3
Recognition and Assessment of Stress and Distress

INTRODUCTION

Recognition of distress in laboratory animals requires knowledge of what is normal for the species and strain used. Genetically modified animals should be evaluated in reference to the normality of their genotype.


Most vertebrate species routinely experience some type of distress either in natural settings (e.g., during a predator attack) or as part of normal development (e.g., following natural maternal separation in rhesus monkeys; Berman et al. 1994). The recognition of distress in laboratory animals, however, requires an understanding of what is “normal” for the species being studied. In this chapter we consider the use of behavioral and physiologic variables to recognize stress and distress.

Lab animals should behave according to species-specific normal behavioral, morphologic, and physiologic values (see Novak and Suomi 1988 and Snowdon and Savage 1989 for a discussion of psychological well-being in captive nonhuman primates). Species-specific normative ranges have been established for many parameters (e.g., hematocrit, blood glucose, body temperature, heart rate, blood pressure, respiration rate). Standardized growth curves and weight ranges can be obtained from laboratory animal suppliers for most species.

Recognition of stress and distress in laboratory animals requires an understanding of the species-, gender-, and age-specific norms, because the normal range of some of these variables may vary as a function of gender, age, physiological state, or genetic characteristics. Values outside



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3 Recognition and Assessment of Stress and Distress INTRODuCTION Recognition of distress in laboratory animals requires knowledge of what is normal for the species and strain used. genetically modified animals should be evaluated in reference to the normality of their genotype. Most vertebrate species routinely experience some type of distress either in natural settings (e.g., during a predator attack) or as part of normal development (e.g., following natural maternal separation in rhesus monkeys; Berman et al. 1994). The recognition of distress in laboratory animals, how- ever, requires an understanding of what is “normal” for the species being studied. In this chapter we consider the use of behavioral and physiologic variables to recognize stress and distress. Lab animals should behave according to species-specific normal behav- ioral, morphologic, and physiologic values (see Novak and Suomi 1988 and Snowdon and Savage 1989 for a discussion of psychological well-being in captive nonhuman primates). Species-specific normative ranges have been established for many parameters (e.g., hematocrit, blood glucose, body tem- perature, heart rate, blood pressure, respiration rate). Standardized growth curves and weight ranges can be obtained from laboratory animal suppliers for most species. Recognition of stress and distress in laboratory animals requires an understanding of the species-, gender-, and age-specific norms, because the normal range of some of these variables may vary as a function of gender, age, physiological state, or genetic characteristics. Values outside 2

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26 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS normalcy, therefore, may or may not serve as clinical indicators of a disease state. Various transgenic and knockout mice that exhibit severe behavioral and physiological phenotypes appear abnormal relative to their control littermates, but are normal for their genotype. For example, it is appropri- ate to evaluate Huntington’s disease transgenic mice for signs of stress and distress only relative to their own “normal” behavior, taking into account their particular genetic makeup, their abnormal motor patterns, and reduced weight gain (Mangiarini et al. 1996). bEHAvIORAL RECOgNITION OF STRESS AND DISTRESS Normal behavior Many parameters have an effect on species-specific normal behavior and should be taken into consideration when behavioral characteristics are used to determine normalcy or the presence of stress and distress. Animals exhibit a variety of behavioral changes as part of the normal aging process. Males and females differ in the baseline values of many stress markers. Inbred murine strains differ in almost every behavioral, sensory, motor, and physiological trait studied and each inbred strain may respond to stress differently. Similar behavioral differences in response to stress have been observed in primates. genetically engineered phenotypes need to be considered when assessing stress and distress in transgenic and knock- out animals. The maternal environment and rearing experiences of the offspring affect their future responses to stress and distress. Special physi- ological states, such as impending parturition, are defined by state-specific behaviors. Housing conditions may also modify species-specific behavioral patterns. behavioral normalcy is further characterized by the absence of bizarre or atypical patterns of species-specific behavior. The presence of stereotypies usually implies suboptimal environments and possibly poor animal welfare. The identification of species-typical behavior often comes from etho- grams developed by researchers to describe the kinds of behavior that animals display in various settings (Bronson 1979; for more references see Additional References). While the use of species-typical behavior as a normative benchmark has considerable value (Latham and Mason 2004), it does have limitations. First, the full range of species-specific behaviors cannot be recreated (or allowed to be expressed) in the laboratory animal care facilities as some types of behavior observed in natural settings (e.g., severe aggression) are clearly undesirable from a laboratory management perspective. Second, species-typical behaviors are neither invariant nor universal, as both the frequency and the presence of such behaviors vary

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2 RECOGNITION AND ASSESSMENT OF STRESS AND DISTRESS as a function of age, gender, physiological state, and genetic constitution. Third, rearing practices and housing environments may affect expected typical behavior. 1. Age: Many young mammals engage in high levels of social play whereas adults rarely do. Thus, play may be normal for young animals but not necessarily so for adults (Ruppenthal et al. 1974; Vanderschuren et al. 1997). All animals display physiological, behavioral, and cognitive changes as they age. Some of these changes, for example changes in coat/ hair appearance and locomotor ability, are overt and easily recognizable. Many laboratory animals display an age-related decline in exploratory activity, which is sometimes correlated to weight gain (as observed, for example, in mice of various strains; Ingram 2000; Ingram et al. 1981). In addition, a number of neurosensory, cardiovascular, endocrine, gastro- intestinal, musculoskeletal, and reproductive changes occur with aging, some of which cannot be directly observed in the living animal. Such age- related changes (e.g., hearing and vision deficits) have been documented for a number of murine strains (Hawkins et al. 1985; for more references see Additional References), while cognitive deficits have been reported in aging mice and rats. It is postulated that some of these changes may be gender- and strain-related (Decker et al. 1988; Fischer et al. 1992; Frick et al. 2000). Changes in pain sensitivity and in emotional behavior that may have direct implications for stress and distress have also been reported in aging animals (Berry et al. 2007; Lamberty and Gower 1992). 2. Gender: Female mammals generally care for infants, whereas the extent of male involvement varies across species. Thus, species-typical behavior may be gender-biased. Moreover, gender-related differences in stress markers can be profound and occur in all vertebrate species. For example, female rats and mice exhibit marked elevations in basal and stress-induced corticosterone release relative to males, although these are buffered by high levels of corticosteroid-binding globulin, thus making free corticosterone levels similar in both sexes (McCormick et al. 1995). Absolute corticosteroid levels in females fluctuate in relation to the stage of estrus, presumably affected by circulating levels of estrogens (Figueiredo et al. 2002). Thus, assessment of HPA activity as a measure of stress (see below) needs to account for the gender of the animal and the type of steroid measurement (i.e., total [plasma] or free [saliva]). Males and females also appear to differ in other aspects of their stress response(s); for example, while females have greater anhedonic and HPA axis responses to chronic mild stress than males, they score lower on tests of behavioral depression caused by chronic stress exposure (Dalla et al. 2005).

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28 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS 3. Genetic traits: Genetic variability among many animal species complicates our understanding of the effects of stress and distress in labora- tory animals. Multiple studies in the mouse have shown that generalizations even across a single species can be problematic. Selective breeding has produced hundreds of inbred mouse strains, providing extensive genetic and phenotypic variability (Beck et al. 2000; Silver 1995). A mouse strain is classified as inbred after 20 inbreedings (that is, 20 generations of brother x sister or offspring x parent matings), at which point its members are virtu- ally genetically identical because at the 20th or subsequent generations all animals are traceable to a single breeding pair. One cannot assume that mice from different inbred strains are alike (or even similar), perform identi- cally, or experience and react uniformly to stimuli—stressful or otherwise. In fact, inbred strains of mice differ in almost every behavioral, sensory, motor, and physiological trait studied to date, such as anxiety, learning and memory, brain structure and size, visual acuity, acoustic startle, exploratory behavior, alcohol sensitivity, depression, pain sensitivity, and motor coordi- nation (Crawley et al. 1997; for more references see Additional References). What is typical for one strain—for example, high levels of play behavior or social interaction (Moy et al. 2004) or novelty seeking and exploratory behavior (Bolivar et al. 2000; Kliethermes and Crabbe 2006)—may not be characteristic of another. For these reasons different inbred murine strains respond to stress dif- ferently and thus may well experience distress in different ways. Indeed, a number of behavioral studies provide evidence that strain differences in distress susceptibility are likely. For instance, inbred strains differ in performance on anxiety, depression, and fear learning assays (Balogh and Wehner 2003; for more references see Additional References). Correlating behavioral performance across such matrices can provide some indication of basic genetic differences among strains in response to stressful situations (Ducottet and Belzung 2005). When exposed to a month of unpredictable mild stress (e.g., cage tilting, damp bedding, lights on for a short period dur- ing the dark phase) most strains groom themselves less resulting in poor fur condition, while only a few display heightened aggression levels (Mineur et al. 2003). In general, inbred strain differences appear in the stress-induced hyperthermia model (Bouwknecht and Paylor 2002; van Bogaert et al. 2006) and in stress-invoked autonomic responses (body temperature and heart rate), although the latter are also a function of the intensity of the insult applied (van Bogaert et al. 2006). Behavioral differences have also been observed in primates. High reactor monkeys1 are much less likely 1 It is now well established that there are marked individual differences in reactivity among nonhuman primates when animals are exposed to novel situations or to relatively minor changes in their social or physical environment. Some rhesus monkeys (~20%) respond to

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2 RECOGNITION AND ASSESSMENT OF STRESS AND DISTRESS to explore a novel stimulus than low reactors (Suomi 2004). Moreover, because even within genetically diverse species individual animals will vary on many dimensions, high levels of exploration may be the norm for some but not for others. 4. Transgenic and knockout mouse models: Many genetic mouse models have intentional or incidental behavioral and/or physiological phenotypes relevant to stress. Disturbances in genes associated with brain stress-regulatory systems can elicit stress hyposensitivity (e.g., deletion of the corticotrophin-releasing hormone [CRH] gene; Muglia et al. 1995) or stress hypersensitivity (e.g., overexpression of CRH; Stenzel-Poore et al. 1994). Moreover, there are any number of transgenic/knockout phenotypes that affect behavioral or physiological indices of stress without producing overt stress or distress. For example, deletion of the S6 kinase gene produces a remarkably small animal, not because of the animal’s “failure to thrive” but rather because absence of this powerful cell-size regulator results in a smaller size of otherwise healthy cells (Thomas 2002). Thus, expressed phenotypes need to be considered when assessing stress and/or distress in genetically engineered animal models because their presence may be even more difficult to recognize and diagnose in these animals than in their con- trol littermates. . Rearing and postnatal separation: In most mammals, the early environment of the young animal is defined by the presence of its mother; therefore maternal characteristics can have a profound impact on the future behavior of adult offspring. There is ample scientific evidence that maternal environment can be an important epigenetic determinant of physiology and behavior, and should be considered as a variable for assessment of stress and distress. Offspring are generally reared with their mothers and may also be reared in larger social groups that include other offspring as well as adult males and females. Some species- or strain-typical behaviors, such as cross fostering, in which the offspring of one species are reared by the parents of another species or of the same species but a different strain, are more susceptible to parent-related environmental manipulations. The extent to which cross fostering may produce distress in the offspring relatively mild environmental stressors with unusual behavioral disruption and physiological arousal including prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by plasma cortisol and adrenocorticotropic hormone (ACTH), increased cerebrospinal fluid levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol, heightened sympathetic nervous system activity as reflected in altered heart rate rhythms, and abnormal immune system response (Coe et al. 1989; Higley et al. 1991). The same stressors elicit only minor behavioral reactions and transient physiological responses in the remainder of the population (Suomi 2004).

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30 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS depends on the degree to which parental care varies across the two species (or strains) in question. In birds, cross fostering can be relatively benign (e.g., rearing of green finches’ offspring by canaries; Guettinger 1979). In other cases, however, cross fostering may complicate the assessment of stress and distress, as cross-fostered rats, mice, and goats frequently exhibit behaviors more similar to the adoptive mother strains (Ahmadiyeh et al. 2004; Anisman et al. 1998; Kendrick et al. 2001). In rats, female offspring of dams bred for high licking and grooming that have been reared with their biological mothers will themselves provide extensive maternal care of their own pups. In contrast, if female offspring of high licking and groom- ing dams are instead cross fostered with low licking and grooming (i.e., “poor”) mothers, they will subsequently provide little maternal care to their own offspring, resulting in behavioral and physiological changes that per- sist into adulthood (Francis et al. 1999). Recent research into the effects of maternal behavior on such developmental traits as DNA methylation, an epigenetic mechanism that alters gene expression, has shown that maternal environmental programming (for example, high or low grooming) affects the glucocorticoid receptor gene and possibly the responses of the offspring to stress. Offspring of high grooming mothers (or those cross fostered to them) appeared less responsive to stressful stimuli and had increased expression of these receptors in the hippocampus compared to those raised by low grooming dams (Fish et al. 2004; Weaver et al. 2004). Microarray analysis has shown that more than 900 genes of the hippocampal transcriptome are stably regulated by maternal care (Weaver et al. 2006). In species such as primates, however, infants may be nursery-reared because of the infant’s illness, the mother’s failure to care for the infant, or demands of the experimental protocol. The two most common nursery rear- ing procedures for macaques are peer rearing (i.e., rearing infants together 24 hours a day) and surrogate peer rearing (i.e., rearing infants on inanimate surrogate mothers 24 hours a day with 1-2 hours of daily peer exposure in a playroom setting). Both conditions commence shortly after an animal’s birth before a strong attachment has been formed to the mother, and thus infants show little in the way of separation anxiety. From a developmental perspective, peer rearing appears to confer the greater risk for distress and social maladjustment. Peer-reared monkeys typically show higher levels of mutual clinging and greater fear responses than surrogate-peer-reared monkeys early in life and have difficulty adapt- ing to larger social groups as juveniles (Ruppenthal et al. 1991). Peer rearing has also been associated with impaired immune responses (Coe et al. 1989; Lubach et al. 1995) and, when combined with repeated separa- tions, appears to promote heightened aggressiveness, impaired impulse control, alcohol abuse, and low levels of 5-hydroxyindoleacetic acid (a serotonin metabolite) in cerebrospinal fluid (Ichise et al. 2006). Although

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31 RECOGNITION AND ASSESSMENT OF STRESS AND DISTRESS less studied, surrogate-peer-reared monkeys appear to behave more like normally reared monkeys. Indeed, a large comparison study of surrogate- peer-reared monkeys (n=506) to normally reared monkeys (n=1,187) failed to detect any differences in growth, health, survival, reproduction, and maternal abilities between the two groups (Sackett et al. 2002). But because some individuals reared in either condition may be more vulnerable to the development of abnormal behavior than normally reared monkeys, careful observation and ongoing assessments would help guide colony manage- ment decisions regarding group composition and enrichment strategies. A different kind of early rearing experience involves separation from the mother or other attachment figure (e.g., other peers) after a strong attach- ment has been formed. Such separations may occur both for research pur- poses or to facilitate weaning. Depending on such variables as the timing of the separation, the nature of the separation environment, and the primate species, separation can induce high levels of stress in infants expressed by vocalizations and heightened activity (Bayart et al. 1990; Jordan et al. 1985; Laudenslager et al. 1990; Levine et al. 1993). It can also alter HPA activity (Levine 2005; Levine and Mody 2003; Parker et al. 2006; Vogt et al. 1980) and immune responses (Laudenslager et al. 1982). Reactions are often stronger when the infant is separated both from its mother and the environment in which it was raised compared to when only the mother is removed from the infant, but this effect can vary by species (Laudenslager et al. 1990). These signs generally disappear when infants are reunited with their mothers or their attachment figures, although neuroendocrine responses may be altered. 6. Physiological state: Many species (such as dogs, sows, rabbits, and mice) need to build nests just before parturition, whereas others do not engage in such behavior (Arey 1997; Broida and Svare 1982; Crawley 2000; Kunkele 1992). . Housing: Environmental conditions can modify species-specific behavioral patterns. Adults housed in same sex groups cannot show some aspects of the species-typical physiological repertoire (e.g., mating or parental behavior). Housing conditions (such as cage types and environ- mental enrichment) affect the amount of time that mice spend engaging in distinct behavioral patterns, as reported by Olsson and Sherwin who, using videorecording, showed that mice in furnished cages (i.e., cages with nest- ing material, running wheels, nest box, and chew box) “spent less time rest- ing, bar-chewing and bar-circling and more time on exploratory/locomotor behaviors” (Olsson and Sherwin 2006, p. 392). Lack of environmental stimulation or social deprivation adversely impacts normal brain function in rats, such as attenuation of the prepulse inhibition (PPI) behavior elicited by

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32 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS startling events, and is accompanied by underlying neurochemical changes such as enhanced dopamine activity (Würbel 2001). Based on significantly fewer instances of abnormal behaviors (i.e., stereotypies) encountered in wild-caught animals vs. their captive-bred controls, the argument for a neuro- protective effect of early environmental enrichment against future abnormal behaviors has been made (Lewis et al. 2006). Moreover, studies have shown that dendritic anatomy in young rats was altered in response to a brief 4-day exposure to a complex environment (Wallace et al. 1992) and so was the hippocampus of adult mice in comparison to controls (Kempermann et al. 2002; for more discussion on enrichment see Chapter 4). Behavioral normalcy is further characterized by the absence of bizarre or atypical patterns of species-specific behavior. Examples of abnormal behavior include excessive barbering observed in mice (Garner et al. 2004; Morton 2002), regurgitation/rumination and coprophagy seen in apes (Nash et al. 1999), or more serious self-injurious behaviors exhibited by rhesus monkeys (Novak 2003). Sometimes, such behaviors represent normal social patterns. For example, coprophagy associated with mother rearing occurs not only in laboratory-housed apes (Nash et al. 1999) but also in the wild where it is postulated to contribute to the reclaiming of unused resources from the feces (Krief et al. 2004). In other cases, however, such patterns are a sign of well-defined diseases or disorders, as, for example, excessive tremors observed in transgenic mice with Huntington’s disease (Mangiarini et al. 1996). In yet other instances, abnormal behavioral patterns, such as stereotypies, may result from suboptimal housing environments (Bayne et al. 1992, 2002; Hubrecht et al. 1992; Mason 1991). Stereotypic behavior is characterized by highly repetitive and ritual- istic actions, the function of which is largely unknown. Environments that elicit or enhance stereotypies not as part of defined pathophysiology or disease models are typically suboptimal (Berkson and Mason 1964; for more references see Additional References). Stereotypies vary across species and appear at different times of day and under different conditions (Mason and Mendl 1997). Classic whole-body stereotypies include circling, pacing (dogs, primates), wall bouncing (dogs), and somersaulting and bar chewing (rodents), whereas self- or other-animal-directed stereotypies often involve the limbs or face and include such patterns as digit sucking, paw lick- ing, and overgrooming (Bayne and Novak 1998; for more references see Additional References). Although there is yet inadequate research on the relationship between distress and stereotypy, a recent meta-analysis of studies linking stereotypy to animal welfare suggests that some stereotypies may function to regulate arousal and possibly reduce distress as “do-it-yourself enrichment” strate- gies to alleviate the effect of a suboptimal environment (see Mason and

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33 RECOGNITION AND ASSESSMENT OF STRESS AND DISTRESS Latham 2004). Overall, however, the presence of stereotypies should be a cause for concern because animals that exhibit such behavioral patterns may not only have experienced some stress or distress in the past but also live in environments that promote or sustain these abnormal behaviors. Moreover, as a study by Krohn and colleagues has shown, stereotypies are probably underreported as they may occur during the night when staff are not present, or cease when staff enter a room (Krohn et al. 1999). If, in fact, Krohn the presence of stereotypies is being investigated, then more sophisticated methods such as closed-circuit television or videorecording, or simpler diagnostics such as partially reversed light cycles, would enable staff to observe nocturnal animals during their most active periods in order to docu- ment instances of abnormal behavior (Hubrecht 1997). Abnormal behavior and Clinical Signs Recognition of distress should be derived from intimate knowledge of the species’ or strain’s normal behavior and may be based on (1) clinical signs and/or (2) significant deviation from the expected behavioral repertoire. Some clinical signs (e.g., changes in temperature, respiration, feeding behavior) indicate an abrupt onset of distress while others (e.g., weight loss) develop over a longer period of time and may serve as warnings. A thorough clinical examination with references to baseline effects of age, gender, genotype, etc., is necessary to establish the presence of distress, while an abrupt and marked change in behavior lasting more than a few days may also indicate a disease state. While the presence of stereotypies is undesirable, the relationship between stereotypic behavior and distress remains largely unknown. Preventing the development of stereotyped behavior by providing species-specific appropriate environments is likely to result in improved welfare. Assuming that an animal’s behavior has been well characterized, indi- cations of distress may include certain clinical signs or marked change from the individual animal’s usual behavioral repertoire (Morton and Griffiths 1985; see score sheet examples in Appendix). An abrupt and marked change in behavior lasting more than a few days may also indicate the presence of a disease state in addition to distress, particularly if these changes occur in conjunction with severe reductions in normal daily activities such as feed- ing behavior, sexual behavior, maternal behavior, or attention to threat. Conversely, animals may exhibit increased activity associated with unusual motions (e.g., head rubbing) or unusually high levels of certain behaviors (e.g., scratching). Even marked changes in behavior, however, must be evaluated in context. For example, females usually exhibit decreased activ- ity the first day following parturition, an expected behavior.

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34 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS Clinical Signs of Distress Clinical examination to establish the presence of distress should focus on, but not be limited to, the following: signs of abnormal respira- tion (shallow, labored, or rapid); assessment of grooming and hair coat (piloerected or greasy, possibly reflecting reduced grooming); examination of the eyes (runny, glassy, or unfocused); examination of motor postures (hunching or cowering in the corner of the cage, lying on one’s side, lack of movement with loss of muscle tone); absence of alertness or quiescence (inattention to ongoing stimuli); changes in body weight; the ability or failure to produce urine or feces; unusual features of urine (volume, smell, and color) or feces (quantity, consistency, and color); the presence of vomit; the status of the animal’s appetite and water intake; and intense or frequent vocalizations (Bennett et al. 1998; Fortman et al. 2002; Fox et al. 2002). It is appropriate to evaluate some of these signs in context, as, for example, rapid breathing could result from vigorous activities such as playing or running on the wheel, lying down may occur as part of social grooming (e.g., among macaques), weight loss is often associated with advanced age, and some mammals raise their hair (piloerection) while eating. In addition, clinical evaluation and diagnosis should consider species, age, gender, physiological state, and genetic variables (Bennett et al. 1998). While some of the clinical signs described above (e.g., respiratory changes, changes in fecal material and/or in urine) are more relevant to the acute onset of a distressful state, other measures may serve as poten- tial early warning signs of distress (e.g., rapid body weight changes in the absence of dietary modifications). Significant and unexpected changes in weight in either direction may be indicators of altered endocrinological, immunological, or neurological parameters. Indeed, the relatively sudden loss of 25% body weight of a nonhuman primate is one of the parameters used to determine humane endpoints in primate research (Association of Primate Veterinarians 2008). This view should not be applied to caloric restriction research protocols where animals may be subject to controlled diets that reduce their weight by as much as 15-20% (Heiderstadt et al. 2000). Such protocols are widely used in gerontology research where diet has been shown to slow aging, extend lifespan, and reduce the incidence of age-related diseases in rodents (Goto et al. 2002; for more references see Additional References), while beneficial effects have also been observed in nonhuman primates (Ingram et al. 2007). Moreover, sensory-motor function and learning studies may use caloric or water restriction as a motivational tool (Heiderstadt et al. 2000; Smith and Metz 2005). In these studies regular monitoring of body weight is essential to ensure that animals either do not fall below an accepted weight

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3 RECOGNITION AND ASSESSMENT OF STRESS AND DISTRESS range or, in the case of young animals, gain the appropriate body weight for their age. Behaioral Signs of Distress It has been suggested that abnormal behavior, such as stereotypies, is a marker for distress (Dawkins 1990). It remains unclear at this time whether any or all abnormal behaviors qualify as indicators of distress. Several alternative (and largely speculative) hypotheses attempt to explain the occurrence of stereotypic behavior in animals (Mason and Latham 2004; Tiefenbacher et al. 2005). Among these, the stimulation hypothesis suggests that when sensory motor input is low, possibly due to existing (i.e., nonstimulating, poor) housing arrangements, animals engage in stereotypic behavior to self-provide increased sensory-motor input (Sherwin 1998). For example, when cage size constrains normal movements, some animals may respond by developing stereotyped pacing in order to satisfy their need for activity (Draper and Bernstein 1963). The habit hypothesis suggests that although stereotypic behavior may have originally arisen in response to stress or distress, it persists as a habit uncoupled from the situation that originally produced it (Dantzer 1986; Mason 1991). Those who favor the arousal reduction hypothesis suggest that stereotypic behavior may serve to calm the animal and thereby avoid distress (reviewed in Mason 1991). Research shows that in some humans and nonhuman primates, even more serious forms of abnormal and self-injurious behavior may function to reduce arousal (Tiefenbacher et al. 2005). The arousal reduction hypothesis is consistent with the view that while an underlying stress or distress state may have initially caused abnormal behavior, eliminating the behavior may be neither desirable nor possible because the stereotypy may sometimes prevent the onset of distress. Preventing the development of stereotyped behavior by providing the animals with species-specific appropriate environments is obviously desirable and likely to result in improved welfare, especially as enrich- ment “therapy” may reduce but will not cure the abnormal behavior (van Praag et al. 2000; Wolfer et al. 2004). Although recent studies suggest that stereotypical animals may experience psychological distress due to a puta- tive common mechanism between stereotypy, schizophrenia, and autism, the relationship between stereotypic behavior and distress remains largely unknown and is in need of further study (Garner 2006; Garner and Mason 2002; Garner et al. 2003; Mason 2006).

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2 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS Zhang, W. and P. Thoren. 1998. Hyper-responsiveness of adrenal sympathetic nerve activity in spontaneously hypertensive rats to ganglionic blockade, mental stress and neuron- glucopenia. Pflugers Arch 437(1):56-60. ADDITIONAL REFERENCES Page 26 The identification of species-typical behavior often comes from ethograms devel- oped by researchers to describe the kinds of behavior that animals display in various settings (Bronson 1979). Chopra, P. K., P. K. Seth, and S. Seth. 1992. Behavioural profile of free-ranging rhesus monkeys. Primate Rep 32:75-105. Latham, N. and G. Mason. 2004. From house mouse to mouse house: The behavioural biol- ogy of free-living Mus musculus and its implications in the laboratory. Appl Anim Beha 86(3-4):261-289. Mayer, J. 2007. Use of behavior analysis to recognize pain in small animals. Lab Anim 36(6):43-48. Morton, D. B. 2002. Behaviour of rabbits and rodents. In The Ethology of Domestic Animals— An Introductory Text, Per Jensen, ed. Oxford: CABI Wallingford Oxford. 193-209 pp. Morton, D. B. and P. H. M. Griffiths. 1985. Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment. Vet Record 116(16):431-436. Olivier B. and D. van Dalen. 1982. Social behaviour in rats and mice: An ethologically based model for differentiating psychoactive drugs. Aggress Beha 8(2):163-168. Page 27 Such age-related changes (e.g., hearing and vision deficits) have been documented for a number of murine strains (Hawkins et al. 1985). Johnson, K. R., Q. Y. Zheng, and K. Noben-Trauth. 2006. Strain background effects and genetic modifiers of hearing in mice. Brain Res 1091(1):79-88. Jones, S. M., T. A. Jones, K. R. Johnson, H. Yu, L. C. Erway, and Q. Y. Zheng. 2006. A comparison of vestibular and auditory phenotypes in inbred mouse strains. Brain Res 1091(1):40-46. Malek, G., L. V. Johnson, B. E. Mace, P. Saloupis, D. E. Schmechel, D. W. Rickman, C. A. Toth, P. M. Sullivan, and C. Bowes Rickman. 2005. Apolipoprotein E allele-dependent pathogenesis: A model for age-related retinal degeneration. Proc Natl Acad Sci USA 102(33):11900-11905. Ohlemiller, K. K. 2006. Contributions of mouse models to understanding of age- and noise- related hearing loss. Brain Res 1091(1):89-102. Smith, R. S., S. W. John, A. Zabeleta, M. T. Davisson, N. L. Hawes, and B. Chang. 2000. The bst locus on mouse chromosome 16 is associated with age-related subretinal neovascu- larization. Proc Natl Acad Sci USA 97(5):2191-2195. Page 28 In fact, inbred strains of mice differ in almost every behavioral, sensory, motor, and physiological trait studied to date, such as anxiety, learning and memory, brain structure and size, visual acuity, acoustic startle, exploratory behavior, alcohol sensitivity, depression, pain sensitivity, and motor coordination (Crawley et al. 2000). Bolivar, V. J., B. J. Caldarone, A. A. Reilly, and L. Flaherty. 2000. Habituation of activity in an open field: A survey of inbred strains and F1 hybrids. Beha Genet 30(4):285-293.

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3 RECOGNITION AND ASSESSMENT OF STRESS AND DISTRESS Bolivar, V. J., O. Pooler, and L. Flaherty. 2001. Inbred strain variation in contextual and cued fear conditioning behavior. Mamm Genome 12(8):651-656. Bothe, G. W. M., V. J. Bolivar, M. J. Vedder, and J. G. Geistfeld. 2005. Behavioral differences among fourteen inbred mouse strains commonly used as disease models. Comparatie Med 55(4):326-334. Bouwknecht, J. A. and R. Paylor. 2002. Behavioral and physiological mouse assays for anxiety: A survey in nine mouse strains. Beha Brain Res 136(2):489-501. Cook, M. N., R. W. Williams, and L. Flaherty. 2001. Anxiety-related behaviors in the elevated zero-maze are affected by genetic factors and retinal degeneration. Beha Neurosci 115(2):468-476. Crabbe, J. C., D. Wahlsten, and B. C. Dudek. 1999. Genetics of mouse behavior: Interactions with laboratory environment. Science 284(5420):1670-1672. Crabbe, J. C., P. Metten, I. Ponomarev, C. A. Prescott, and D. Wahlsten. 2006. Effects of genetic and procedural variation on measurement of alcohol sensitivity in mouse inbred strains. Beha Genet 36(4):536-552. Guillot, P. V., P. L. Roubertoux, and W. E. Crusio. 1994. Hippocampal mossy fiber distributions and intermale aggression in seven inbred mouse strains. Brain Res 660(1):167-169. Kliethermes, C. L. and J. C. Crabbe. 2006. Genetic independence of mouse measures of some aspects of novelty seeking. Proc Natl Acad Sci USA 103(13):5018-5023. Liu, X. and H. K. Gershenfeld. 2001. Genetic differences in the tail-suspension test and its relationship to imipramine response among 11 inbred strains of mice. Biol Psychiat 49(7):575-581. Logue, S. F., E. H. Owen, D. L. Rasmussen, and J. M. Wehner. 1997. Assessment of locomotor activity, acoustic and tactile startle, and prepulse inhibition of startle in inbred mouse strains and F1 hybrids: Implications of genetic background for single gene and qualitative trait loci analyses. Neuroscience 80(4):1075-1086. Lucki, I., A. Dalvi, and A. J. Mayorga. 2001. Sensitivity to the effects of pharmacologically selec- tive antidepressants in different strains of mice. Psychopharmacology 155(3):315-322. McFadyen, M. P., G. Kusek, V. J. Bolivar, and L. Flaherty. 2003. Differences among eight inbred strains of mice in motor ability and motor learning on a rotorod. Genes Brain Beha 2(4):214-219. Mogil, J. S., S. G. Wilson, K. Bon, S. E. Lee, K. Chung, P. Raber, J. O. Pieper, H. S. Hain, J. K. Belknap, L. Hubert, G. I. Elmer, J. M. Chung, and M. Devor. 1999. Heritability of nociception I: Responses of 11 inbred mouse strains on 12 measures of nociception. Pain 80(1-2):67-82. Moy, S. S., J. J. Nadler, A. Perez, R. P. Barbaro, J. M. Johns, T. R. Magnuson, J. Piven, and J. N. Crawley. 2004. Sociability and preference for social novelty in five inbred strains: An approach to assess autistic-like behavior in mice. Genes Brain Beha 3(5):287-302. Owen, E. H., S. F. Logue, D. L. Rasmussen, and J. M. Wehner. 1997. Assessment of learning by the Morris water task and fear conditioning in inbred mouse strains and F1 hybrids: Implications of genetic background for single gene mutations and quantitative trait loci analyses. Neuroscience 80(4):1087-1099. Rustay, N. R., D. Wahlsten, and J. C. Crabbe. 2003. Influence of task parameters on rotarod performance and sensitivity to ethanol in mice. Beha Brain Res 141(2):237-249. Trullas, R. and P. Skolnick. 1993. Differences in fear motivated behaviors among inbred mouse strains. Psychopharmacology 111(3):323-331. van Bogaert, M. J., L. Groenink, R. S. Oosting, K. G. Westphal, J. van der Gugten, and B. Olivier. 2006. Mouse strain differences in autonomic responses to stress. Genes Brain Beha 5(2):139-149.

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4 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS Wahlsten, D., P. Metten, and J. C. Crabbe. 2003a. A rating scale for wildness and ease of handling laboratory mice: Results for 21 inbred strains tested in two laboratories. Genes Brain Beha 2(2):71-79. Wahlsten, D., P. Metten, and J. C. Crabbe. 2003b. Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+ tf/tf has severely reduced hippocampal commissure and absent corpus callosum. Brain Res 971(1):47-54. Wahlsten, D., S. F. Cooper, and J. C. Crabbe. 2005. Different rankings of inbred mouse strains on the Morris maze and a refined 4-arm water escape task. Beha Brain Res 165(1):36-51. Willott, J. F., L. Tanner, J. O’Steen, K. R. Johnson, M. A. Bogue, and L. Gagnon. 2003. Acoustic startle and prepulse inhibition in 40 inbred strains of mice. Beha Neurosci 117(4):716-727. Wong, A. A. and R. E. Brown. 2005. Visual detection, pattern discrimination and visual acuity in 14 inbred strains. Genes Brain Beha 5(5):389-403. Page 28 For instance, inbred strains differ in performance on anxiety, depression, and fear learning assays (Balogh and Wehner 2003). Bolivar, V. J., O. Pooler, and L. Flaherty. 2001. Inbred strain variation in contextual and cued fear conditioning behavior. Mamm Genome 12(8):651-656. Bouwknecht, J. A. and R. Paylor. 2002. Behavioral and physiological mouse assays for anxiety: A survey in nine mouse strains. Beha Brain Res 136(2):489-501. Cook, M. N., R. W. Williams, and L. Flaherty. 2001. Anxiety-related behaviors in the elevated zero-maze are affected by genetic factors and retinal degeneration. Beha Neurosci 115(2):468-476. Trullas, R. and P. Skolnick. 1993. Differences in fear motivated behaviors among inbred mouse strains. Psychopharmacology 111(3):323-331. Page 32 Environments that elicit or enhance stereotypies not as part of defined pathophysiology or disease models are typically suboptimal (Berkson and Mason 1964). Garner, J. P. and G. Mason. 2002. Evidence for a relationship between cage stereotypies and behavioural disinhibition in laboratory rodents. Beha Brain Res 136(1):83-92. Garner, J. P., C. L. Meehan, and J. A. Mench. 2003. Stereotypies in caged parrots, schizophrenia and autism: Evidence for a common mechanism. Beha Brain Res 145(1-2):125-134. Mason, G. 1991. Stereotypies: A critical review. Anim Beha 41(6):1015-1037. Mason, G. J. and N. R. Latham. 2004. Can’t stop, won’t stop: Is stereotypy a reliable animal welfare indicator? Anim Welf 13(Suppl):557-569. Ridley, R. M. and H. F. Baker. 1982. Stereotypy in monkeys and humans. Psychol Med 12(1):61-72. Würbel, H. 2001. Ideal homes? Housing effects on rodent brain and behaviour. Trends Neurosci 24(4):207-211. Page 32 Classic whole-body stereotypies include circling, pacing (dogs, primates), wall bouncing (dogs), and somersaulting and bar chewing (rodents), whereas self- or other-animal- directed stereotypies often involve the limbs and/or face and include such patterns as digit sucking, paw licking, and overgrooming (Bayne and Novak 1998). Callard, M. D., S. N. Bursten, and E. O. Price. 2000. Repetitive backflipping behaviour in captive roof rats (Rattus rattus) and the effects of cage enrichment. Anim Welf 9(2):139-152.

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 RECOGNITION AND ASSESSMENT OF STRESS AND DISTRESS Garner, J. P. 2005. Stereotypies and other abnormal repetitive behaviors: Potential impact on validity, reliability, and replicability of scientific outcomes. ILAR J 46(2):106-117. Hubrecht, R. C., J. A. Serpell, and T. B. Poole. 1992. Correlates of pen size and housing condi- tions on the behaviour of kennelled dogs. Appl Anim Beha Sci 34:365-383. Luescher, U. A., D. B. McKeown, and J. Halip. 1991. Stereotypic or obsessive-compulsive disorders in dogs and cats. Vet Clin North Am-Small 21(2):401-413. Morton, D. B., M. Jennings, G. R. Batchelor, D. Bell, L. Birke, K. Davies, J. R. Eveleigh, D. Gunn, M. Heath, B. Howard, P. Koder, J. Phillips, T. Poole, A. W. Sainsbury, G. Sales, D. J. A. Smith, M. Stauffacher, and R. J. Turner. 1993. Refinements in rabbit husbandry. Lab Anim 27(4):301-329. Waiblinger, E. and B. Konig. 2004. Refinement of gerbil housing and husbandry in the labora- tory. Anim Welf 13(Suppl):S229-S235. Page 34 Such protocols are widely used in gerontology research where diet has been shown to slow aging, extend lifespan, and reduce the incidence of age-related diseases in rodents (Goto et al. 2002). Goto, S., R. Takahashi, Z. Radak, and R. Sharma. 2007. Beneficial biochemical outcomes of late-onset dietary restriction in rodents. Ann N Y Acad Sci 1100:431-441. Jamieson, H. A., S. N. Hilmer, V. C. Cogger, A. Warren, R. Cheluvappa, D. R. Abernethy, A. V. Everitt, R. Fraser, R. de Cabo, and D. G. Le Couteur. 2007. Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid. Exp Gerontol 42(4):374-378. Hyun, D. H., S. S. Emerson, D. G. Jo, M. P. Mattson, and R. de Cabo. 2006. Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. Proc Natl Acad Sci USA 103(52):19908-19912. Seymour, E. M., R. V. Parikh, A. A. Singer, and S. F. Bolling. 2006. Moderate calorie restric- tion improves cardiac remodeling and diastolic dysfunction in the Dahl-SS rat. J Mol Cell Cardiol 41(4):661-668. Page 36 Types of behavior commonly explored to investigate the presence of stress include open-field activity, movements in an elevated plus maze, changes in innate behaviors (e.g., movement, grooming, feeding, sexual behavior), defensive behaviors (to external threats), and avoidance/escape (Beck and Luine 2002). Blanchard, R. J., C. R. McKittrick, and D. C. Blanchard. 2001. Animal models of social stress: Effects on behavior and brain neurochemical systems. Physiol Beha 73(3):261-271. Ely, D. R., V. Dapper, J. Marasca, J. B. Correa, G. D. Gamaro, M. H. Xavier, M. B. Michalowski, D. Catelli, R. Rosat, M. B. Ferreira, and C. Dalmaz. 1997. Effect of restraint stress on feeding behavior of rats. Physiol Beha 61(3):395-398. Harkin, A., T. J. Connor, J. M. O’Donnell, and J. P. Kelly. 2002. Physiological and behavioral responses to stress: What does a rat find stressful? Lab Anim 31(4):42-50. Mangiavacchi, S., F. Masi, S. Scheggi, B. Leggio, M. G. De Montis, and C. Gambarana. 2001. Long-term behavioral and neurochemical effects of chronic stress exposure in rats. J Neurochem 79(6):1113-1121. Pare, W. P. and S. M. Tejani-Butt. 1996. Effect of stress on the behavior and 5-HT system in Sprague-Dawley and Wistar Kyoto rat strains. Integr Physiol Beh Sci 31(2):112-121. Perrot-Sinal, T. S., A. Gregus, D. Boudreau, and L. E. Kalynchuk. 2004. Sex and repeated restraint stress interact to affect cat odor-induced defensive behavior in adult rats. Brain Res 1027:161-172.

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6 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS Retana-Marquez, S., E. D. Salazar, and J. Velazquez-Moctezuma. 1996. Effect of acute and chronic stress on masculine sexual behavior in the rat. Psychoneuroendocrinology 21(1):39-50. Rittenhouse, P. A., C. Lopez-Rubalcava, G. D. Stanwood, and I. Lucki. 2002. Amplified behavioral and endocrine responses to forced swim stress in the Wistar-Kyoto rat. Psycho- neuroendocrinology 27(3):303-318. Page 37 Glucocorticoids are typically measured in blood serum or plasma but can also be quantified in saliva, urine, feces, and hair (Abelson et al. 2005). Anderson, S. M., G. A. Saviolakis, R. A. Bauman, K. Y. Chu, S. Ghosh, and G. J. Kant. 1996. Effects of chronic stress on food acquisition, plasma hormones, and the estrous cycle of female rats. Physiol Beha 60:325-329. Atkinson, H. C., S. A. Wood, Y. M. Kershaw, E. Bate, and S. L. Lightman. 2006. Diurnal varia- tion in the responsiveness of the hypothalamic-pituitary-adrenal axis of the male rat to noise stress. J Neuroendocrinol 18(7):526-533. Belz, E. E., J. S. Kennell, R. K. Czambel, R. T. Rubin, and M. E. Rhodes. 2003. Environmental enrichment lowers stress-responsive hormones in singly housed male and female rats. Pharmacol Biochem Beha 76(3-4):481-486. Blanchard, R. J., C. R. McKittrick, and D. C. Blanchard. 2001. Animal models of social stress: Effects on behavior and brain neurochemical systems. Physiol Beha 73(3):261-271. Brown, K. J. and N. E. Grunberg. 1995. Effects of housing on male and female rats: Crowding stresses males but calms females. Physiol Beha 58(6):1085-1089. Cavigelli, S. A., S. L. Monfort, T. K. Whitney, Y. S. Mechref, M. Novotny, and M. K. McClintock. 2005. Frequent serial fecal corticoid measures from rats reflect circadian and ovarian corticosterone rhythms. J Endocrinol 184(1):153-163. Culman, J., I. J. Kopin, and J. M. Saavedra. 1991. Regulation of corticotropin-releasing hor- mone and pituitary-adrenocortical response during acute and repeated stress in the rat. Endocr Reg 25(3):151-158. Davenport, M. D, S. T. Tiefenbacher, C. K. Lutz, M. A. Novak, and J. S. Meyer. 2006. Analysis of endogenous cortisol concentrations in the hair of rhesus macaques. Gen Comp Endocr 147(3):255-261. De Boer, S. F., J. L. Slangen, and G. J. van der Gugten. 1988. Adaptation of plasma catechol- amine and corticosterone responses to short-term repeated noise stress in rats. Physiol Beha 44(2):273-280. De Boer, S. F., S. J. Koopmans, J. L. Slangen, and G. J. van der Gugten. 1990. Plasma catecholamine, corticosterone and glucose responses to repeated stress in rats: Effect of interstressor interval length. Physiol Beha 47(6):1117-1124. Dhabhar, F. S., B. S. McEwen, and R. L. Spencer. 1993. Stress response, adrenal steroid recep- tor levels and corticosteroid-binding globulin levels—a comparison between Sprague- Dawley, Fischer 344 and Lewis rats. Brain Res 616(1-2):89-98. Donnerer, J. and F. Lembeck. 1990. Different control of the adrenocorticotropin-corticosterone response and of prolactin secretion during cold stress, anesthesia, surgery, and nicotine injection in the rat: Involvement of capsaicin-sensitive sensory neurons. Endocrinology 126(2):921-926. Faraday, M. M., K. H. Blakeman, and N. E. Grunberg. 2005. Strain and sex alter effects of stress and nicotine on feeding, body weight, and HPA axis hormones. Pharmacol Biochem Be 80(4):577-589. Fediuc, S., J. E. Campbell, and M. C. Riddell. 2006. Effect of voluntary wheel running on circadian corticosterone release and on HPA axis responsiveness to restraint stress in Sprague-Daley rats. J Appl Physiol 100(6):1867-1875.

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 RECOGNITION AND ASSESSMENT OF STRESS AND DISTRESS Guo, A. L., F. Petraglia, M. Criscuolo, G. Ficarra, R. E. Nappi, M. Palumbo, A. Valentini, and A. R. Genazzani. 1994. Acute stress- or lipopolysaccharide-induced corticosterone secretion in female rats is independent of the oestrous cycle. Eur J Endocrinol 131(5):535-539. Hall, F. S., J. M. Sundstrom, J. Lerner, and A. Pert. 2001. Enhanced corticosterone release after a modified forced swim test in Fawn hooded rats is independent of rearing experience. Pharmacol Biochem Be 69(3-4):629-634. Harper, J. M. and S. N. Austad. 2000. Fecal glucocorticoids: A noninvasive method of measur- ing adrenal activity in wild and captive rodents. Physiol Biochem Zool 73(1):12-22. Ishikawa, M., S. Ohdo, H. Watanabe, C. Hara, and N. Ogawa. 1995. Alteration in circadian rhythm of plasma corticosterone in rats following sociopsychological stress induced by communication box. Physiol Beha 57(1):41-47. Kirschbaum, C. and D. H. Hellhammer. 1994. Salivary cortisol in psychoneuroendocrine research: Recent developments and applications. Psychoneuroendocrinology 19(4):313-333. Klosterman, L. L, J. T. Murai, and P. K. Siiteri. 1986. Cortisol levels, binding, and prop- erties of corticosteroid-binding globulin in the serum of primates. Endocrinology 118(1):424-434. Ling, S. and F. Jamali. 2003. Effect of cannulation surgery and restraint stress on the plasma corticosterone concentration in the rat: Application of an improved corticosterone HPLC assay. J Pharm Pharm Sci 6(2):246-251. Livezey, G. T., J. M. Miller, and W. H. Vogel. 1985. Plasma norepinephrine, epinephrine and corticosterone stress responses to restraint in individual male and female rats, and their correlations. Neurosci Lett 62(1):51-56. Lynch, J. W., M. Z. Khan, J. Altmann, M. N. Njahira, and N. Rubenstein. 2003. Concentrations of four fecal steroids in wild baboons: Short-term storage conditions and consequences for data interpretation. Gen Comp Endocr 132(2):264-271. Marti, O., A. Gavalda, T. Jolin, and A. Armario. 1993. Effect of regularity of exposure to chronic immobilization stress on the circadian pattern of pituitary adrenal hormones, growth hormone, and thyroid stimulating hormone in the adult male rat. Psychoneuro- endocrinology 18(1):67-77. Moncek, F., R. Duncko, B. B. Johansson, and D. Jezova. 2004. Effect of environmental enrich- ment on stress related systems in rats. J Neuroendocrinol 16(5):423-431. Orr, T. E., J. L. Meyerhoff, E. H. Mougey, and B. N. Bunnell. 1990. Hyperresponsiveness of the rat neuroendocrine system due to repeated exposure to stress. Psychoneuroendocrinology 15(5-6):317-328. Rivier, C. and W. Vale. 1987. Diminished responsiveness of the hypothalamic-pituitary-adrenal axis of the rat during exposure to prolonged stress: A pituitary-mediated mechanism. Endocrinology 121(4):1320-1328. Royo, F., N. Bjork, H. E. Carlsson, S. Mayo, and J. Hau. 2004. Impact of chronic catheteriza- tion and automated blood sampling (Accusampler) on serum corticosterone and fecal immunoreactive corticosterone metabolites and immunoglobulin A in male rats. J Endo- crinol 180(1):145-153. Sakellaris, P. C. and J. Vernikos-Danellis. 1975. Increased rate of response of the pituitary- adrenal system in rats adapted to chronic stress. Endocrinology 97(3):597-602. Sapolsky, R., M., L. C. Krey, and B. S. McEwen. 1983. The adrenocortical stress-response in the aged male rat: impairment of recovery from stress. Exp Gerontol 18(1):55-64. Tannenbaum, B. M., W. Rowe, S. Sharma, J. Diorio, A. Steverman, M. Walker, and M. J. Meaney. 1997a. Dynamic variations in plasma corticosteroid-binding globulin and basal HPA activity following acute stress in adult rats. J Neuroendocrinol 9(3):163-168. Tannenbaum, B. M., D. N. Brindley, G. S. Tannenbaum, M. F. Dallman, M. D. McArthur, and M. J. Meaney. 1997b. High-fat feeding alters both basal and stress-induced hypothalamic- pituitary-adrenal activity in the rat. Am J Physiol 273(6 Pt 1):E1168-E1177.

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8 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS Tuli, J., J. A. Smith, and D. B. Morton. 1995a. Corticosterone, adrenal and spleen weight in mice after tail bleeding, and its effect on nearby animals. Lab Anim 29(1):90-95. Tuli, J., J. A. Smith, and D. B. Morton. 1995b. Effects of acute and chronic restraint on the adrenal gland weight and serum corticosterone concentration of mice and their faecal output of oocysts after infection with Eimeria apionoides. Res Vet Sci 59(1):82-86. Tuli, J., J. A. Smith, and D. B. Morton. 1995c. Stress measurements in mice after transportation. Lab Anim 29(2):132-138. Vachon, P. and J. P. Moreau. 2001. Serum corticosterone and blood glucose in rats after two jugular vein blood sampling methods: Comparison of the stress response. Contemp Top Lab Anim 40(5):22-24. Vahl, T. P., Y. M. Ulrich-Lai, M. M. Ostrander, C. M. Dolgas, E. E. Elfers, R. J. Seeley, D. A. D’Alessio, and J. P. Herman. 2005. Comparative analysis of ACTH and corticosterone sampling methods in rats. Am J Physiol-Endoc M 289:E823-E828. Viau, V. and M. J. Meaney. 1991. Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat. Endocrinology 129(5):2503-2511. Viveros, M. P., R. Hernandez, I. Martinez, and P. Gonzalez. 1988. Effects of social isolation and crowding upon adrenocortical reactivity and behavior in the rat. Re Esp Fisiol 44(3):315-321. Weinstock, M., M. Razin, D. Schorer-Apelbaum, D. Men, and R. McCarty. 1998. Gender dif- ferences in sympathoadrenal activity in rats at rest and in response to footshock stress. Int J De Neurosci 16(3-4):289-295. Windle, R. J., S. A. Wood, N. Shanks, P. Perks, G. L. Conde, A. P. da Costa, C. D. Ingram, and S. L. Lightman. 1997. Endocrine and behavioural responses to noise stress: Comparison of virgin and lactating female rats during non-disrupted maternal activity. J Neuroendo- crinol 9(6):407-414. Windle, R. J., S. A. Wood, S. L. Lightman, and C. D. Ingram. 1998a. The pulsatile character- istics of hypothalamo-pituitary-adrenal activity in female Lewis and Fischer 344 rats and its relationship to differential stress responses. Endocrinology 139(10):4044-4052. Page 38 While some (prolactin, α-MSH, oxytocin) increase during stress, others decrease (growth hormone, luteinizing hormone, prolactin), depending on the animal species and the physiological state in which stress occurs (Armario et al. 1984). Bingaman, E. W., L. D. Van de Kar, J. M. Yracheta, Q. Li, and T. S. Gray. 1995. Castration attenuates prolactin response but potentiates ACTH response to conditioned stress in the rat. Am J Physiol 269(4 Pt 2):R856-R863. Brown, G. M., D. S. Schalch, and S. Reichlin. 1971. Patterns of growth hormone and cortisol responses to psychological stress in the squirrel monkey. Endocrinology 88(4):956-963. Brown, G. M., J. Seggie, and J. Feldmann. 1977. Effect of psychosocial stimuli and limbic lesions on prolactin at rest and following stress. Clin Endocrinol 6(Suppl):29S-41S. Cates, P. S., M. L. Forsling, and K. T. O’byrne. 1999. Stress-induced suppression of pulsatile luteinising hormone release in the female rat: Role of vasopressin. J Neuroendocrinol 11(9):677-683. Collu, R., J. C. Jequier, J. Letarte, G. Leboeuf, and J. R. Ducharme. 1973. Effect of stress and hypothalamic deafferentation on the secretion of growth hormone in the rat. Neuro- endocrinology 11(3):183-190. Cronin, M. T., B. J. Siegel, and G. P. Moberg. 1981. Effect of behavioral stress on plasma levels of growth hormone in sheep. Physiol Beha 26(5):887-890. Day, T. A., M. J. West, and J. O. Willoughby. 1983. Stress suppression of growth hormone secretion in the rat: Effects of disruption of inhibitory noradrenergic afferents to the median eminence. Aust J Biol Sci 36(5-6):525-530.

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60 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS Seggie, J. A. and G. M. Brown. 1975. Stress response patterns of plasma corticosterone, prolactin, and growth hormone in the rat, following handling or exposure to novel envi- ronment. Can J Physiol Pharmacol 53(4):629-637. Siegel, R. A., N. Conforti, and I. Chowers. 1980. Neural pathways mediating the prolactin secretory response to acute neurogenic stress in the male rat. Brain Res 198(1):43-53. Simms, D. D., L. V. Swanson, and R. Bogart. 1978. Effect of collection stress on serum growth hormone levels in pygmy goats. J Anim Sci 46(2):458-462. Yelvington, D. B., G. K. Weiss, and A. Ratner. 1984. Effect of corticosterone on the prolactin response to psychological and physical stress in rats. Life Sci 35(16):1705-1711. Page 39 Moreover, their usefulness is subjected to the same limitations as discussed above, although chronic indwelling vascular catheters and automated blood collection systems may circumvent this limitation to some degree (Abelson et al. 2005). Atkinson, H. C., S. A. Wood, Y. M. Kershaw, E. Bate, and S. L. Lightman. 2006. Diurnal varia- tion in the responsiveness of the hypothalamic-pituitary-adrenal axis of the male rat to noise stress. J Neuroendocrinol 18(7):526-533. Lightman, S. L., R. J. Windle, M. D. Julian, M. S. Harbuz, N. Shanks, S. A. Wood, Y. M. Kershaw, and C. D. Ingram. 2000. Significance of pulsatility in the HPA axis. Noar Fnd Symp 227:244-257. Rogers, W. R., J. H. Lucas, B. C. Mikiten, H. D. Smith, and J. L. Orr. 1995. Chronically in- dwelling venous cannula and automatic blood sampling system for use with nonhuman primates exposed to 60 Hz electric and magnetic fields. Bioelectromagnetics Suppl 3:103-110. Windle, R. J., S. A. Wood, N. Shanks, P. Perks, G. L. Conde, A. P. da Costa, C. D. Ingram, and S. L. Lightman. 1997. Endocrine and behavioural responses to noise stress: Comparison of virgin and lactating female rats during non-disrupted maternal activity. J Neuroendo- crinol 9(6):407-414. Windle, R. J., S. A. Wood, S. L. Lightman, and C. D. Ingram. 1998a. The pulsatile character- istics of hypothalamo-pituitary-adrenal activity in female Lewis and Fischer 344 rats and its relationship to differential stress responses. Endocrinology 139(10):4044-4052. Windle, R. J., S. A. Wood, N. Shanks, S. L. Lightman, and C. D. Ingram. 1998b. Ultradian rhythm of basal corticosterone release in the female rat: Dynamic interaction with the response to acute stress. Endocrinology 139(2):443-450. Page 39 Many different types of stressors cause the rapid activation of the sympathetic division of the autonomic nervous system (ANS) (Blanc et al. 1991). Blanc, J., M. L. Grichois, M. Vincent, and J. L. Elghozi. 1994. Spectral analysis of blood pres- sure and heart rate variability in response to stress from air-jet in the Lyon rat. J Auton Pharmacol 14(1):37-48. Inagaki, H., M. Kuwahara, and H. Tsubone. 2004. Effects of psychological stress on autonomic control of heart in rats. Exp Anim 53(4):373-378. McDougall, S. J., J. R. Paull, R. E. Widdop, and A. J. Lawrence. 2000. Restraint stress: Dif- ferential cardiovascular responses in Wistar-Kyoto and spontaneously hypertensive rats. Hypertension 35:126-129. Saunders, P. R., P. Miceli, B. A. Vallance, L. Wang, S. Pinto, G. Tougas, M. Kamath, and K. Jacobson. 2006. Noradrenergic and cholinergic neural pathways mediate stress-induced reactivation of colitis in the rat. Autonom Neurosci 124(1-2):56-68.

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61 RECOGNITION AND ASSESSMENT OF STRESS AND DISTRESS Stiedl, O., M. Meyer, T. Kishimoto, M. G. Rosenfeld, and J. Spiess. 2003. Stress-mediated heart rate dynamics after deletion of the gene encoding corticotropin-releasing factor receptor 2. Eur J Neurosci 17(10):2231-2235. Tornatzky, W. and K. A. Miczek. 1994. Behavioral and autonomic responses to intermittent social stress: Differential protection by clonidine and metoprolol. Psychopharmacology 116(2):346-356. van den Buuse, M., G. Lambert, M. Fluttert, and N. Eikelis. 2001a. Cardiovascular and behavioural responses to psychological stress in spontaneously hypertensive rats: Effect of treatment with DSP-4. Beha Brain Res 119(2):131-142. Wood, S. K., R. E. Verhoeven, A. Z. Savit, K. C. Rice, P. S. Fischbach, and J. H. Woods. 2006. Facilitation of cardiac vagal activity by CRF-R1 antagonists during swim stress in rats. Neuropsychopharmacology 31(12):2580-2590. Xie, Y. F., Q. Jiao, S. Guo, F. Z. Wang, J. M. Cao, and Z. G. Zhang. 2005. Role of parasym- pathetic overactivity in water immersion stress-induced gastric mucosal lesion in rat. J Appl Physiol 99(6):2416-2422. Zhang, W. and P. Thoren. 1998. Hyper-responsiveness of adrenal sympathetic nerve activity in spontaneously hypertensive rats to ganglionic blockade, mental stress and neuron- glucopenia. Pflugers Arch 437(1):56-60. Page 39 Some stressors may also increase the activity of the parasympathetic division affecting both core body temperature and the gastrointestinal system (e.g., disturbed intestinal absorp- tion, gastric ulceration, colitis; Johnson et al. 2002). Ray, A., R. M. Sullivan, and P. G. Henke. 1987. Adrenergic modulation of gastric stress pathol- ogy in rats: A cholinergic link. J Auton Ner Syst 20(3):265-268. Saunders, P. R., N. Hanssen, and M. H. Perdue. 1997. Cholinergic nerves mediate stress- induced intestinal transport abnormalities in Wistar-Kyoto rats. Am J Physiol 273: G486-G490. Saunders, P. R., P. Miceli, B. A. Vallance, L. Wang, S. Pinto, G. Tougas, M. Kamath, and K. Jacobson. 2006. Noradrenergic and cholinergic neural pathways mediate stress-induced reactivation of colitis in the rat. Autonom Neurosci 124(1-2):56-68. Xie, Y. F., Q. Jiao, S. Guo, F. Z. Wang, J. M. Cao, and Z. G. Zhang. 2005. Role of parasym- pathetic overactivity in water immersion stress-induced gastric mucosal lesion in rat. J Appl Physiol 99(6):2416-2422. Page 39 For example, telemetry in conscious, unrestrained animals is an effective method for the continuous monitoring of physiologic alterations in heart rate, respiration, blood pressure, ECG, and body temperature (Akutsu et al. 2002). Azar, T., J. Sharp, and D. Lawson. 2005. Stress-like cardiovascular responses to common procedures in male versus female spontaneously hypertensive rats. Contemp Top Lab Anim 44(3):25-30. Brockway, B. P., P. A. Mills, and S. H. Azar. 1991. A new method for continuous chronic measurement and recording of blood pressure, heart rate and activity in the rat via radio- telemetry. Clin Exp Hypertens A 13(5):885-895. Caplea, A., D. Seachrist, G. Dunphy, and D. Ely. 2000. SHR Y chromosome enhances the nocturnal blood pressure in socially interacting rats. Am J Physiol Heart Circ Physiol 279(1):H58-H66. Harkin, A., T. J. Connor, J. M. O’Donnell, and J. P. Kelly. 2002. Physiological and behavioral responses to stress: What does a rat find stressful? Lab Anim 31(4):42-50.

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62 RECOGNITION AND ALLEVIATION OF DISTRESS IN LABORATORY ANIMALS Irvine, R. J., J. White, and R. Chan. 1997. The influence of restraint on blood pressure in the rat. J Pharmacol Toxicol 38(3):157-162. Kramer, K., J. A. Grimbergen, L. van der Gracht, D. J. van Iperen, R. J. Jonker, and A. Bast. 1995. The use of telemetry to record electrocardiogram and heart rate in freely swimming rats. Method Find Exp Clin 17(2):107-112. Lawson, D. M., M. Churchill, and P. C. Churchill. 2000. The effects of housing enrichment on cardiovascular parameters in spontaneously hypertensive rats. Contemp Top Lab Anim 39(1):9-13. Lemaire, V. and P. Mormede. 1995. Telemetered recording of blood pressure and heart rate in different strains of rats during chronic social stress. Physiol Beha 58(6):1181-1188. Nakashima, T., M. Akamatsu, A. Hatanaka, and T. Kiyohara. 2004. Attenuation of stress- induced elevations in plasma ACTH level and body temperature in rats by green odor. Physiol Beha 80(4):481-488. Rubini, R., A. Porta, G. Baselli, S. Cerutti, and M. Paro. 1993. Power spectrum analysis of cardiovascular variability monitored by telemetry in conscious unrestrained rats. J Auton Ner Syst 45(3):181-190. Sato, K., F. Chatani, and S. Sato. 1995. Circadian and short-term variabilities in blood pres- sure and heart rate measured by telemetry in rabbits and rats. J Autonom Ner Syst 54(3):235-246. Schierok, H., M. Markert, M. Pairet, and B. Guth. 2000. Continuous assessment of multiple vital physiological functions in conscious freely moving rats using telemetry and a plethysmography system. J Pharmacol Toxicol 43(3):211-217. Sharp, J., T. Zammit, T. Azar, and D. Lawson. 2002a. Does witnessing experimental procedures produce stress in male rats? Contemp Top Lab Anim 41(5):8-12. Sharp, J. L., T. Zammit, T. Azar, and D. M. Lawson. 2002b. Stress-like responses to com- mon procedures in male rats housed alone or with other rats. Contemp Top Lab Anim 41(4):8-14. Sharp, J. L., T. Zammit, and D. Lawson. 2002c. Stress-like responses to common procedures in rats: Effect of the estrous cycle. Contemp Top Lab Anim 41:15-22. Sharp, J., T. Zammit, T. Azar, and D. Lawson. 2003a. Are “by-stander” female Sprague-Dawley rats affected by experimental procedures? Contemp Top Lab Anim 42(1):19-27. Sharp, J., T. Zammit, T. Azar, and D. Lawson. 2003b. Stress-like responses to common procedures in individually and group-housed female rats. Contemp Top Lab Anim 42(1):9-18. Sharp, J., T. Azar, and D. Lawson. 2005a. Effects of a cage enrichment program on heart rate, blood pressure, and activity of male Sprague-Dawley and spontaneously hypertensive rats monitored by radiotelemetry. Contemp Top Lab Anim 44(2):32-40. Sharp, J., T. Azar, and D. Lawson. 2005b. Selective adaptation of male rats to repeated social encounters and experimental manipulations. Contemp Top Lab Anim 44(2):28-31. van den Buuse, M. 1994. Circadian rhythms of blood pressure, heart rate, and locomotor activity in spontaneously hypertensive rats as measured with radio-telemetry. Physiol Beha 55(4):783-787. van den Buuse. M., S. A. Van Acker, M. Fluttert, and E. R. De Kloet. 2001b. Blood pressure, heart rate, and behavioral responses to psychological “novelty” stress in freely moving rats. Psychophysiology 38(3):490-499. Wood, S. K., R. E. Verhoeven, A. Z. Savit, K. C. Rice, P. S. Fischbach, and J. H. Woods. 2006. Facilitation of cardiac vagal activity by CRF-R1 antagonists during swim stress in rats. Neuropsychopharmacology 31(12):2580-2590.