990). A modified version of the chronic stress model employs milder

manipulations, such as exposure to flashing lights, intermittent white noise, and short-term

deprivation of food or water. After several weeks of chronic mild stress, rats exhibit decreased

consumption of a palatable sucrose solution (Willner 1997). This measure of anhedonia is restored

to normal in rats who receive concurrent treatment with an antidepressant during exposure to

stress (three different TCAs and two atypical antidepressants were effective in restoring normal

consumption behavior). Evidence that antidepressants reverse the anhedonic effects of chronic

stress by potentiating dopamine neurotransmission comes from studies in which the therapeutic

response to TCAs was reversed by administration of dopamine receptor antagonists (Willner 1997).

These findings concur with numerous studies linking dopamine neurotransmission with stress (Pani

et al. 2000), reward processing (Martin-Soelch et al. 2001), and the neural mechanisms of action

for antidepressants (Willner et al. 2005).

In the original chronic stress model, it was reported that sustained elevations in glucocorticoid

levels were restored to normal by antidepressants (Katz and Sibel 1982; Katz et al. 1981). These

findings are of interest because patients with major depression often present with increased levels

of the glucocorticoid stress hormone cortisol (see Chapter 45, “Neurobiology of Mood Disorders”).

In rodents, however, chronically elevated glucocorticoid levels are difficult to maintain (Rivier and

Vale 1987; E. A. Young and Akil 1985), and rodent models often rely on manipulations that differ

from the stressors that induce or exacerbate depression in humans. An intriguing exception is the

visible burrow model, which enables small groups of rats to produce natural stress-engendering

social interactions well suited for behavioral, neural, and hormonal investigations of stress

pathophysiology (Blanchard et al. 1995).

SOCIAL LOSS

Life events that signify loss or departure from the social network are risk factors for the

development of hypercortisolism and depression in humans (Biondi and Picardi 1996; Kendler et al.

2002). A model of social loss–induced hypercortisolism based on species-typical patterns of social

organization has been developed in squirrel monkeys (Parker et al. 2003). In their natural

environment, squirrel monkeys live in sexually segregated groups. Adult males and females within

a group spend most of their time with same-sex companions, and social interactions between the

sexes are limited to mating activities (Lyons et al. 1992). When adults are separated from

same-sex companions, they respond with increased cortisol levels that frequently persist for

several weeks (Lyons and Levine 1994; Lyons et al. 1999). Hypercortisolism occurs not only when

monkeys are separated and temporarily housed alone but also when males and females are housed

without same-sex companions in male–female pairs and when males are housed without male

companions in multifemale groups (Mendoza et al. 1991).

Hypercortisolism in this animal model is initially driven by hypersecretion of adrenocorticotropic

hormone (ACTH). This finding concurs with the widely held view that stress induces hypothalamic

release of corticotropin-releasing factor (CRF), which stimulates pituitary secretion of ACTH and

thereby triggers secretion of cortisol from the adrenal cortex (see Chapter 7,

“Psychoneuroendocrinology”). In socially separated monkeys, however, cortisol levels remainPrint: Chapter 6. Animal Models

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elevated while significant reductions occur in plasma levels of ACTH (Lyons and Levine 1994). Low

ACTH levels also occur in the context of hypercortisolism in humans with major depression (Murphy

1991). Despite reductions in ACTH, hypercortisolism is maintained because of enhanced adrenal

responsiveness to ACTH in socially separated monkeys (Lyons et al. 1995) and in humans with

major depression (Plotsky et al. 1998). The low ACTH levels seen in major depression are also

observed in response to administration of CRF (Gold et al. 1986). Metyrapone blockade of cortisol

biosynthesis abolishes the attenuated ACTH response to exogenous CRF (von Bardeleben et al.

1988), and metyrapone alone increases baseline ACTH levels in humans with major depression (E.

1. Young et al. 1997) and monkeys subjected to social separation (Lyons et al. 1999). These results

together suggest that hypercortisolism inhibits the response to excessive CRF at the level of

pituitary corticotrophs. Evidence that hypercortisolism and excessive CRF are also involved in

behavioral and not just neuroendocrine aspects of depression in humans comes from animal models

described in the next section.

PHYSIOLOGICAL MANIPULATIONS

Direct administration of naturally occurring neuropeptides, hormones, and cytokines has been used

in animal models to identify physiological factors that induce behavioral symptoms of depression in

humans. For example, chronic stress levels of cortisol systemically administered to squirrel

monkeys impair prefrontal-dependent cognitive control of impulsive behavior (Lyons et al. 2000).

Cortisol administered to healthy humans induces prefrontal-dependent cognitive impairments that

resemble those that are caused in humans by prefrontal lesions (Lupien et al. 1999; A. H. Young et

1. 1999). Humans with psychotic major depression consistently present with endogenous

hypercortisolism (Nelson and Davis 1997), and patients with psychotic major depression are

impaired on standardized tests of prefrontal cognitive functions (Schatzberg et al. 2000). Based on

these findings, drugs that block cortisol at the receptor level are now being tested as novel

treatments for psychotic major depression (DeBattista and Belanoff 2006) and bipolar disorder (A.

1. Young 2006).

In various animals, administration of CRF in the brain increases heart rate, arterial blood pressure,

limbic brain glucose metabolism, and depressive- and anxiety-like behavior (Heinrichs and Koob

2004; Lowry and Moore 2006; Strome et al. 2002). Conversely, mice genetically engineered to be

deficient in the CRF type 1 receptor (CRF-R1) demonstrate diminished depressive- and anxiety-like

behavior in response to CRF administration (Muller et al. 2003). These findings from animal models

support clinical studies of depression in humans (Nemeroff and Vale 2005) and suggest that drugs

that dampen CRF signaling may be therapeutic for patients with depressive disorders. Receptors for

CRF, and particularly CRF-R1, are therefore targets of interest in contemporary drug development

(Chen 2006).

In rodents and monkeys, peripheral administration of proinflammatory cytokines (i.e.,

interleukin-1) mimics the effects of stress as a cause of so-called sickness behavior (Hennessy et

1. 2001). Sickness behavior in animals is characterized by anhedonia, reduced activity, diminished

social and sexual interests, increased sleep, and behaviors reminiscent of depression in humans.

Administration of interferon, a potent inducer of proinflammatory mediators, triggers depression in

a subset of humans receiving interferon treatment for cancer or hepatitis C (Asnis and De La Garza

2006). These findings suggest that drugs that block proinflammatory mediators may be novel

antidepressants. Recent support for this possibility comes from a guinea pig model of

stress-induced sickness behavior (Hennessy et al. 2007).

EARLY LIFE STRESS

Early exposure to parental neglect, child abuse, and severe forms of stress is a risk factor for the

development of mood and anxiety disorders. Rhesus macaque monkeys raised without mothers

tend to exhibit depression-like behavior (Kraemer 1997), fragmented sleep patterns (Kaemingk and

Reite 1987), and excessive consumption of alcohol (Fahlke et al. 2000). Ecologically informed

studies of maternal availability have identified similar effects in primate psychosocial development.

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impaired on tests of psychosocial and emotional functions (Rosenblum and Andrews 1994). These

same monkeys in early adulthood exhibit elevated cerebrospinal fluid levels of monoamines,

somatostatin, and CRF (Coplan et al. 2006). Prenatal stress decreases hippocampal volume and

inhibits neurogenesis in the dentate gyrus of adolescent rhesus monkey offspring (Coe et al. 2003).

Conversely, all known antidepressants increase neurogenesis in the dentate gyrus, as modeled in

adult monkeys (Perera et al. 2007), tree shrews (Czeh et al. 2001), and rodents (Drew and Hen

2007).

Hippocampal volumes are smaller in humans with major depression compared with healthy control

subjects (Videbech and Ravnkilde 2004), and preliminary evidence in humans suggests that prior

exposure to early life stress causes hippocampal volume loss (Vythilingam et al. 2002). To test this

hypothesis, we recently examined early life stress and hippocampal volume variation in squirrel

monkeys (Lyons et al. 2007). Paternal half-siblings raised apart from one another by different

mothers in the absence of fathers were randomized to intermittent postnatal stress or no-stress

conditions from 10 to 21 weeks of age. After weaning, at 9 months of age, all monkeys were

socially housed in identical conditions. Sexual maturity occurs at 2–3 years of age, and the average

maximum squirrel monkey life span is 21 years (Brady 2000). In early adulthood, at 5 years of age,

hippocampal volumes were determined in vivo from T1-weighted brain images acquired by

magnetic resonance imaging (MRI).

Hippocampal volumes did not differ with respect to prior postnatal stress versus no-stress

conditions in squirrel monkeys (Lyons et al. 2001). Rhesus monkeys raised in social isolation do not

show hippocampal atrophy despite striking changes in other brain systems and associated behavior

(Sanchez et al. 1998). In keeping with studies of humans (Sullivan et al. 2001; van Erp et al. 2004),

however, significant heritabilities were discerned by paternal half-sibling analysis of squirrel

monkey hippocampal volumes (Lyons et al. 2001). These and related findings suggest that the

morphology of specific brain regions is determined in part by genes (Lyons 2002). Moreover, we

found that small hippocampal volumes predicted increased stress levels of ACTH after pretreatment

with saline or hydrocortisone (Lyons et al. 2007). Small hippocampal volumes may be a risk factor

for, and not just an effect of, impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis

response to stress. Similar studies in humans are needed to determine whether small hippocampi

are a marker for HPA axis dysregulation in major depression.

GENETIC MANIPULATIONS

Major depression is a heritable disorder that likely involves multiple genes, each with small effects

(Wong and Licinio 2001). Targeted gene deletions and gene transfers in animal models are

beginning to elucidate the functional significance of potentially relevant genes (Insel 2007).

Consider, for example, dysregulation of the HPA axis evinced in depression by an increase in

cortisol levels (see Chapter 45, “Neurobiology of Mood Disorders”). Receptors for cortisol are

densely expressed in the prefrontal cortex (Webster et al. 2002), where they function as

transcription factors that regulate gene expression (Chrousos and Kino 2005). Hundreds of genes in

prefrontal cortex appear to be differentially expressed in humans with a history of major

depression based on postmortem analysis of whole-genome microarray data (Choudary et al. 2005;

Evans et al. 2004; Iwamoto et al. 2004; Sequeira et al. 2006). Genetic manipulations of receptors

for cortisol are not yet feasible in human patients but have recently been studied in various animal

models (Boyle et al. 2005; Kaufer et al. 2004; Ridder et al. 2005; Wei et al. 2004). These studies

suggest that high-throughput technologies designed to identify candidate genes regulated by

receptors for cortisol may yield novel targets for the development of new antidepressants.

Another promising genetic approach involves selective breeding of rodents and subsequent

genomewide scans to identify predisposing candidate genes. An intriguing example is the

swim-test-susceptible rat, which is bred for extreme passivity in response to uncontrollable stress

(Weiss and Kilts 1998). In the swim-test-susceptible rat, eight different antidepressants restore

normal swim-test activity after exposure to uncontrollable stress. Four drugs that produce

false-positive results in swim tests administered to normal rats (Porsolt et al. 1991) all fail toPrint: Chapter 6. Animal Models

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restore normal swim-test activity in swim-test-susceptible rats. None of the eight tested

antidepressants have any effect on a selectively bred line of swim-test-resistant rats, indicating

that the detection of antidepressants is best achieved with genetically susceptible rats (Weiss and

Kilts 1998). This model is well suited to identify genes involved in a common mechanism of action

of diverse antidepressants.

A related strategy combining genetic and developmental approaches to investigate

gene–environment interactions is exemplified by studies of BALB/cByJ mice, which typically are

more reactive to stress than C57BL/6ByJ mice (Anisman et al. 1998). When stress-susceptible

BALB/cByJ mouse pups are raised by stress-resistant C57BL/6ByJ dams, the development of

excessive reactivity to stress is diminished in the cross-fostered pups. However, when

stress-resistant C57BL/6ByJ pups are raised by stress-susceptible BALB/cByJ dams, the

development of subsequent stress reactivity is not affected in the cross-fostered pups. This model

demonstrates that genetic factors affect mother–infant interactive styles, which in turn influence

the subsequent development of stress susceptibility in mice.

A complementary approach involves targeted disruptions of gene expression in specific brain

regions only during critical periods of postnatal brain development. An example is provided by mice

engineered to lack the serotonin1A receptor (5-HT1AR) protein. These mice exhibit increased

anxiety-like behavior on a variety of tests. Selective expression of 5-HT1AR in the hippocampus and

cortex, but not the raphe nuclei, restores to normal the behavior of 5-HT1AR knockout mice (Gross

et al. 2002). Additional evidence suggests that tissue-specific 5-HT1AR expression during postnatal

development, but not in adulthood, is necessary to achieve the behavioral rescue effect. This model

indicates that developmental changes in 5-HT1AR gene expression within specific brain regions are

involved in the emergence of anxiety-like behavior in adulthood.

UTILITY AND LIMITATIONS

Most animal models used to study aspects of depression in humans have utilized males, but the

prevalence of depression in humans is nearly two times higher in women than in men (Shively et al.

2005). Another limitation of animal models is the tendency to focus on single factors as the cause

of depression in humans (Willner 1990). In certain cases, one causal factor may be identified, but

more often than not, depression evolves from a nexus of causal risk factors that accumulate over

the life span (Kendler et al. 2002). Attempts to model aspects of depression in animals based on

one causal factor may be impractical if no single factor is sufficiently potent to trigger the

development of depression in humans.

Prefrontal cortical enlargement in humans and associated cognitive complexities raise additional

concerns for animal models of psychiatric disorders (Keverne 2004). The difficulty stems from

problems in identifying homologous brain regions in humans and animals (Porrino and Lyons 2000;

Preuss 1995; Sasaki et al. 2004), especially for the rodents now widely used in neuroscience

research. Transgenic mouse models likewise require homologous genes, and the resulting mouse

phenotypes are not necessarily isomorphic with the human condition, because genes expressed on

different backgrounds can produce different phenotypes (Yoshiki and Moriwaki 2006).

Despite these concerns, many important aspects of human psychiatric disorders are amenable to

modeling in animal research. Because the life span of most animals is shorter than that of humans,

longitudinal studies of development are facilitated by animal models. Randomized, controlled

experiments can be conducted in animals without the common confounds that characterize clinical

studies, such as comorbidity, polydrug abuse, and medication effects. Animal models also provide

brain tissue of the highest possible quality for cellular and molecular research. Discoveries first

made in clinical settings and subsequently tested in animals form the foundation of psychiatric

neuroscience and will continue to play a key role in psychopharmacological research.

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