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Parasites and behavior: an ethopharmacological analysis and biomedical implications
NBR 385 NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
PERGAMON
Neuroscience and Biobehavioral Reviews 23 (1999) 1037–1045 www.elsevier.com/locate/neubiorev
Parasites and behavior: an ethopharmacological analysis and biomedical implications M. Kavaliers a,*, D.D. Colwell b, E. Choleris c a
Department of Psychology and Neuroscience Program, University of Western Ontario, London, Ontario, Canada N6A 5C1 b Agriculture and Agri-Food Canada, Box 3000 Main, Lethbridge, Alberta, Canada T1J 4B1 c Department of Nuclear Medicine and Magnetic Resonance, Lawson Research Institute, London, Ontario, Canada N6A 4V2 Accepted 12 April 1999
Abstract Parasites and disease are increasingly recognized as agents of behavioral, ecological and evolutionary importance having a variety of influences on their hosts other than the more obvious pathological and immunological changes. Parasites can have significant behavioral effects even when parasitism is sub-clinical with these effects proposed to either benefit the parasite (parasite ‘manipulation’), benefit the host, or to simply arise as side-effects of the infection (parasitic ‘constraints’). However, until relatively recently little attention has been paid to the neuromodulatory substrates that mediate these behavioral changes. Ethopharmacology incorporates an evolutionary approach to the study of behavior with pharmacological analysis of neuromodulatory mechanisms. As such, this approach is appropriate for, and has been applied to, the analysis of the effects of ectoparasites (e.g. biting and blood-feeding flies) and endoparasites (e.g. protozoa, nematodes) on a number of behaviors (e.g. pain inhibition, learning and memory, responses to predators and anxiety, mate selection) in selected host–parasite systems. Ethopharmacology suggests a promising direction by which neuromodulatory mechanisms that underlie the effects of parasites on behavior, including that of humans, can be addressed. q 1999 Elsevier Science Ltd. All rights reserved. Keywords: Parasites and behavior; Predator–prey; Anxiety; Mate choice; Fear conditioning; Analgesia; Conditioned analgesia; Learning and memory
1. Introduction Parasites influence almost every conceivable level of biological organization with the extent of parasitism depending largely on how one defines the term. The classical definition of parasitism holds that it is an intimate and obligatory relationship between two heterospecific organisms in which one lives on, off, and at the expense of the other. In a broader sense parasites can be considered as organisms that exploit their host’s resources by using the behavioral, physiological and energetic investment of the host to reduce the cost of obtaining their own resources. As such, more than 50% of all plant and animal species are parasitic at some point in their life cycle. Just as important is the question of how many animals are parasitized. This number approaches one hundred percent when one considers all of the internal parasites (endoparasites) and external parasites (ectoparasites) that are present in nature. * Corresponding author. Department of Psychology, Social Sciences Centre, University of Western Ontario, London, Ontario, Canada N6A 5C2. Tel.: 1 1-519-679-2111 ext.: 6084; fax: 1 1-519-661-3961. E-mail address: [email protected] (M. Kavaliers)
In studying and observing animals that live in clean, ‘aseptic’, laboratory environments it is easy to forget that animals have evolved and thrive in environments with an array of parasites. Parasites and disease are increasingly recognized as having a major impact on the evolution, ecology and behavior of their hosts [1–6], with parasites and their hosts in a constant co-evolutionary ‘arms race’ [7]. Parasites evolve to optimize host exploitation, while hosts evolve to minimize the parasite-induced loss of fitness (virulence). In general, infections involving single hosts and requiring contact between individuals or their bodily products are of a lower virulence, because the host must be able to interact with other individuals. Parasites that involve multiple hosts and are transmitted by vectors are usually more virulent and may incapacitate their host. However, in single host–parasite systems that are evolutionarily ‘young’, such as many human host–parasite systems, virulence may still be high. Results of behavioral and ecological studies have shown that parasites have significant effects on their hosts even when parasitism is sub-clinical. The altered behavioral responses have been proposed to either benefit the parasite (parasite ‘manipulation’), benefit the host, or to simply arise
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vertebrates, have shown that certain parasitic infections elicit modifications in the levels and expression of classical neurotransmitters and neuropeptides e.g. see Refs. [11–13]. Results of studies focusing on decreases in nociceptive and pain sensitivity (antinociception and analgesia, respectively) have provided evidence for altered opioid peptide activity in several host–parasite systems [14–21]. Exposure to a variety of environmental stressors can produce potent pain inhibition or analgesia in laboratory animals and humans with this analgesia involving either opioid or non-opioid mediated mechanisms. Analgesia has been observed in rodents following exposure to laboratory stressors [22,23] and is an important component of an animals response to stimuli associated with behaviorally and ecologically important dangers such as threatening conspecifics and predators (e.g. see Refs. [22,24,25]. As such, analgesia is adaptive in these threatening situations reducing responses to distracting stimuli and facilitating the performance of various active and passive defensive behaviors. 2.1. Ectoparasites
Fig. 1. Effects of a 30 min exposure to either house flies, different densities of stable flies (LO 10–15 flies; HI 50–55 flies) or control handling (no flies) on the nociceptive responses (latency of response to a 508C thermal surface) of individual male mice. Response latencies were determined before (pre) and after (post) exposure to the flies on two consecutive days. Exposure to the stable flies elicited an significant p , 0:01 analgesic response on both days whereas the house flies and control handling had no significant effects on nociceptive sensitivity. n 10. Vertical lines denote a SEM.
as side-effects of the infection (parasitic ‘constraints’), with no obvious direct adaptive significance [8]. Correspondingly, vertebrates use various behavioral strategies in an attempt to either increase their fitness in the presence of external parasites and internal parasitic infections and, or to avoid or minimize their exposure to parasites [4,5,8]. Recently ethological and pharmacological approaches have been applied to the investigation of host–parasite systems. Ethopharmacology attempts to delineate the mechanisms that regulate and modulate behavior by combining ethological analysis, that take into account the adaptive significance and evolutionary pressures that underlie behavior, with pharmacological manipulations [9,10]. This review briefly considers the results of selected ethopharmacological investigations of the effects of parasites on behavior.
2. Parasites and analgesia Investigations with invertebrates, and to a lesser extent
Among the aversive stimuli that can elicit analgesia are ectoparasitic arthropods. Biting and blood-feeding flies are among the most prevalent of biologically and economically important natural stressors. These hematophagous insects are responsible for many deleterious effects in domestic and wild animals and on human comfort and prosperity [4,26,27]. Large ungulates such as cattle often exhibit defensive and avoidance behaviors indicative of heightened levels of anxiety and fear during attacks by biting flies [4,14,15]. In humans, the swarming and biting behavior of flies are not only stressful ‘nuisances’, but these insects are also hosts and vectors of a wide range of viruses, bacteria, and protozoa [26,27]. Stable flies, Stomoxy calcitrans (L.) and mosquitoes, e.g. Aedes togoi, attack and feed on a wide range of mammal’s [26]. Results of investigations with laboratory mice and deer mice showed that a 30–60 min exposure to either stable flies or mosquitoes elicited opioid mediated analgesia that was blocked by the prototypic opiate antagonist naloxone (Fig. 1), while brief exposure elicited a non-opioid mediated analgesia that was insensitive to naloxone and other more selective opiate antagonists [14,15,17,24,28]. These analgesic responses interacted synergistically with the effects elicited by other stressors, magnifying the impact of low levels of biting flies on host behavior and potentially host fitness [24]. Sex differences were observed in both the levels and mediation of biting-fly induced analgesia, with males displaying greater levels of opioid mediated analgesia than females [29]. In addition, in males the non-opioid analgesia involved N-methyl-d-aspartate (NMDA) receptor systems, while in females it involved other receptor systems. These male–female differences in non-opioid
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analgesia are hormonally mediated with both estradiol and progesterone being associated with the expression of the NMDA independent non-opioid analgesia in reproductive females. These male–female differences underscore the need to consider sex and reproductive status when examining the effects of parasites and other aversive stimuli [29– 31]. While innately recognized danger stimuli (e.g. predators) provoke behavioral avoidance, analgesia and fear responses, fear can also be learned to stimuli associated with threat. Conditioned fear, including that of analgesia, has been shown to be rapidly acquired with a single experience sufficient to produce acquisition [32]. This rapid one-trial aversive conditioning has also been shown to be true for biting fly exposure [28]. Exposure to either non-biting house flies, Musca domestica, or altered biting flies whose biting mouthparts are removed normally has no significant effects on the nociceptive sensitivity of fly-naive mice. However, in mice with a single previous 30 min session of experience of attacks by intact biting flies, opioid-mediated analgesia was induced by the presence of altered flies that were incapable of biting. This acquired aversive response was specific for the altered biting fly, with similar sized non-biting house flies having no evident effects on mice that were preexposed to biting flies. The individual acquisition of the conditioned analgesia to biting flies involved NMDA receptor mechanisms and did not need the expression of analgesia [28]. Administration of a competitive NMDA antagonist to fly-naive mice before exposure to intact biting flies, although not significantly reducing the analgesic responses, blocked the acquisition of the subsequent conditioned analgesia. In contrast, administration of naloxone before exposure to intact biting flies blocked the initial analgesia without affecting the acquisition of the conditioned analgesia. The initial analgesic response may have been induced by the bites of the fly. The flies may be decreasing host pain sensitivity so that if their initial feeding attempts are only partially successful, subsequent bites may not be felt as much and the flies will succeed in feeding. However, a preparatory or ‘anticipatory’ analgesia could be an adaptive response of the host, facilitating the activation of defense mechanisms before receipt of bites. This conditioned analgesia can also be acquired without direct individual aversive experience with the biting flies (in preparation). Mice (observers) that witnessed other mice (demonstrators) being attacked by biting flies, but themselves were not bitten, displayed analgesic responses. Upon subsequent exposure to altered biting flies the observers also displayed a conditioned analgesia. The initial analgesic responses were likely elicited by the stress-related cues (odors, ultrasonic vocalizations, etc. e.g. see Refs. [8,46,78]) emitted by the attacked demonstrators, whereas the subsequent responses to the altered flies involved socially mediated ‘observational’ learning.
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2.2. Endoparasites A number of endoparasitic infections also elicit analgesia in rodents. Schistosoma mansoni is a trematode parasite of humans and is responsible for schistosomiasis, a severe and often debilitating disease. Hamsters clinically infected with S. mansoni displayed naloxone sensitive analgesic responses [33,34] that were accompanied by changes in locomotor activity, with 25 day infected hamsters displaying naloxone reversible increases in activity and 40 day infected hamsters showing decreased activity that was sensitive to a delta opiate receptor directed antagonist. Male mice clinically infected with the nematode, Nippostrongylus brasiliensis, displayed similar naloxone sensitive analgesia and delta opioid mediated decreases in locomotor activity [21]. In contrast, the early stages of clinical schistosome infection in mice were associated with a slight increase in pain sensitivity, while the latter stages involved analgesia [35–37]. This was accompanied by opioid mediated shifts in locomotor activity similar to those seen in the infected hamsters. These alterations in nociception and locomotor activity may arise either from modifications in host endogenous opioid systems and, or directly through the active secretion of opioid peptides by either the parasite or the host’s immune system. S. mansoni exhibits proopiomelanocortinrelated gene activity and produces b-endorphin and other opioid peptides that may play a role in immune evasion by these parasites [11]. Elevated opioid peptide levels are reported in schistosome infected mice [13], though, the alterations in nociceptive sensitivity observed in S. mansoni infected mice were proposed to be primarily related to increased levels of nerve growth factor and cytokines [35]. Opioid-mediated changes in nociceptive sensitivity, independent of any changes in locomotor activity, have also been reported from male mice subclinically infected with the naturally occurring, single host, enteric, protozoan (coccidian) parasite, Eimeria vermiformis [16,18,19]. Analgesia was evident in E. vermiformis infected mice by day 2 post-infection, with the intensity of analgesia increasing through the pre-infective period. Following the onset of infectivity (day 8 post infection) the analgesic responses declined, with nociceptive responses returning to basal levels with the cessation of infectivity by day 15–16 postinfection. The analgesia in the pre-infective period involved k and m opioid activity, while the decreasing analgesia observed after the onset of infectivity was correlated with enhanced d and m opioid activity [19]. These shifts in opioid activity may be associated with changes in immune and inflammatory responses. Opioids modulate immune activity, with the enhancement or suppression of immune responses depending on the duration and extent of opioid activation [38,39]. Reproductive stages of Eimeria are the most immunogenic and it is during those pre-infective stages that the greatest increases in the level of
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Fig. 2. Responses of uninfected male mice (uninfected), mice infected with Eimeria vermiformis (infected) or sham infected (uninfected) mice (sham) in a Y maze odor preference apparatus to either: predator (cat) and nonpredator (non-pred; guinea pig) odor; predator and control (blank, blk) odor; or non-predator and control odor combinations. Responses are given as preference ratios (e.g. time spent in vicinity of predator/ time spent in vicinity of non-predator 1 time spent in vicinity of predator) determined over a 5 min period. n 5. Parasitized male mice displayed a reduced aversion to p , 0:05 and avoidance (i.e. increased preference) of the predator odor relative to that shown by uninfected (sham) mice. Vertical lines denote SEM. (after [40]).
analgesia, suggestive of maximal opioid activation, are evident. Not all parasitic infections are, however, associated with the induction of analgesia. Chronic infection with the single host enteric nematode parasite, Heligmosomoides polygyrus, has no significant effect on the nociceptive sensitivity of male and female mice [40,41]. Moreover acute, though not repeated or chronic, administration of ‘illness-inducing agents’ such as lipopolysaccharide (LPS), the smallest immunogenic component of the cell wall of gram-positive bacteria, induces hyperalgesia [38]. These acute symptoms were considered to be mediated by the increased production and release of cytokines. In mammals the immune responses to parasites differ from that evoked by bacteria and viruses; therefore, hosts may respond differently to various types of infection.
3. Parasites, predators and anxiety Results of laboratory and field studies with parasitized rodents have revealed alterations in a variety of behaviors that may either directly or indirectly increase vulnerability to predation facilitating parasite transmission from the intermediate host (prey) to a definitive host (predators). Mice infected with the protozoan, Toxoplama gonodii, of which felines are the definitive host, displayed heightened activity,
reduced avoidance of novel environments, and less caution to uninfected individual [30]. Mice infected with the nematode, Toxocara canis, displayed decreased anxiety and defensive responses to predators that were independent of any changes in locomotor activity [42–44]. Male mice infected with Trypanosoma gambiense, and lemmings infected with the protozoan, Sarcocystis rauschorum, showed decreased reactivity to predators [45,46]. All of these responses are consistent with an enhanced susceptibility to predation. Humans subclinically infected with T. gondii were also reported to exhibit altered behaviors and personality factors [47], though it was not demonstrated that these changes increased the probability of parasite transmission. Similarly there is evidence that viral infections may cause symptoms of depressive illness and attendant changes in anxiety-associated behaviors in humans and laboratory animal models [2,48]. Even single host systems revealed significant changes in the responses to predator threat in infected individuals (Fig. 2). Male mice infected with E. vermiformis displayed reduced opioid and non-opioid analgesia and avoidance responses following brief exposure to a cat [25]. Mice infected with H. polygyrus displayed reduced opioid and attenuated serotoninergic (5-HT) and NMDA mediated non-opioid predator odor induced analgesia [49]. Changes in 5-HT and NMDA mediated responses, both of which are implicated in fear and anxiety [22,25,28,29], could result in a decreased fearfulness and anxiety upon predator exposure. These reductions in predator responses and avoidance observed in E. vermiformis and H. polygyrus infected individuals are probably not directly related to the facilitation of parasite transmission. Reduction in predator sensitivity is likely to be detrimental to both the parasite and the host and calls into question the possible adaptive value or evolutionary significance of the altered predator response. However, parasites that do not obviously appear to benefit from changes in host behavior often have the greatest impact on host behavior [50]. The reduction in predator sensitivity may be part of a general reduction in fearfulness and anxiety in the infected individuals, decreasing avoidance of conspecifics and increasing interactions between the infected and uninfected individuals, thereby, facilitating parasite transmission in single host systems. This contrasts with the anxiogenic consequences of acute LPS administration in mice [51]. These responses were proposed to be related to illness (sickness) behaviors that are associated with reduced mobility and reactivity to external stimuli consistent with an anxiogenic profile [4]. Mice sub-clinically infected with the gram negative bacteria, Campylobacter jeueni, and laboratory rats with ‘inapparent’ wound infections also exhibited anxiogenic responses consistent with alterations in neuromodulatory functions [52,53]. Together, these findings indicate the need to consider the effects of parasites and other infection, along
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with the intensity, virulence, nature and duration of infection, and modes of transmission, when considering anxiety and associated behaviors.
4. Parasites, learning and memory A variety of studies have indicated detrimental effects of parasitic infection on cognition. For example, both S. mansoni and T. canis are reported to decrease the performance of rats and mice on a variety of maze discrimination tasks [43,54,55]. As well, apparent correlation between parasitic infection and cognitive ability in children are reported [55–57] but see also Ref. [58]. Successful foraging, reproduction, predator avoidance and territorial defense, all of which have been reported to be influenced by parasitism [8], depend on the host’s spatial abilities and memories and in particular the spatial localization of patches, mates, escape routes and neighbors. Results of several studies have reported that parasitic infection can affect host spatial performance in laboratory maze tasks. Male mice subclinically infected with either E. veriformis or H. polygyrus displayed reduced performance in a Morris water maze task, whereby individual mice have to acquire and retain the location of a hidden platform [59,60]. Spatial learning impairments have also been reported in male mice subclinically infected with either a mouse leukemia virus or the gram negative bacterium Legionella pneumiophila [61,62]. In E. vermiformis infected mice, the greatest deficits in spatial acquisition occurred during the pre-infective period when maximum increases in opioid activity and modifications in immune activity are evident [60]. Immune components, such as interleukin-1, have been shown to impair performance in the water maze task [63]. Opioid systems have also been shown to be involved in the modulation of spatial learning and memory, with opiates having inhibitory effects and opiate antagonists facilitating learning [64]. The behavior of sheep infected with the abonasal nematode, Haemonchus controtus, in a ‘motivational-choice’ test was improved by treatment with an opiate antagonist [65], while exposure to stable flies was shown to decrease in a naloxone-reversible manner the spatial performance of mice [66]. In contrast, infection with the nematode Strongyloides rattii, had no evident effects on the performance of mice and rats in a water maze task [67]. It is likely that the effects of various parasitic infections on learning and memory are dependent on the life history of the parasite, nature of the infection, ecology and mating systems and the specific endocrine–immune features of the host. Ethopharmacological investigations of animals in ethologically relevant spatial and non-spatial tasks are necessary to determine the impacts of infection on the acquisition and use of stored memory.
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5. Parasites and mate responses Parasites have been reported to affect mate choice and mating patterns [1,5,6,68]. Hamilton and Zuk [69] suggested that females prefer to mate with males with showy sexual displays because they are the healthiest and the most resistant to parasites. By avoiding infected males, choosy females can reduce their risk of contracting contagious diseases, obtain more parental investment and increase the resistance of their offspring to parasites. In the original Hamilton–Zuk hypothesis choosy females acquire indirect benefits while in the two alternatives (parasite avoidance, efficient parent) the benefits are direct. In their original proposal Hamilton and Zuk [69] speculated that during mate choice animals should examine urine and faecal cues in an attempt to detect mates that were disease- and parasite-free. Chemical signals can serve as good indicators of an individual health and infection status being more direct and labile than morphological traits [70]. In rodents urine and other odor cues are of major importance in individual recognition, mate detection and choice [40,71–73]. Results of a number of odor preference tests, which are considered to give reliable indications of mate choice [73,74], revealed that female laboratory mice can discriminate between infected and uninfected males on the basis of odor. Female mice displayed a reduced interest in the urine and other odorous secretions of male mice infected with either influenza virus [75], the protozoan, E. vermiformis, or the nematode, H. polygyrus [40,41,74,76]. The urine odor of the influenza-infected mice appeared to simply lose its attractiveness [75], whereas the odor of the parasitized males both lost attractiveness and elicited aversive responses [40,76]. These alterations in female odor preference reduce the likelihood of mating occurring by decreasing the probability of subsequent contact between individuals. It does not, however, necessarily preclude mating when the individuals are in close proximity. In this regard, pre-exposure to the odor cues of H. polygyrus infected males affected the subsequent responses of estrous female mice to infected and uninfected male mice, with females displaying a decreased aversion for the odors of infected males and a reduced preference for the odors of uninfected males (submitted). This suggests that brief preexposures to the odors of infected males can have substantial motivational influences on the subsequent mate preferences of females by modifying their relative responses to both infected and uninfected individuals. This likely contributes to the variation that is evident in female mate choice evident under natural conditions. The extent of the female aversion/avoidance of the odors of E. vermiformis parasitized male mice was related to the development stage of the infection (Fig. 3). Females displayed maximum discrimination against the odors of infective males consistent with a direct avoidance of males and their excretory products in an attempt to minimize contagion [1]. However, females also avoided the
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Fig. 3. Responses of uninfected estrous female mice in a Y-maze odor preference apparatus to the odors of uninfected male mice and male mice subclinically infected with the protozoan E. vermiformis. responses of females to: left uninfected male [sham-infected (uninfected, treated same way as infected) day 4, 7 or 10 post sham infection (D4 (non-infective), D7 (onset of infectivity) and D10 (infective), respectively] and blank (control neutral odor); middle infected (days 4, 7 and 10 post infection and blank; right infected and sham infected odor combinations are shown. Responses are given as preference ratios (e.g. time spent in the vicinity of the infected male odor/time spent in the vicinity of the uninfected (sham) male odor 1 time spent in the vicinity of the infected male odor). Preferences were determined over a 5-min period. Females displayed a significantly p , 0:01 reduced preference for and an increased aversion to the odors of infected males. n 5, in all cases. vertical lines denote SEM after [74]).
odors of pre-infective males, which are not yet shedding any parasite components, suggesting recognition of odors associated with a parasitized male. This is consistent with both the original Hamilton and Zuk [69] model of parasitemediated sexual selection and the contagion indicator and avoidance hypothesis [1]. In order to separate the Hamilton–Zuk model from the transmission avoidance model, both resistance and expression of the trait (i.e. odor response) has to be shown to be heritable. This necessitates the direct examinations of mating behavior as well as the behavior and susceptibility to infection of the progeny. An additional consequence of exposure to the olfactory cues associated with either an E. vermiformis or H. polygyrus infected male was the induction of analgesia in female mice [18,20,40]. The nature of this analgesia varied as a function of the duration of exposure, with prolonged (15 min) exposure to male odors inducing a relatively long-lasting, opioid mediated analgesia and brief (1 min) exposures eliciting a lower amplitude and short lasting non-opioid analgesia. The non-opioid mediated analgesic responses may represent anxiety related anticipatory defense reactions designed to prepare the female mouse for a potential encounter with a parasitized male, while the more protracted opioid mediated analgesia may be
associated with stress and related defense responses including that of immune activation. These analgesic responses and their anxiety/stress associated behavioral correlates could elicit either a reduced interest in, or avoidance of parasitized male mice by the females, potentially serving as a component of female mate choice. Female mice, rats and meadow voles can, on the basis of urine, also discriminate against males infected with either the cestodes Taenia crassiceps, Hymenolepis diminuita, or Trichinella spiralis [77,78]. In contrast to E. vermiformis and H. polygyrus, these parasites have a complex life cycle and, thus, are not directly transmissible and infectious to females. However, in most cases the infected males also displayed substantially reduced levels of testosterone, with T. crassiceps reducing testosterone levels by 95% and inhibiting male sexual behavior [80]. It is, therefore, possible that in these multi-host systems females may be responding to a combination of odor cues that relates to male conditions. Reduced testosterone levels are unlikely to be a major factor in determining female odor responses in the single host system of E. vermifomis and H. polygyrus where infected males maintain their sexual interest [81,82], or in the case of E. vermiformis, showed enhanced interest in females [74]. Testosterone has been proposed to be immunosuppressive, rendering males more susceptible to infection [30,31], suggesting a trade off between parasite defenses and testosterone mediated behaviors [31,68,71]. Ethopharmacological investigations of endocrine–immune interactions and mate choice are necessary to address these questions. Substantial evidence exists that mice and rats can distinguish between urinary odors on the basis of differences in the major histocompatibility complex (MHC) and use MHC-mediated or related odors for both kin recognition and mating preferences [70,83]. The MHC activity is part of the immune system with infection activating the release of MHC antigens [70]. Parasite-induced alterations in endocrine, immune, and neurochemical function may affect MHC functions, the expression of odor cues, and the subsequent aversive responses that are displayed. The possible sources of the infected odor cues (e.g. urine, fecal material, scent and salivary gland products) and roles of various olfactory mediation systems remains to be determined. Investigations of the effects of parasites have been primarily carried out with females, with generally little attention given to the responses of males to parasitized females. Recently, it was shown that male mice also displayed analgesic responses to the odors of infected females, though the responses were of a lower magnitude than those displayed by females exposed to the odors of correspondingly parasitized males [41]. Although both sexually experienced and sexually naive males were capable of distinguishing between the odors of infected and uninfected females, the sexually experienced males displayed a significantly greater analgesia than the sexually naive males. There are data indicating that a male’s sexual
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experience may influence a variety of behavioral and hormonal, responses, with male mice of a higher social rank and likely more experience with females, displaying greater susceptibility to parasitic infection [71]. Consequently, if a greater analgesic response has a role in eliciting avoidance of a parasitized conspecific, such a response would be adaptive for the sexually experienced males that are potentially more susceptible to infection. Little attention has also been given to the possible effects of parasites on the host’s responses to sexual cues. In two host systems male mice clinically infected with the nematode, T. crassiceps, and females infected with the nematode, Trichinella spiralis, were reported to be inhibited in their sexual behaviours limiting possible mate responses [44,80]. Conversely, data from single host systems suggest that parasitized individuals may display augmented mate responses [74]. At 4 days post-infection E. vermifomis infected male mice had a significantly decreased preference for the odors of estrous females, whereas at 10 days post-infection infective males had a significantly increased preference for the odors of estrous females. Administration of a k opioid receptor antagonist increased the responsiveness of the pre-infective males, while a d opioid receptor antagonist reduced the augmented responses of the infected male mice to the estrous female mice suggesting that alterations in opioid systems contribute to the shifts in the responses of infected males to females. As well, there is data from single host systems suggesting that parasitized individuals may be less choosy in their mate preference [41]. H. polygyrus infected females displayed reduced analgesic responses to the odors of infected males with the extent of the analgesic response being related to the nature of the male infection [41]. Infected females did not display an analgesic response to the odors of males infected with the same parasite as themselves (H. polygyrus) and displayed an attenuated analgesic response to males infected with a different parasite, E. vermiformis. Similarly, H. polygyrus infected males displayed lower analgesic responses to the odors of H. polygyrus infected females [82]. This potentially could support assortative mating with respect to parasite load and contribute to the variability in female mate preference [84]. The reduced analgesia displayed by the H. polygyrus infected mice could be interpreted in terms of odor familiarity and responses to group odor templates. Parasiteinduced alterations in endocrine, immune and neurochemical functions [6,68,70] may affect MHC activity and the expression of urinary of associated odor cues and subsequent analgesic responses displayed by uninfected females. Uninfected mice could be construed as displaying analgesic responses to the odors of infected individuals because the odors are different from the group or self-odor template. The attenuation in analgesia displayed by the parasitized males and females may also be part of a general reduction in fearfulness and anxiety in the infected individuals. There is evidence that humans also use various indices of
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health and potentially infection status and resistance to parasites in mate choice. Humans universally find signs of disease and infection sexually unattractive and people living in geographical areas with the highest risk of parasitic infection value a mate’s physical attractiveness the most [85]. Although this has been primarily based on visual signals there is some evidence that humans may also respond to olfactory cues that are linked to the MHC system [90]. Women have been reported to prefer the scent of men with symmetrical features that are apparently correlated with resistance to parasites [86] with both men and women tending to prefer the odor of MHC-dissimilar individuals [87,88], see however Ref. [89]. What roles prior experience and an individuals own infection status may play in determining these olfactory related mate preferences in humans remains to be determined. 6. Conclusions Examinations of host–parasite relationships and the effects of parasites on behavior have to be considered from evolutionary and phylogenetic perspectives that take into account a variety of factors, including; virulence, mode of transmission, intensity and persistence of the infection, host ecology, mating structure, sex and reproductive status. Ethopharmacology incorporates an evolutionary approach to the study of behavior with pharmacological analysis of the underlying neuromodulatory mechanisms. It suggests a promising direction by which the mechanisms that underlie the often subtle effects of parasites on behavior can be addressed. Acknowledgements This work was supported by the Natural Sciences and Engineering Research Council of Canada and Agriculture and Agri-Food Canada.
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M. Kavaliers et al. / Neuroscience and Biobehavioral Reviews 23 (1999) 1037–1045 [56] Kvalvig JD. The effects of parasitic infection on cognitive performance. Parasitol Today 1988;4:206–8. [57] Meeks Gardner J, Grantham-McGregor S, Baddley A. Trichuris trichiura infection and cognitive function in Jamaican children. Ann Trop Med Parasitol 1996;90:55–63. [58] Nokes C, Bundy DAP. Does helminth infection affect mental processing and educational achievement? Parasitol Today 1994;10:14–8. [59] Kavaliers M, Colwell DD. Reduced spatial learning in mice infected with the nematode Heligosomoides polygyrus. Parasitology 1995;110:591–7. [60] Kavaliers M, Colwell DD, Galea LAM. Parasitic infection impairs spatial learning in mice. Anim Behav 1995;50:223–9. [61] Gibertini M, Newton C, Friedman H, Klein TW. Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-b. Brain Behav Immun 1995;9:113– 28. [62] Sei Y, Arora PK, Skolnick P, Paul IA. Spatial-learning impairment in a murine model of AIDS. FASEB J 1992;6:3008–13. [63] Oitzl MS, OersVan H, Schobitz B, DeKloet ER. Interleukin-IB, but not interleukin-6, impairs spatial navigation learning. Brain Res 1993;613:160–3. [64] McGaugh JL, Introini-Collison IB, Castellan C. Involvement of opioid peptides in learning and memory. In: Herz A, editor. Opioids II, New York: Springer, 1993. p. 429–47. [65] Adams DB, Fell LR. The effect of infection with the abonasal nematode Haemonchus contortus, on the avoidance behaviour of a sheep. Int J Parasitol 1997;27:665–73. [66] Kavaliers M, Colwell DD. Exposure to stable flies reduces spatial learning in mice: involvement of endogenous opioid systems. Med Vet Entomol 1995;9:300–6. [67] Braithwaite VA, Salkeld DJ, McAdam HM, Hockings CG, Ludlow AM, Read AF. Spatial and discrimination learning in rodents infected with the nematode Strongyloides rattii. Parasitology 1998;117:145– 54. [68] Folstad I, Karter AJ. Parasites, bright males and the immunocompetence handicap. Am Nat 1992;139:603–22. [69] Hamilton WD, Zuk M. Heritable true fitness and bright birds: a role for parasites. Science 1982;218:384–7. [70] Penn D, Potts WK. Chemical signals and parasite-mediated sexual selection. Trends Ecol Evol 1998;13:391–6. [71] Barnard CJ, Behnke JM, Gage AR, Brown H, Smithurst PR. Immunity costs and behavioural modulation in male laboratory mice (Mus musculus) exposed to the odours of females. Physiol Behav 1997;62:857–66. [72] Hurst JL. Urine marking in populations of wild house mice Mus domesticus. Rutty III Communication between the sexes. Anim Behav 1990;40:233–43. [73] Lenington A. Social preferences for partners carrying good genes in wild house mice. Anim Behav 1983;32:325–33.
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[74] Kavaliers M, Colwell DD, Ossenkopp KP, Perrot-Sinal TS. Altered responses to female odors in parasitized male mice: neuromodulatory mechanisms and relations to female choice. Behav Ecol Sociobiol 1997;40:373–84. [75] Penn D, Schneider G, White K, Slev P, Potts W. Influenza infection neutralizes the attractiveness of male odours to female mice (Mus musculus). Ethology 1998;104:685–94. [76] Kavaliers M, Colwell DD. Discrimination by female mice between the odours of parasitized and non-parasitized males. Proc R Soc Lond B 1995;261:31–5. [77] Klein SL, Gamble HR, Nelson RJ. Trichinella spiralis infection alters female odor preference, but not mate preference, in voles. Behav Ecol Sociobiol 1999;45:323–9. [78] Righi M, Gabrion C. Is a male mouse parasitized with Taenia crassiceps deprived of sex appeal? Parasitology 1999, in press. [79] Willis C, Poulin R. Preference of female rats for the odours of nonparasitized males: the smell of good genes? Can J Zool 1999; In press. [80] Morales J, Larraide C, Artega M, Govezensky T, Romano MC, Morali G. Inhibition of sexual behavior in male mice infected with Taenia crassiceps cysterci. J Parasitol 1996;82:689–93. [81] Freeland WJ. Parasitism and behavioral dominance among male mice. Science 1981;213:461–2. [82] Kavaliers M, Colwell DD, Choleris E. Analgesic responses of male mice exposed to the odors of parasitized females: effects of male sexual experience and infection status. Behav Neurosci 1998;112:1001–11. [83] Yamazaki K, Boyse EA, Mike V, Thaler HT, Mathieson BJ, Abbott J, Zoyas ZA, Thomas L. Control of mating preferences in mice by genes in the major histocompatibility complex. J Exp Med 1976;144:1324– 35. [84] Jennions MD, Petrie M. Variations in mate choice and mating preferences: a review of causes and consequences. Biol Rev 1997;72:283– 95. [85] Gangestad WD, Buss DM. Pathogen prevalence and human mate preferences. Ethol Sociobiol 1992;14:89–96. [86] Gangestad SW, Thornhill R. Female preferences for human male scent and fluctuating asymmetry. Proc R Soc London B 1992;265:927–33. [87] Wedekind C, Furi S. Body odour preferences in men and women: do they aim for specific MHC combinations or simple heterozygosity? Proc R Soc London B 1997;264:1471–9. [88] Wedekind C, Seebeck T, Bettens F, Papke AJ. MHC-dependent mate preferences in humans. Proc R Soc London B 1995;260:245–9. [89] Hedrick PW, Black FL. HLA and mate selection: no evidence in south amerindians. Am J Hum Genet 1997;61:505–11. [90] Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S. HLA and mate choice in humans. Am J Hum Genet 1997;61:497–504.
PERGAMON
Neuroscience and Biobehavioral Reviews 23 (1999) 1037–1045 www.elsevier.com/locate/neubiorev
Parasites and behavior: an ethopharmacological analysis and biomedical implications M. Kavaliers a,*, D.D. Colwell b, E. Choleris c a
Department of Psychology and Neuroscience Program, University of Western Ontario, London, Ontario, Canada N6A 5C1 b Agriculture and Agri-Food Canada, Box 3000 Main, Lethbridge, Alberta, Canada T1J 4B1 c Department of Nuclear Medicine and Magnetic Resonance, Lawson Research Institute, London, Ontario, Canada N6A 4V2 Accepted 12 April 1999
Abstract Parasites and disease are increasingly recognized as agents of behavioral, ecological and evolutionary importance having a variety of influences on their hosts other than the more obvious pathological and immunological changes. Parasites can have significant behavioral effects even when parasitism is sub-clinical with these effects proposed to either benefit the parasite (parasite ‘manipulation’), benefit the host, or to simply arise as side-effects of the infection (parasitic ‘constraints’). However, until relatively recently little attention has been paid to the neuromodulatory substrates that mediate these behavioral changes. Ethopharmacology incorporates an evolutionary approach to the study of behavior with pharmacological analysis of neuromodulatory mechanisms. As such, this approach is appropriate for, and has been applied to, the analysis of the effects of ectoparasites (e.g. biting and blood-feeding flies) and endoparasites (e.g. protozoa, nematodes) on a number of behaviors (e.g. pain inhibition, learning and memory, responses to predators and anxiety, mate selection) in selected host–parasite systems. Ethopharmacology suggests a promising direction by which neuromodulatory mechanisms that underlie the effects of parasites on behavior, including that of humans, can be addressed. q 1999 Elsevier Science Ltd. All rights reserved. Keywords: Parasites and behavior; Predator–prey; Anxiety; Mate choice; Fear conditioning; Analgesia; Conditioned analgesia; Learning and memory
1. Introduction Parasites influence almost every conceivable level of biological organization with the extent of parasitism depending largely on how one defines the term. The classical definition of parasitism holds that it is an intimate and obligatory relationship between two heterospecific organisms in which one lives on, off, and at the expense of the other. In a broader sense parasites can be considered as organisms that exploit their host’s resources by using the behavioral, physiological and energetic investment of the host to reduce the cost of obtaining their own resources. As such, more than 50% of all plant and animal species are parasitic at some point in their life cycle. Just as important is the question of how many animals are parasitized. This number approaches one hundred percent when one considers all of the internal parasites (endoparasites) and external parasites (ectoparasites) that are present in nature. * Corresponding author. Department of Psychology, Social Sciences Centre, University of Western Ontario, London, Ontario, Canada N6A 5C2. Tel.: 1 1-519-679-2111 ext.: 6084; fax: 1 1-519-661-3961. E-mail address: [email protected] (M. Kavaliers)
In studying and observing animals that live in clean, ‘aseptic’, laboratory environments it is easy to forget that animals have evolved and thrive in environments with an array of parasites. Parasites and disease are increasingly recognized as having a major impact on the evolution, ecology and behavior of their hosts [1–6], with parasites and their hosts in a constant co-evolutionary ‘arms race’ [7]. Parasites evolve to optimize host exploitation, while hosts evolve to minimize the parasite-induced loss of fitness (virulence). In general, infections involving single hosts and requiring contact between individuals or their bodily products are of a lower virulence, because the host must be able to interact with other individuals. Parasites that involve multiple hosts and are transmitted by vectors are usually more virulent and may incapacitate their host. However, in single host–parasite systems that are evolutionarily ‘young’, such as many human host–parasite systems, virulence may still be high. Results of behavioral and ecological studies have shown that parasites have significant effects on their hosts even when parasitism is sub-clinical. The altered behavioral responses have been proposed to either benefit the parasite (parasite ‘manipulation’), benefit the host, or to simply arise
0149-7634/99/$ - see front matter q 1999 Elsevier Science Ltd. All rights reserved. PII: S0149-763 4(99)00035-4
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vertebrates, have shown that certain parasitic infections elicit modifications in the levels and expression of classical neurotransmitters and neuropeptides e.g. see Refs. [11–13]. Results of studies focusing on decreases in nociceptive and pain sensitivity (antinociception and analgesia, respectively) have provided evidence for altered opioid peptide activity in several host–parasite systems [14–21]. Exposure to a variety of environmental stressors can produce potent pain inhibition or analgesia in laboratory animals and humans with this analgesia involving either opioid or non-opioid mediated mechanisms. Analgesia has been observed in rodents following exposure to laboratory stressors [22,23] and is an important component of an animals response to stimuli associated with behaviorally and ecologically important dangers such as threatening conspecifics and predators (e.g. see Refs. [22,24,25]. As such, analgesia is adaptive in these threatening situations reducing responses to distracting stimuli and facilitating the performance of various active and passive defensive behaviors. 2.1. Ectoparasites
Fig. 1. Effects of a 30 min exposure to either house flies, different densities of stable flies (LO 10–15 flies; HI 50–55 flies) or control handling (no flies) on the nociceptive responses (latency of response to a 508C thermal surface) of individual male mice. Response latencies were determined before (pre) and after (post) exposure to the flies on two consecutive days. Exposure to the stable flies elicited an significant p , 0:01 analgesic response on both days whereas the house flies and control handling had no significant effects on nociceptive sensitivity. n 10. Vertical lines denote a SEM.
as side-effects of the infection (parasitic ‘constraints’), with no obvious direct adaptive significance [8]. Correspondingly, vertebrates use various behavioral strategies in an attempt to either increase their fitness in the presence of external parasites and internal parasitic infections and, or to avoid or minimize their exposure to parasites [4,5,8]. Recently ethological and pharmacological approaches have been applied to the investigation of host–parasite systems. Ethopharmacology attempts to delineate the mechanisms that regulate and modulate behavior by combining ethological analysis, that take into account the adaptive significance and evolutionary pressures that underlie behavior, with pharmacological manipulations [9,10]. This review briefly considers the results of selected ethopharmacological investigations of the effects of parasites on behavior.
2. Parasites and analgesia Investigations with invertebrates, and to a lesser extent
Among the aversive stimuli that can elicit analgesia are ectoparasitic arthropods. Biting and blood-feeding flies are among the most prevalent of biologically and economically important natural stressors. These hematophagous insects are responsible for many deleterious effects in domestic and wild animals and on human comfort and prosperity [4,26,27]. Large ungulates such as cattle often exhibit defensive and avoidance behaviors indicative of heightened levels of anxiety and fear during attacks by biting flies [4,14,15]. In humans, the swarming and biting behavior of flies are not only stressful ‘nuisances’, but these insects are also hosts and vectors of a wide range of viruses, bacteria, and protozoa [26,27]. Stable flies, Stomoxy calcitrans (L.) and mosquitoes, e.g. Aedes togoi, attack and feed on a wide range of mammal’s [26]. Results of investigations with laboratory mice and deer mice showed that a 30–60 min exposure to either stable flies or mosquitoes elicited opioid mediated analgesia that was blocked by the prototypic opiate antagonist naloxone (Fig. 1), while brief exposure elicited a non-opioid mediated analgesia that was insensitive to naloxone and other more selective opiate antagonists [14,15,17,24,28]. These analgesic responses interacted synergistically with the effects elicited by other stressors, magnifying the impact of low levels of biting flies on host behavior and potentially host fitness [24]. Sex differences were observed in both the levels and mediation of biting-fly induced analgesia, with males displaying greater levels of opioid mediated analgesia than females [29]. In addition, in males the non-opioid analgesia involved N-methyl-d-aspartate (NMDA) receptor systems, while in females it involved other receptor systems. These male–female differences in non-opioid
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analgesia are hormonally mediated with both estradiol and progesterone being associated with the expression of the NMDA independent non-opioid analgesia in reproductive females. These male–female differences underscore the need to consider sex and reproductive status when examining the effects of parasites and other aversive stimuli [29– 31]. While innately recognized danger stimuli (e.g. predators) provoke behavioral avoidance, analgesia and fear responses, fear can also be learned to stimuli associated with threat. Conditioned fear, including that of analgesia, has been shown to be rapidly acquired with a single experience sufficient to produce acquisition [32]. This rapid one-trial aversive conditioning has also been shown to be true for biting fly exposure [28]. Exposure to either non-biting house flies, Musca domestica, or altered biting flies whose biting mouthparts are removed normally has no significant effects on the nociceptive sensitivity of fly-naive mice. However, in mice with a single previous 30 min session of experience of attacks by intact biting flies, opioid-mediated analgesia was induced by the presence of altered flies that were incapable of biting. This acquired aversive response was specific for the altered biting fly, with similar sized non-biting house flies having no evident effects on mice that were preexposed to biting flies. The individual acquisition of the conditioned analgesia to biting flies involved NMDA receptor mechanisms and did not need the expression of analgesia [28]. Administration of a competitive NMDA antagonist to fly-naive mice before exposure to intact biting flies, although not significantly reducing the analgesic responses, blocked the acquisition of the subsequent conditioned analgesia. In contrast, administration of naloxone before exposure to intact biting flies blocked the initial analgesia without affecting the acquisition of the conditioned analgesia. The initial analgesic response may have been induced by the bites of the fly. The flies may be decreasing host pain sensitivity so that if their initial feeding attempts are only partially successful, subsequent bites may not be felt as much and the flies will succeed in feeding. However, a preparatory or ‘anticipatory’ analgesia could be an adaptive response of the host, facilitating the activation of defense mechanisms before receipt of bites. This conditioned analgesia can also be acquired without direct individual aversive experience with the biting flies (in preparation). Mice (observers) that witnessed other mice (demonstrators) being attacked by biting flies, but themselves were not bitten, displayed analgesic responses. Upon subsequent exposure to altered biting flies the observers also displayed a conditioned analgesia. The initial analgesic responses were likely elicited by the stress-related cues (odors, ultrasonic vocalizations, etc. e.g. see Refs. [8,46,78]) emitted by the attacked demonstrators, whereas the subsequent responses to the altered flies involved socially mediated ‘observational’ learning.
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2.2. Endoparasites A number of endoparasitic infections also elicit analgesia in rodents. Schistosoma mansoni is a trematode parasite of humans and is responsible for schistosomiasis, a severe and often debilitating disease. Hamsters clinically infected with S. mansoni displayed naloxone sensitive analgesic responses [33,34] that were accompanied by changes in locomotor activity, with 25 day infected hamsters displaying naloxone reversible increases in activity and 40 day infected hamsters showing decreased activity that was sensitive to a delta opiate receptor directed antagonist. Male mice clinically infected with the nematode, Nippostrongylus brasiliensis, displayed similar naloxone sensitive analgesia and delta opioid mediated decreases in locomotor activity [21]. In contrast, the early stages of clinical schistosome infection in mice were associated with a slight increase in pain sensitivity, while the latter stages involved analgesia [35–37]. This was accompanied by opioid mediated shifts in locomotor activity similar to those seen in the infected hamsters. These alterations in nociception and locomotor activity may arise either from modifications in host endogenous opioid systems and, or directly through the active secretion of opioid peptides by either the parasite or the host’s immune system. S. mansoni exhibits proopiomelanocortinrelated gene activity and produces b-endorphin and other opioid peptides that may play a role in immune evasion by these parasites [11]. Elevated opioid peptide levels are reported in schistosome infected mice [13], though, the alterations in nociceptive sensitivity observed in S. mansoni infected mice were proposed to be primarily related to increased levels of nerve growth factor and cytokines [35]. Opioid-mediated changes in nociceptive sensitivity, independent of any changes in locomotor activity, have also been reported from male mice subclinically infected with the naturally occurring, single host, enteric, protozoan (coccidian) parasite, Eimeria vermiformis [16,18,19]. Analgesia was evident in E. vermiformis infected mice by day 2 post-infection, with the intensity of analgesia increasing through the pre-infective period. Following the onset of infectivity (day 8 post infection) the analgesic responses declined, with nociceptive responses returning to basal levels with the cessation of infectivity by day 15–16 postinfection. The analgesia in the pre-infective period involved k and m opioid activity, while the decreasing analgesia observed after the onset of infectivity was correlated with enhanced d and m opioid activity [19]. These shifts in opioid activity may be associated with changes in immune and inflammatory responses. Opioids modulate immune activity, with the enhancement or suppression of immune responses depending on the duration and extent of opioid activation [38,39]. Reproductive stages of Eimeria are the most immunogenic and it is during those pre-infective stages that the greatest increases in the level of
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Fig. 2. Responses of uninfected male mice (uninfected), mice infected with Eimeria vermiformis (infected) or sham infected (uninfected) mice (sham) in a Y maze odor preference apparatus to either: predator (cat) and nonpredator (non-pred; guinea pig) odor; predator and control (blank, blk) odor; or non-predator and control odor combinations. Responses are given as preference ratios (e.g. time spent in vicinity of predator/ time spent in vicinity of non-predator 1 time spent in vicinity of predator) determined over a 5 min period. n 5. Parasitized male mice displayed a reduced aversion to p , 0:05 and avoidance (i.e. increased preference) of the predator odor relative to that shown by uninfected (sham) mice. Vertical lines denote SEM. (after [40]).
analgesia, suggestive of maximal opioid activation, are evident. Not all parasitic infections are, however, associated with the induction of analgesia. Chronic infection with the single host enteric nematode parasite, Heligmosomoides polygyrus, has no significant effect on the nociceptive sensitivity of male and female mice [40,41]. Moreover acute, though not repeated or chronic, administration of ‘illness-inducing agents’ such as lipopolysaccharide (LPS), the smallest immunogenic component of the cell wall of gram-positive bacteria, induces hyperalgesia [38]. These acute symptoms were considered to be mediated by the increased production and release of cytokines. In mammals the immune responses to parasites differ from that evoked by bacteria and viruses; therefore, hosts may respond differently to various types of infection.
3. Parasites, predators and anxiety Results of laboratory and field studies with parasitized rodents have revealed alterations in a variety of behaviors that may either directly or indirectly increase vulnerability to predation facilitating parasite transmission from the intermediate host (prey) to a definitive host (predators). Mice infected with the protozoan, Toxoplama gonodii, of which felines are the definitive host, displayed heightened activity,
reduced avoidance of novel environments, and less caution to uninfected individual [30]. Mice infected with the nematode, Toxocara canis, displayed decreased anxiety and defensive responses to predators that were independent of any changes in locomotor activity [42–44]. Male mice infected with Trypanosoma gambiense, and lemmings infected with the protozoan, Sarcocystis rauschorum, showed decreased reactivity to predators [45,46]. All of these responses are consistent with an enhanced susceptibility to predation. Humans subclinically infected with T. gondii were also reported to exhibit altered behaviors and personality factors [47], though it was not demonstrated that these changes increased the probability of parasite transmission. Similarly there is evidence that viral infections may cause symptoms of depressive illness and attendant changes in anxiety-associated behaviors in humans and laboratory animal models [2,48]. Even single host systems revealed significant changes in the responses to predator threat in infected individuals (Fig. 2). Male mice infected with E. vermiformis displayed reduced opioid and non-opioid analgesia and avoidance responses following brief exposure to a cat [25]. Mice infected with H. polygyrus displayed reduced opioid and attenuated serotoninergic (5-HT) and NMDA mediated non-opioid predator odor induced analgesia [49]. Changes in 5-HT and NMDA mediated responses, both of which are implicated in fear and anxiety [22,25,28,29], could result in a decreased fearfulness and anxiety upon predator exposure. These reductions in predator responses and avoidance observed in E. vermiformis and H. polygyrus infected individuals are probably not directly related to the facilitation of parasite transmission. Reduction in predator sensitivity is likely to be detrimental to both the parasite and the host and calls into question the possible adaptive value or evolutionary significance of the altered predator response. However, parasites that do not obviously appear to benefit from changes in host behavior often have the greatest impact on host behavior [50]. The reduction in predator sensitivity may be part of a general reduction in fearfulness and anxiety in the infected individuals, decreasing avoidance of conspecifics and increasing interactions between the infected and uninfected individuals, thereby, facilitating parasite transmission in single host systems. This contrasts with the anxiogenic consequences of acute LPS administration in mice [51]. These responses were proposed to be related to illness (sickness) behaviors that are associated with reduced mobility and reactivity to external stimuli consistent with an anxiogenic profile [4]. Mice sub-clinically infected with the gram negative bacteria, Campylobacter jeueni, and laboratory rats with ‘inapparent’ wound infections also exhibited anxiogenic responses consistent with alterations in neuromodulatory functions [52,53]. Together, these findings indicate the need to consider the effects of parasites and other infection, along
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with the intensity, virulence, nature and duration of infection, and modes of transmission, when considering anxiety and associated behaviors.
4. Parasites, learning and memory A variety of studies have indicated detrimental effects of parasitic infection on cognition. For example, both S. mansoni and T. canis are reported to decrease the performance of rats and mice on a variety of maze discrimination tasks [43,54,55]. As well, apparent correlation between parasitic infection and cognitive ability in children are reported [55–57] but see also Ref. [58]. Successful foraging, reproduction, predator avoidance and territorial defense, all of which have been reported to be influenced by parasitism [8], depend on the host’s spatial abilities and memories and in particular the spatial localization of patches, mates, escape routes and neighbors. Results of several studies have reported that parasitic infection can affect host spatial performance in laboratory maze tasks. Male mice subclinically infected with either E. veriformis or H. polygyrus displayed reduced performance in a Morris water maze task, whereby individual mice have to acquire and retain the location of a hidden platform [59,60]. Spatial learning impairments have also been reported in male mice subclinically infected with either a mouse leukemia virus or the gram negative bacterium Legionella pneumiophila [61,62]. In E. vermiformis infected mice, the greatest deficits in spatial acquisition occurred during the pre-infective period when maximum increases in opioid activity and modifications in immune activity are evident [60]. Immune components, such as interleukin-1, have been shown to impair performance in the water maze task [63]. Opioid systems have also been shown to be involved in the modulation of spatial learning and memory, with opiates having inhibitory effects and opiate antagonists facilitating learning [64]. The behavior of sheep infected with the abonasal nematode, Haemonchus controtus, in a ‘motivational-choice’ test was improved by treatment with an opiate antagonist [65], while exposure to stable flies was shown to decrease in a naloxone-reversible manner the spatial performance of mice [66]. In contrast, infection with the nematode Strongyloides rattii, had no evident effects on the performance of mice and rats in a water maze task [67]. It is likely that the effects of various parasitic infections on learning and memory are dependent on the life history of the parasite, nature of the infection, ecology and mating systems and the specific endocrine–immune features of the host. Ethopharmacological investigations of animals in ethologically relevant spatial and non-spatial tasks are necessary to determine the impacts of infection on the acquisition and use of stored memory.
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5. Parasites and mate responses Parasites have been reported to affect mate choice and mating patterns [1,5,6,68]. Hamilton and Zuk [69] suggested that females prefer to mate with males with showy sexual displays because they are the healthiest and the most resistant to parasites. By avoiding infected males, choosy females can reduce their risk of contracting contagious diseases, obtain more parental investment and increase the resistance of their offspring to parasites. In the original Hamilton–Zuk hypothesis choosy females acquire indirect benefits while in the two alternatives (parasite avoidance, efficient parent) the benefits are direct. In their original proposal Hamilton and Zuk [69] speculated that during mate choice animals should examine urine and faecal cues in an attempt to detect mates that were disease- and parasite-free. Chemical signals can serve as good indicators of an individual health and infection status being more direct and labile than morphological traits [70]. In rodents urine and other odor cues are of major importance in individual recognition, mate detection and choice [40,71–73]. Results of a number of odor preference tests, which are considered to give reliable indications of mate choice [73,74], revealed that female laboratory mice can discriminate between infected and uninfected males on the basis of odor. Female mice displayed a reduced interest in the urine and other odorous secretions of male mice infected with either influenza virus [75], the protozoan, E. vermiformis, or the nematode, H. polygyrus [40,41,74,76]. The urine odor of the influenza-infected mice appeared to simply lose its attractiveness [75], whereas the odor of the parasitized males both lost attractiveness and elicited aversive responses [40,76]. These alterations in female odor preference reduce the likelihood of mating occurring by decreasing the probability of subsequent contact between individuals. It does not, however, necessarily preclude mating when the individuals are in close proximity. In this regard, pre-exposure to the odor cues of H. polygyrus infected males affected the subsequent responses of estrous female mice to infected and uninfected male mice, with females displaying a decreased aversion for the odors of infected males and a reduced preference for the odors of uninfected males (submitted). This suggests that brief preexposures to the odors of infected males can have substantial motivational influences on the subsequent mate preferences of females by modifying their relative responses to both infected and uninfected individuals. This likely contributes to the variation that is evident in female mate choice evident under natural conditions. The extent of the female aversion/avoidance of the odors of E. vermiformis parasitized male mice was related to the development stage of the infection (Fig. 3). Females displayed maximum discrimination against the odors of infective males consistent with a direct avoidance of males and their excretory products in an attempt to minimize contagion [1]. However, females also avoided the
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Fig. 3. Responses of uninfected estrous female mice in a Y-maze odor preference apparatus to the odors of uninfected male mice and male mice subclinically infected with the protozoan E. vermiformis. responses of females to: left uninfected male [sham-infected (uninfected, treated same way as infected) day 4, 7 or 10 post sham infection (D4 (non-infective), D7 (onset of infectivity) and D10 (infective), respectively] and blank (control neutral odor); middle infected (days 4, 7 and 10 post infection and blank; right infected and sham infected odor combinations are shown. Responses are given as preference ratios (e.g. time spent in the vicinity of the infected male odor/time spent in the vicinity of the uninfected (sham) male odor 1 time spent in the vicinity of the infected male odor). Preferences were determined over a 5-min period. Females displayed a significantly p , 0:01 reduced preference for and an increased aversion to the odors of infected males. n 5, in all cases. vertical lines denote SEM after [74]).
odors of pre-infective males, which are not yet shedding any parasite components, suggesting recognition of odors associated with a parasitized male. This is consistent with both the original Hamilton and Zuk [69] model of parasitemediated sexual selection and the contagion indicator and avoidance hypothesis [1]. In order to separate the Hamilton–Zuk model from the transmission avoidance model, both resistance and expression of the trait (i.e. odor response) has to be shown to be heritable. This necessitates the direct examinations of mating behavior as well as the behavior and susceptibility to infection of the progeny. An additional consequence of exposure to the olfactory cues associated with either an E. vermiformis or H. polygyrus infected male was the induction of analgesia in female mice [18,20,40]. The nature of this analgesia varied as a function of the duration of exposure, with prolonged (15 min) exposure to male odors inducing a relatively long-lasting, opioid mediated analgesia and brief (1 min) exposures eliciting a lower amplitude and short lasting non-opioid analgesia. The non-opioid mediated analgesic responses may represent anxiety related anticipatory defense reactions designed to prepare the female mouse for a potential encounter with a parasitized male, while the more protracted opioid mediated analgesia may be
associated with stress and related defense responses including that of immune activation. These analgesic responses and their anxiety/stress associated behavioral correlates could elicit either a reduced interest in, or avoidance of parasitized male mice by the females, potentially serving as a component of female mate choice. Female mice, rats and meadow voles can, on the basis of urine, also discriminate against males infected with either the cestodes Taenia crassiceps, Hymenolepis diminuita, or Trichinella spiralis [77,78]. In contrast to E. vermiformis and H. polygyrus, these parasites have a complex life cycle and, thus, are not directly transmissible and infectious to females. However, in most cases the infected males also displayed substantially reduced levels of testosterone, with T. crassiceps reducing testosterone levels by 95% and inhibiting male sexual behavior [80]. It is, therefore, possible that in these multi-host systems females may be responding to a combination of odor cues that relates to male conditions. Reduced testosterone levels are unlikely to be a major factor in determining female odor responses in the single host system of E. vermifomis and H. polygyrus where infected males maintain their sexual interest [81,82], or in the case of E. vermiformis, showed enhanced interest in females [74]. Testosterone has been proposed to be immunosuppressive, rendering males more susceptible to infection [30,31], suggesting a trade off between parasite defenses and testosterone mediated behaviors [31,68,71]. Ethopharmacological investigations of endocrine–immune interactions and mate choice are necessary to address these questions. Substantial evidence exists that mice and rats can distinguish between urinary odors on the basis of differences in the major histocompatibility complex (MHC) and use MHC-mediated or related odors for both kin recognition and mating preferences [70,83]. The MHC activity is part of the immune system with infection activating the release of MHC antigens [70]. Parasite-induced alterations in endocrine, immune, and neurochemical function may affect MHC functions, the expression of odor cues, and the subsequent aversive responses that are displayed. The possible sources of the infected odor cues (e.g. urine, fecal material, scent and salivary gland products) and roles of various olfactory mediation systems remains to be determined. Investigations of the effects of parasites have been primarily carried out with females, with generally little attention given to the responses of males to parasitized females. Recently, it was shown that male mice also displayed analgesic responses to the odors of infected females, though the responses were of a lower magnitude than those displayed by females exposed to the odors of correspondingly parasitized males [41]. Although both sexually experienced and sexually naive males were capable of distinguishing between the odors of infected and uninfected females, the sexually experienced males displayed a significantly greater analgesia than the sexually naive males. There are data indicating that a male’s sexual
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experience may influence a variety of behavioral and hormonal, responses, with male mice of a higher social rank and likely more experience with females, displaying greater susceptibility to parasitic infection [71]. Consequently, if a greater analgesic response has a role in eliciting avoidance of a parasitized conspecific, such a response would be adaptive for the sexually experienced males that are potentially more susceptible to infection. Little attention has also been given to the possible effects of parasites on the host’s responses to sexual cues. In two host systems male mice clinically infected with the nematode, T. crassiceps, and females infected with the nematode, Trichinella spiralis, were reported to be inhibited in their sexual behaviours limiting possible mate responses [44,80]. Conversely, data from single host systems suggest that parasitized individuals may display augmented mate responses [74]. At 4 days post-infection E. vermifomis infected male mice had a significantly decreased preference for the odors of estrous females, whereas at 10 days post-infection infective males had a significantly increased preference for the odors of estrous females. Administration of a k opioid receptor antagonist increased the responsiveness of the pre-infective males, while a d opioid receptor antagonist reduced the augmented responses of the infected male mice to the estrous female mice suggesting that alterations in opioid systems contribute to the shifts in the responses of infected males to females. As well, there is data from single host systems suggesting that parasitized individuals may be less choosy in their mate preference [41]. H. polygyrus infected females displayed reduced analgesic responses to the odors of infected males with the extent of the analgesic response being related to the nature of the male infection [41]. Infected females did not display an analgesic response to the odors of males infected with the same parasite as themselves (H. polygyrus) and displayed an attenuated analgesic response to males infected with a different parasite, E. vermiformis. Similarly, H. polygyrus infected males displayed lower analgesic responses to the odors of H. polygyrus infected females [82]. This potentially could support assortative mating with respect to parasite load and contribute to the variability in female mate preference [84]. The reduced analgesia displayed by the H. polygyrus infected mice could be interpreted in terms of odor familiarity and responses to group odor templates. Parasiteinduced alterations in endocrine, immune and neurochemical functions [6,68,70] may affect MHC activity and the expression of urinary of associated odor cues and subsequent analgesic responses displayed by uninfected females. Uninfected mice could be construed as displaying analgesic responses to the odors of infected individuals because the odors are different from the group or self-odor template. The attenuation in analgesia displayed by the parasitized males and females may also be part of a general reduction in fearfulness and anxiety in the infected individuals. There is evidence that humans also use various indices of
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health and potentially infection status and resistance to parasites in mate choice. Humans universally find signs of disease and infection sexually unattractive and people living in geographical areas with the highest risk of parasitic infection value a mate’s physical attractiveness the most [85]. Although this has been primarily based on visual signals there is some evidence that humans may also respond to olfactory cues that are linked to the MHC system [90]. Women have been reported to prefer the scent of men with symmetrical features that are apparently correlated with resistance to parasites [86] with both men and women tending to prefer the odor of MHC-dissimilar individuals [87,88], see however Ref. [89]. What roles prior experience and an individuals own infection status may play in determining these olfactory related mate preferences in humans remains to be determined. 6. Conclusions Examinations of host–parasite relationships and the effects of parasites on behavior have to be considered from evolutionary and phylogenetic perspectives that take into account a variety of factors, including; virulence, mode of transmission, intensity and persistence of the infection, host ecology, mating structure, sex and reproductive status. Ethopharmacology incorporates an evolutionary approach to the study of behavior with pharmacological analysis of the underlying neuromodulatory mechanisms. It suggests a promising direction by which the mechanisms that underlie the often subtle effects of parasites on behavior can be addressed. Acknowledgements This work was supported by the Natural Sciences and Engineering Research Council of Canada and Agriculture and Agri-Food Canada.
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