Brain Behav Evol 2002;60:370–377
DOI: 10.1159/000067790
Modulating the Modulators:
Parasites, Neuromodulators and
Host Behavioral Change
Shelley A. Adamo
Department of Psychology, Dalhousie University, Halifax, Canada
Key Words
Parasites W Neuromodulators W Host behavior W
Invertebrate W Neuroimmunology
Abstract
Neuromodulators can resculpt neural circuits, giving an
animal the behavioral flexibility it needs to survive in a
complex changing world. This ability, however, provides
parasites with a potential mechanism for manipulating
host behavior. This paper reviews three invertebrate
host-parasite systems to examine whether parasites can
change host behavior by secreting neuromodulators.
The parasitic wasp, Cotesia congregata, suppresses host
feeding partly by inducing the host (Manduca sexta) to
increase the octopamine concentration in its hemolymph. The increased octopamine concentration disrupts the motor pattern produced by the frontal ganglion, preventing the ingestion of food. Polymorphus
paradoxus (Acanthocephalan) alters the escape behavior of its host, Gammarus lacustris (Crustacea), possibly
through an effect on the host’s serotonergic system. The
trematode Trichobilharzia ocellata inhibits egg-laying in
its snail host (Lymnaea stagnalis), partly by inducing the
host to secrete schistosomin. Schistosomin decreases
electrical excitability of the caudodorsal cells. The parasite also alters gene expression for some neuromodulators within the host’s central nervous system. In at least
two of these three examples, it appears that the host, not
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the parasite, produces the neuromodulators that alter
host behavior. Producing physiologically potent concentrations of neuromodulators may be energetically expensive for many parasites. Parasites may exploit indirect less energetically expensive methods of altering
host behavior. For example, parasites may induce the
host’s immune system to produce the appropriate neuromodulators. In many parasites, the ability to manipulate host behavior may have evolved from adaptations
designed to circumvent the host’s immune system. Immune-neural-behavioral connections may be pre-adapted for parasitic manipulation.
Copyright © 2003 S. Karger AG, Basel
Introduction
Neuromodulators [see Katz, 1999, for definition] can
resculpt neural circuits enabling an animal to alter its
behavioral response to its environment [e.g., see Kravitz,
1990; Harris-Warrick and Marder, 1991]. This plasticity
gives an animal the flexibility it needs to survive in a complex changing world. This ability, however, comes at a
cost. The animal leaves itself vulnerable to the possibility
that a parasite, using the same or similar neuromodulators, will usurp control of the animal’s behavior. In this
paper, I will present evidence suggesting that some parasites have exploited this strategy. I will focus on three
invertebrate host-parasite relationships: (1) the decline in
Shelley A. Adamo
Department of Psychology
Dalhousie University
Halifax, NS B3H 4J1 (Canada)
Tel. +1 902 494 8853, Fax +1 902 494 6585, E-Mail sadamo@is.dal.ca
feeding and locomotion in the caterpillar, Manduca sexta,
infested with the braconid wasp Cotesia congregata;
(2) the clinging behavior observed in the amphipod Gammarus lacustris infested with the acanthocephalan Polymorphus paradoxus, and (3) the absence of egg laying in
adult snails (Lymnaea stagnalis) infested with the trematode Trichobilharzia ocellata.
Many parasitized animals show changes in behavior
[see Moore, 2002; Horton and Moore, 1993]. For example, ants, infested with the trematode Dicrocoelium dendriticum, climb to the top of nearby plants and fix themselves there with their mandibles [Romig et al., 1980].
This behavior is thought to increase the probability that
the ant will be eaten by a mammalian herbivore, the next
step in the trematode’s life cycle. Because some changes in
host behavior appear to benefit the parasite, many researchers suspect that parasites actively alter the behavior
of their hosts by secreting neuromodulators [e.g., Romig
et al., 1980, also see discussion in Holmes and Zohar,
1990; Thompson and Kavaliers, 1994; Adamo, 1997;
Katz and Edwards, 1999; Moore, 2002]. Despite this
widespread belief, there is little evidence that parasites
change host behavior by secreting any substance that acts
directly on the host’s central nervous system (CNS).
There is good evidence, however, that parasites secrete
hormones into their hosts [e.g., see Beckage and Gelman,
2001]. The parasitic wasp Cotesia congregata, for example, secretes ecdysteroids into its host [e.g., Gelman et al.,
1998, 1999]. Changes in host ecdysteroid titers alter host
development, and this alteration benefits the wasp [Gelman et al., 1999]. Although some neurons are known to
have receptors for ecdysteroids [Hewes and Truman,
1994; Truman et al., 1994], changes in ecdysteroid titers
in parasitized hosts have not been correlated with specific
changes in host behavior.
Some animals have a direct effect on another animal’s
nervous system by secreting venoms [Adams et al., 1999].
Although most venoms cause gross behavioral changes
(e.g., paralysis), others are capable of more subtle influences. For example, the venom of the wasp Ampulex
compressa, leaves its victim, a cockroach, incapable of
spontaneous movement [Fouad et al., 1994]. The cockroach is not paralyzed, however, and will walk when led
by the wasp. The wasp guides the cockroach back to the
wasp’s nest, where it is sealed up with a wasp egg [Fouad
et al., 1994].
Given the existence of hormone-secreting parasites
and neuroactive venoms, a neuromodulatory-secreting
parasite would seem a likely possibility [but see Adamo,
1997 for a discussion of some of the difficulties facing
putative neuromanipulative parasites]. Demonstrating
that a parasite secretes compounds that alter host CNS
function, however, requires disentangling the interactions
between two complex organisms.
Adding to this complexity, host behavior can change
for reasons other than a direct effect of parasitic products
on the host’s CNS. Hosts may induce their own changes of
behavior in response to parasitism in an attempt to rid
themselves of the parasite [e.g., behavioral fever; Adamo,
1999]. Parasites can also have indirect effects on behavior
[e.g., due to destruction of sensory organs or muscle; see
Holmes and Zohar, 1990]. Some of these indirect effects
may be difficult to distinguish from direct effects. For
example, the rat tapeworm Hymenolepis diminuta secretes substances that interfere with vitellogenin production in the fat body of its intermediate host, the mealworm Tenebrio molitor [Webb and Hurd, 1999]. Eggs do
not develop normally, and egg laying behavior declines
[Hurd and Arme, 1986]. However, egg laying behavior
may decline because: (1) fewer mature eggs in the ovary
trigger less egg laying; and/or (2) the parasite may secrete
some substance that disrupts the neural circuits regulating
egg-laying.
Difficulties in demonstrating that a parasite’s secretion/excretion has a direct effect on the host’s CNS will be
compounded in systems in which the parasite’s production of a neuromodulator and/or its effect are dependent
on the developmental stage of the host and/or parasite.
Many systems probably have this restriction. For example, some hosts of intermediate parasites do not show
altered behavior until they reach the infective stage for the
definitive host [see Moore, 2002]. In other host-parasite
systems, the parasite’s products may not directly alter the
host’s CNS, but may induce the host to release its own
neuromodulatory substances in order to do so. In these
more complex and probably more common scenarios,
determining how parasites affect host behavior will require ingenuity.
This paper does not examine whether the parasiteinduced changes in host behavior benefit host, parasite,
both, or neither animal. Although it might seem that a
behavior that is altered by a parasitic product must be
beneficial to the parasite (because of its metabolic cost), it
is possible that the host could induce the parasite to
release neuromodulatory substances by stressing it, with
no benefit to either animal. Also, neuroactive substances
released by a parasite may have been selected to influence
the host’s immune system or its intermediate metabolism,
and its effect on host behavior (i.e., CNS) may be an incidental non-adaptive effect. The neuroactive compound
Parasites, Neuromodulators and Host
Behavioral Change
Brain Behav Evol 2002;60:370–377
371
Fig. 1. Response to a forcep pinch by a normal M. sexta larva (A) and one parasitized
by C. congregata (B). The brown scars on the
larva in (B) were created by the wasps while
exiting the host.
could also be a parasitic waste product, with accidental
effects on the host’s CNS. Poulin [1995] and Moore and
Gottelli [1996] discuss some of the tests needed to determine whether a change in host behavior is adaptive for
the parasite, and whether the parasite has been selected to
manipulate its host.
Below I discuss three unusual host-parasite systems.
These systems are unusual because, unlike most host-parasite systems, we have some information about how host
behavior is altered.
Cotesia congregata and Its Host, the Tobacco
Hornworm Manduca sexta
The female wasp injects venom, polydnavirus and
wasp eggs into its host, M. sexta [see review Beckage and
Gelman, 2001]. The wasp larvae hatch and develop within the host’s hemocoel. They do not damage any of the
host’s internal organs or physically contact the host’s CNS
[Adamo et al., 1997], but absorb nutrients from the host’s
hemolymph. During the wasps’ ecdysis to the 3rd instar,
they exit through the host’s cuticle [Fulton, 1940]. They
then spin cocoons, which remain attached to the host.
Four to five days later the wasps emerge as adults [Beckage and Templeton, 1986], and the host typically dies
about 2 weeks after wasp emergence [Beckage and Riddiford, 1978; Adamo et al., 1997].
The materials injected by the wasp exert a number of
effects on the host, resulting in changes in endocrine function, intermediate metabolism, and development [see
Beckage and Gelman, 2001]. Despite these physiological
changes, many of which occur soon after the wasps enter
the host, host behavior remains indistinguishable from
non-parasitized controls for most of the wasps’ development [Adamo et al., 1997; Alleyne and Beckage, 1997].
However, about one day prior to the wasps’ exit from the
host, feeding [Beckage and Riddiford, 1978; Miles and
372
Brain Behav Evol 2002;60:370–377
Booker, 2000] and spontaneous locomotion [Adamo et
al., 1997] decline. The host remains in a non-feeding and
non-moving state until its death. The wasp larvae alone,
without the polydnavirus or venom, can induce these
behavioral changes [Adamo et al., 1997]. The decline in
host feeding and locomotion appears to benefit the parasitoid by preventing the host from feeding on, or dislodging,
the wasp cocoons [Adamo, 1998]. The decline in host
feeding and locomotion does not appear to be due to
debilitation of the host [Adamo et al., 1997; Beckage and
Gelman, 2001]. For example, host reflexes remain intact
after the wasps emerge (fig. 1) [Adamo et al., 1997].
Removal of the host’s supraesophageal ganglion results in
increased host locomotion [the host becomes hyperkinetic; Beckage and Templeton, 1986], suggesting that there is
neural inhibition of locomotion in parasitized M. sexta
[Beckage and Gelman, 2001].
At about the same time as feeding and locomotion
decline, there is a sharp increase in the amount of octopamine in the host’s hemolymph and CNS (fig. 2); [Adamo et al., 1997; Adamo and Shoemaker, 2000]. Not all
compounds increase in amount during parasitism, suggesting some specificity [Adamo and Shoemaker, 2000].
The increased octopamine concentrations are not a result
of the lack of feeding; food deprivation has no effect on
the amount of octopamine in the CNS [Adamo and Shoemaker, 2000] and induces only a small increase in octopamine concentration in the hemolymph [Adamo et al.,
1997].
The increased octopamine in the hemolymph appears
to play a role in the decline in host feeding [Miles and
Booker, 2000]. Injections of octopamine decrease feeding
in nonparasitized M. sexta, and this decrease can be
blocked by injections of phentolamine, an octopamine
antagonist [Adamo et al., 1997]. Increased concentrations
of octopamine in the hemolymph may depress feeding
partly by suppressing normal activity in the frontal ganglion. The frontal ganglion controls peristalsis in the fore-
Adamo
Fig. 2. Feeding declines as octopamine concentration increases in
both the brain (supra- and subesophageal ganglia) and hemolymph of
parasitized M. sexta. Note that the increase in octopamine in the
CNS precedes the increase observed in the hemolymph. Samples
were analyzed prior to wasp emergence (after the host larvae molted
to 4th and 5th instars (4th Day 0, 5th Day 0)), 12 h prior to wasp
emergence (12 h PreEm), at the time of wasp emergence (P Em), and
1 and 3 days after the wasps had emerged (1 Day Post Em, 3 Days
Post Em). Error bars have been omitted for clarity, but can be found
in Adamo et al. [1997] and Adamo and Shoemaker [2000].
gut which is critical for the ingestion of food [Miles and
Booker, 1994, 2000]. Patterned neural output from the
frontal ganglion can be disrupted by the addition of octopamine in vitro [Miles and Booker, 2000]. Phentolamine
and mianserin (another octopamine antagonist) can block
this disruption. Hemolymph from non-feeding hosts also
disrupts the motor pattern of the frontal ganglion, whereas hemolymph from non-parasitized M. sexta, or from
parasitized M. sexta prior to wasp emergence, typically
does not [Miles and Booker, 2000]. The disruption induced by the addition of hemolymph from non-feeding
hosts can be prevented by the addition of phentolamine or
mianserin, suggesting that the increased octopamine concentration in the host’s hemolymph is causally involved in
suppressing host feeding [Miles and Booker, 2000].
Although wasp larvae secrete hormones and other
compounds into their host [Beckage and Gelman, 2001],
they do not appear to secrete octopamine, at least in vitro
[Adamo, unpublished results]. The rate of removal of
octopamine from the host’s hemolymph declines after the
wasps emerge [Adamo, unpublished results], and this may
partly explain why the octopamine titer increases at this
Parasites, Neuromodulators and Host
Behavioral Change
time. It is also possible that the wasps induce the host to
secrete octopamine, which could come from a number of
sources [see Adamo et al., 1997]. For example, octopamine enhances immune responses in some insects [Baines et
al., 1992; Baines and Downer, 1994] and increases in concentration in the hemolymph in response to infection with
bacteria [Dunphy and Downer, 1994]. By manipulating a
host immune response, the wasps may be able to induce
the host to raise its octopamine levels.
The increase in host octopamine concentrations is
unlikely to be responsible for all the behavioral changes
observed in the post-emergent host. Not surprisingly,
other neuromodulators are affected during parasitism.
Dopamine concentrations increase in the hemolymph
just prior to wasp emergence [Hopkins et al., 1998].
There are also changes in the concentration of some neuropeptides within the parasitized M. sexta brain [supraesophageal ganglion; Zitnan et al., 1995]. Zitnan et al.
[1995] found increases in immunohistochemical staining
for 9 of the 10 different peptides examined in parasitized
M. sexta. One peptide, proctolin, showed an increase in
staining at about the same time as the host’s behavior
changes. How these changes are induced is unknown, nor
do we know whether they relate to the observed behavioral changes.
Polymorphus paradoxus (Acanthocephala) and
Its Intermediate Host, Gammarus lacustris
(Crustacea)
Gammarids infested with P. paradoxus have an altered
escape response [Bethel and Holmes, 1977]. When disturbed, infested animals skim along the surface of the
water until they encounter some solid material, then cling
to it, remaining immobile in a flexed posture. When disturbed, non-infested gammarids dive towards the bottom
and burrow into the mud. The altered escape response of
the infested gammarids increases the probability that they
will be eaten by a duck (Anas platyrhynchos), the parasite’s definitive host [Bethel and Holmes, 1977].
The parasite lives in the gammarid’s hemocoel, and
does not physically damage the host or come into direct
contact with the host’s CNS [Maynard et al., 1996]. This
observation suggests that the parasite uses some kind of
chemical interaction to influence host behavior [Maynard
et al., 1996]. Injections of serotonin into the hemocoel of
other crusteacea can induce a flexed posture [Livingston
et al., 1980; Tierney and Mangiamele, 2001], suggesting
that if P. paradoxus could increase host serotonin titers it
Brain Behav Evol 2002;60:370–377
373
could induce a flexed clinging behavior in its host. In support of this hypothesis, Helluy and Holmes [1990] found
that injections of serotonin into non-infested gammarids
induced the clinging response typical of parasitized gammarids. Similar doses of octopamine, noradrenalin, and
GABA did not increase clinging behavior. Maynard et al.
[1996] then searched for changes in the host’s serotonergic
system. In neurons showing serotonin-like immunoreactivity, parasitized gammarids had an increase in the number of varicosities, suggesting either an increase in the
number of varicosities (potential release sites) or an
increase in the amount of serotonin stored in each varicosity [Maynard et al., 1996]. This increase in staining
was not observed in gammarids infested with a related
acanthocephalan, Polymorphus marilis, which does not
induce clinging behavior [Maynard et al., 1996]. The presence of the parasite seems to induce a change in the host’s
serotonergic system [Maynard et al., 1996]. However, if
increased serotonin levels are key in altering host behavior, and if this serotonin is being produced by the host,
then infested gammarids must simultaneously increase
both secretion and accumulation of serotonin to account
for the immunohistochemical results.
It would be interesting to test whether the parasite is
capable of secreting serotonin. Parasitic secretion of serotonin could also explain Maynard et al.’s [1996] immunohistochemical results. If the parasite is secreting large
amounts of serotonin, this release could have a negative
feedback effect on the host, reducing host serotonin
release, and increasing serotonin storage in the host’s
CNS. Holmes and Zohar [1990], however, suggest that
P. paradoxus is unlikely to secrete serotonin because of
the low concentrations of serotonin found in most acanthocephalans. They favor the hypothesis that P. paradoxus secretes something that activates the host’s serotonergic system.
Helluy and Holmes [1990] also found that injections of
octopamine could decrease clinging behavior in infested
gammarids. Could the change in host behavior be due to a
decrease in octopamine release as opposed to (or in addition to) an increase in serotonin? Unfortunately, we do
not know whether octopamine concentration changes
during parasitism.
It is possible that parasitic secretions/excretions do not
have a direct effect on the host’s nervous system. The
change in host behavior could be caused indirectly, by the
parasite interacting with the host’s immune system. Increased serotonin concentrations in the hemolymph are
known to enhance immune responses in cockroaches
[Baines et al., 1992] and could be part of a host response
374
Brain Behav Evol 2002;60:370–377
to infestation. Thus, the parasite may manipulate its host
by activating selected components of its immune system.
The Freshwater Snail Lymnaea stagnalis
Infested with the Trematode Trichobilharzia
ocellata
The freshwater snail, Lymnaea stagnalis, is attacked
by an avian schistosome, Trichobilharzia ocellata [reviewed in de Jong-Brink, 1995; de Jong-Brink et al.,
1997]. After penetrating the snail’s skin, sporocysts form
and migrate to the area of the digestive gland/ovotestis.
The sporocysts then give rise to the final larval stage, the
cercariae. The cercariae leave the snail in search of their
definitive host, a duck (A. platyrhynchos).
One of the most striking changes in host behavior is the
cessation of egg-laying [de Jong-Brink et al., 1999], a
behavior non-parasitized snails perform every 3 to 4 days
[van Duivenboden, 1984]. In snails infested as adults,
reproduction declines once differentiated cercariae are
present [Schallig et al., 1991]. The decline in egg laying
does not appear to be due to host debilitation. Infested
snails continue to grow at the same rate as non-infested
controls [Schallig et al., 1991]. The decline in host egg laying benefits the parasite by diverting the energy that the
host would have invested in its own reproduction into the
parasite’s reproduction [de Jong-Brink, 1995].
The parasite appears to use both direct and indirect
mechanisms to inhibit host egg laying [de Jong-Brink et
al., 2001]. The parasite secretes a substance that induces
the host to release schistosomin from its connective tissue
and hemocytes [de Jong-Brink, 1995]. Schistosomin acts
as a neuromodulator, reducing the electrical excitability
of the host’s caudodorsal cells (CDC) [Hordijk et al.,
1992]. These cells are located in both cerebral ganglia,
close to the cerebral commissure [Chase, 2002]. In normal
snails, these neurons fire en masse to release peptides that
result in ovulation and egg laying. In parasitized snails,
the CDCs are no longer capable of the prolonged firing
needed for peptide release [Hordijk et al., 1992]. Purified
schistosomin and hemolymph from infested snails can
induce a similar inhibition of the CDCs in normal snails
[Hordijk et al., 1992]. Interestingly, neither schistosomin
nor hemolymph from parasitized snails changes the resting potential of CDC neurons. Hordijk et al. [1992] suggest that schistosomin may exert its effect via an intracellular signal transduction system.
Parasitic extracts can induce schistosomin production
in non-infested snails both in vivo and in vitro [de Jong-
Adamo
Brink, 1995]. Although the function of schistosomin in
the normal snail remains unclear, it may play a role in the
snail’s immune system [de Jong-Brink et al., 2001]. By
inducing the host to produce schistosomin, the parasite
may be exploiting a host response to stress or infection [de
Jong-Brink, 1995]. Although long term stressors such as
starvation or cold do not increase schistosome production
in non-infested snails, acute stressors such as physical disturbance during egg laying do [de Jong-Brink, 1995].
The parasite also appears to have a direct effect on the
host’s CNS by altering gene expression for specific neuromodulators. For example, parasitism results in an up-regulation of the gene for neuropeptide Y (Lymnaea neuropeptide Y homologue). Infusion or injection of neuropeptide Y inhibits egg-laying, but does not reduce feeding [de
Jong-Brink et al., 1999], suggesting that the treatments do
not simply have an aversive effect. Neuropeptide Y does
not directly interact with the CDCs (i.e., via classical synapses), but it may have an indirect effect on them [de
Jong-Brink et al., 1999]. The parasite is thought to alter
host gene expression in the CNS directly (i.e., via some
parasitic product), because changes in gene expression are
visible within 1.5 h of infection [Hoek et al., 1997]. The
parasite also secretes a number of neuropeptide-like compounds; however, these appear to act on the host’s immune system, not the nervous system [de Jong-Brink,
2001].
A related schistosome (Schistosoma mansoni) attacks
the freshwater snail Biomphalaria glabrata, inhibiting
egg-laying in the infested host. Parasitized snails show a
decrease in serotonin, dopamine and L-dopa concentrations in both plasma and CNS. The decline in serotonin in
the plasma and/or CNS is linked to the decline in egg laying. Normal snails exposed to serotonin in their tank
water show an increase in their egg laying. Under the
same conditions, parasitized snails also show an increase
in egg laying, reversing the effect of the parasite [Manger
et al., 1996]. Manger et al. [1996] suggest that the parasite
may alter host serotonergic function indirectly by competing for the neuromodulator and/or its precursors. This
hypothesis is supported by the finding that larval S. mansoni take up serotonin through their tegument via a serotonin transporter [Yoshino et al., 2001].
Parasitic Manipulation in Vertebrate Hosts
In vertebrates, too, the presence of some parasites has
been shown to correlate with changes in host behavior
[e.g., the host’s pain response, learning abilities, response
Parasites, Neuromodulators and Host
Behavioral Change
to predators and mate selection; see Kavaliers et al.,
1999]. Some of these behavioral changes appear to be
induced by endogenous opiates [Kavaliers et al., 1999].
Interestingly, Schistosoma mansoni, a trematode, produces both ß-endorphin and other opioid peptides when
infesting mice [Duvaux-Miret et al., 1992; Pryor and Elizee, 2000]. These peptides are thought to suppress the
host immune system [Pryor and Elizee, 2000]. Because
opioids can be both immuno- and neuro-modulators [Salzet, 2000], the parasite could potentially use the same
compound to suppress the host’s immune system and
alter its neural function. However, whether parasite-produced opioids also have direct CNS and behavioral effects
is unknown [Thompson and Kavaliers, 1994; Kavaliers et
al., 1999; Pryor and Elizee, 2000]. The parasites could
also induce changes in host behavior indirectly by manipulating immune-neural connections in the host [Thompson and Kavaliers, 1994; Kavaliers et al., 1999; Pryor and
Elizee, 2000].
Conclusions
Evidence from the examples provided suggests that
parasites can ‘manipulate’ neuromodulators to alter host
behavior. There is little evidence, however, that they
secrete these neuromodulators themselves. In 2 of the 3
examples discussed in this paper, it appears that the host,
not the parasite, produces the neuromodulators that result
in a change in host behavior. This arrangement may be a
common one, especially for parasites that do not reside
within the host’s CNS. From the point of view of the parasite, secreting substances such as biogenic amines or neuropeptides (e.g., FMRFamide) would be metabolically
expensive. These substances often have short half-lives in
hemolymph [e.g., Goosey and Candy, 1980]. Moreover,
in many invertebrates, the parasite would need to produce
high hemolymph concentrations of these substances in
order for them to reach the CNS through the blood-brain
barrier. For example, Helluy and Holmes [1990] needed
to raise the serotonin concentration in the hemolymph of
non-parasitized G. lacustris to 10 –3 M to induce the clinging behavior seen in parasitized animals. To maintain this
level in the host, the parasite would need to secrete large
amounts of neuromodulator continuously. Although this
need would be decreased for substances that are actively
transported into the brain, a parasite that could produce
small long-lasting compounds, capable of inducing the
host to increase secretion of the necessary neuromodulators and/or inhibit their breakdown, would have an ener-
Brain Behav Evol 2002;60:370–377
375
getic advantage over a parasite producing the neuromodulator itself. In cases in which host behavior appears
to be modified by a peptide or biogenic amine, the source
will probably be the host. Thus, parasites appear to exploit
indirect and less energetically expensive methods of altering host neuromodulators.
Fortunately for the parasite, it has easy access to a host
system that has modulatory connections to the host’s
CNS – i.e., the host’s immune system. Parasites are in
intimate contact with the host’s immune system and,
therefore, do not need to produce high concentrations of
product in order to interact with it. Parasites are under
intense selection pressure to suppress host immunity, and
some parasites do this by secreting immunosuppressive
substances [e.g., de Jong-Brink, 1995]. It may be a small
evolutionary step for a parasite to move from suppressing
the host’s immune system, to inducing it to release its
endogenous neuromodulatory contents.
Neuromodulators released by the host’s immune system may serve an adaptive function in the non-parasitized animal [Maier and Watkins, 1999], but when their
release is manipulated by the parasite, they could lead to
changes in host behavior that are adaptive for the parasite. In many parasites, the ability to manipulate host
behavior may have evolved from adaptations designed to
circumvent the host’s immune system. Immune-neuralbehavioral connections may be especially susceptible to
parasitic manipulation.
References
Adamo, S.A. (1997) How parasites alter the behavior of their insect hosts. In Parasitic Effects on
Host Hormones and Behavior (ed. by N.E.
Beckage), Chapman and Hall, New York. pp.
231–245.
Adamo, S.A. (1998) Feeding suppression in the
tobacco hornworm, Manduca sexta: Costs and
benefits to the parasitoid wasp Cotesia congregata. Can. J. Zool., 76: 1634–1640.
Adamo, S.A. (1999) The specificity of behavioral
fever in the cricket Acheta domesticus. J. Parasitol., 84: 529–533.
Adamo, S.A., and K.L. Shoemaker (2000) The
effects of parasitism on the octopaminergic system of Manduca sexta: a possible mechanism
underlying host behavioral change. Can. J.
Zool., 78: 1–8.
Adamo, S.A., C.E. Linn, and N.E. Beckage (1997)
Correlation between changes in host behaviour
and octopamine levels in the tobacco hornworm, Manduca sexta, parasitized by the gregarious braconid parasitoid wasp Cotesia congregata. J. Exp. Biol., 200: 117–127.
Adams, D.J., P.F. Alewood, D.J. Craik, R.D.
Drinkwater, and R.J. Lewis (1999) Conotoxins
and their potentail pharmaceutical applications. Drug-Devel. Res., 46: 219–234.
Alleyne, M., and N.E. Beckage (1997) Parasitisminduced effects on host growth and metabolic
efficiency in tobacco hormworm larvae parasitized by Cotesia congregata. J. Insect Physiol.,
43: 407–423.
Baines, D., and R.G.H. Downer (1994) Octopamine enhances phagocytosis in cockroach hemocytes: involvement of inositol triphosphate.
Arch. Insect Biochem. Physiol., 26: 249–261.
Baines, D., T. DeSantis, and R.G.H. Downer
(1992). Octopamine and 5-hydroxytryptamine
enhance the phagocytic and nodule formations
activities of the cockroach (Periplaneta americana) haemocytes. J. Insect Physiol., 38: 905–
914.
376
Beckage, N.E., and D.B. Gelman (2001) Parasitism
of Manduca sexta by Cotesia congregata: a
multitude of disruptive endocrine effects. In
Endocrine Interactions of Insect Parasites and
Pathogens (ed. by J.P. Edwards and R.J. Weaver), Bios Scientific Publishers, Oxford, UK, pp.
59–81.
Beckage, N.E., and L.M. Riddiford (1978) Developmental interactions between the tobacco
hornworm, Manduca sexta, and its braconid
parasite, Apanteles congregatus. Ent. Exp.
Appl., 23: 139–151.
Beckage, N.E. and T.J. Templeton (1986) Physiological effects of parasitism by Apanteles congregatus in terminal stage tobacco hornworm
larvae. J. Insect Physiol., 32: 299–314.
Bethel, W.M., and J.C. Holmes (1977) Increased
vulnerability of amphipods to predation owing
to altered behavior induced by larval acanthocephalans. Can. J. Zool., 55: 110–115.
Chase, R. (2002) Behavior and Its Neural Control
in Gastropod Molluscs. Oxford University
Press, New York.
de Jong-Brink, M. (1995) How schistosomes profit
from the stress responses of their hosts. Adv.
Parasitol., 35: 177–256.
de Jong-Brink, M., R.M. Hoek, W. Lageweg, and
A.B. Smit (1997) Schistosome parasites induce
physiological changes in their snail host be
interfering with two regulatory systems, the
internal defense system and the neuroendocrine system. In Parasites and Pathogens: Effects on Host Hormones and Behavior (ed. by
N.E. Beckage), Chapman and Hall, New York,
pp. 57–75.
de Jong-Brink, M., C.N. Reid, C.P. Tensen, and A.
ter Maat (1999) Parasites flicking the NPY
gene on the host’s switchboard: why NPY?
F.A.S.E.B., 13: 1972–1984.
de Jong-Brink M., M. Bergamin-Sassen, and M.S.
Soto (2001) Multiple strategies of schistosomes
to meet their requirements in the intermediate
snail host. Parasitology, 123: S129–S141.
Brain Behav Evol 2002;60:370–377
Dunphy, G.B. and R.G.W. Downer (1994) Octopamine, a modulator of the haemocytic nodulation response of non-immune Galleria mellonella larvae. J. Insect Physiol., 40: 267–272.
Duvaux-Miret, O., G.B. Stefano, E.M. Smith, C.
Dissous, and A. Capron (1992) Immunosuppression in the definitive and intermediate
hosts of the human parasite Schistomoma mansoni by the release of immunoactive neuropeptides. Proc. Natl. Acad. Sci. USA, 89: 778–
781.
Fouad, K., F. Libersat, and W. Rathmayer (1994)
The venom of the cockroach-hunting wasp Ampulex compressa changes motor thresholds: A
novel tool for studying the neural control of
arousal? Zoology, 98: 23–34.
Fulton, B.B. (1940). The hornworm parasite, Apanteles congregatus Say and the hyperparasite Hypopteromalus tabacum Fitch. Ann Ent. Soc.
Am., 33: 231–244.
Gelman, D.B., T.J. Kelly, D.A. Reed, and N.E.
Beckage (1999) Synthesis/release of ecdysteroids by Cotesia congregata, a parasitoid wasp
of the tobacco hornworm, Manduca sexta.
Arch. Insect Biochem. Physiol., 40: 17–29.
Gelman, D.B., D.A. Reed, and N.E. Beckage
(1998) Manipulation of fifth-instar host (Manduca sexta) ecdysteroid levels by the parasitoid
wasp Cotesia congregata. J. Insect Physiol., 44:
833–843.
Goosey, M.W., and D.J. Candy (1980) The D-octopamine content in the haemolymph of the
locust, Schistocera americana gregaria and its
elevation during flight. Insect Biochem., 10:
393–397.
Harris-Warwick, R.M., and E. Marder (1991) Modulation of neural networks for behavior. Ann.
Rev. Neurosci., 14: 39–57.
Helluy, S., and J.C. Holmes (1990) Serotonin, octopamine, and the clinging behavior induced by
the parasite Polymorphus paradoxus (Acanthocephala) in Gammarus lacustris (Crustacea).
Can. J. Zool., 68: 1214–1220.
Adamo
Hewes, R.S., and J. W. Truman (1994) Steroid regulation of excitability in identified insect neurosecretory cells. J. Neurosci., 14: 1812–1819.
Hoek, R.M., R.E. van Kesteren, A.B. Smit, M. De
Jong-Brink, and W.P.M. Geraerts (1997) Altered gene expression in the host brina caused
by a trematode parasite: neuropeptide genes
are preferentially affected during parasitosis.
P.N.A.S., 94: 14072–14076.
Holmes, J.C., and S. Zohar (1990) Pathology and
host behaviour. In Parasitism and Host Behaviour (ed. by C.J. Bernard and J.M. Behnke),
Taylor and Francis, New York, pp. 34–63.
Hopkins, T.L., S.R. Starkey, and N.E. Beckage
(1998) Tyrosine and catecholamine levels in
hemolymph of tobacco hornworm larvae, Manduca sexta, parasitized by the braconid wasp,
Cotesia congregata, and in the developing parasitoids. Arch. Insect Biochem. Physiol., 38:
193–201.
Hordijk P.L., M. de Jong-Brink, A. ter Maat, A.W.
Pieneman, J. C. Lodder, and K.S. Kits (1992)
The neuropeptide schistosomin and haemolymph from parasitized snails induce similar
changes in excitability in neuroendocrine cells
controlling reproduction and growth in a freshwater snail. Neurosci. Lett., 136: 193–197.
Horton, D.R., and J. Moore (1993). Behavioral
effects of parasites and pathogens in insect
hosts. In Parasites and Pathogens of Insects,
Vol. 1 (ed. by N.E. Beckage, S.N. Thompson
and B.A. Federici), Academic Press, San Diego, CA, pp. 107–124.
Hurd, H., and C. Arme (1986) Hymenolepis diminuta: effect of metacestodes on production and
viability of eggs in the intermediate host, Tenebrio molitor. J. Invert. Pathol., 93: 111–120.
Katz, P.S. (1999) What are we talking about?
Modes of neuronal communication. In Beyond
Neurotransmission (ed. by P.S. Katz), Oxford
University Press, New York, pp. 1–28.
Katz, P.S., and D.H. Edwards (1999) Metamodulation: the control and modulation of neuromodulation. In Beyond Neurotransmission (ed. by
P.S. Katz), Oxford University Press, New
York, pp. 349–381.
Parasites, Neuromodulators and Host
Behavioral Change
Kavaliers, M., D.D. Colwell, and E. Choleris (1999)
Parasites and behavior: an ethopharmacological analysis and biomedical implications. Neurosci. Biobehav. Rev., 23: 1037–1045.
Kravitz, E.A. (1990) Hormonal control of behavior: amines as gain-setting elements that bias
behavioral output in lobsters. Am. Zool., 30:
595–608.
Livingston, M.S., R.M. Harris-Warrick, and E.A.
Kravitz (1980) Serotonin and octopamine produce opposite postures in lobsters. Science,
208: 76–79.
Maier, S.F., and L.R. Watkins (1999) Bidirectional
communication between the brain and the immune system: implications for behaviour.
Anim. Behav., 57: 741–751.
Manger, P., L. Jianyong, B.M. Christensen, and
T.P. Yoshino (1996) Biogenic monoamines in
the freshwater snail, Biomphalaria glabrata: influence of infections by the human blood fluke,
Schistosoma mansoni. Comp. Biochem. Physiol., 114A: 227–234.
Maynard, B.J., L. DeMartini, and W.G. Wright
(1996) Gammarus lacustris harboring Polymorphus paradoxus show altered patterns of sertonin-like immunoreactivity. J. Parasitol., 82:
663–666.
Miles, C.I., and R. Booker (1994) The role of the
frontal ganglion in foregut movements of the
moth Manduca sexta. J. Comp. Physiol. A,
174: 755–767
Miles, C.I., and R. Booker (2000) Octopamine
mimics the effects of parasitism on the foregut
of the tobacco hornworm Manduca sexta. J.
Exp. Biol., 203: 1689–1700.
Moore, J. (2002) Parasites and the Behavior of Animals. Oxford University Press, New York.
Moore, J., and N.J. Gotelli (1996) Evolutionary
patterns of altered behavior and susceptibility
in parasitized hosts. Evolution, 50: 807–816.
Poulin, R. (1995). ‘Adaptive’ changes in the behaviour of parasitized animals: a critical review.
Int. J. Parasitol., 25: 1371–1383.
Pryor, S.C., and R. Elizee (2000) Evidence of
opiates and opioid neuropeptides and their immune effects in parasitic invertebrates representing three different phyla: Schistosoma
mansoni, Theromyzon tessulatum, Trichinella
spiralis. Acta Biol. Hung., 51: 331–341.
Romig, T., R. Luciaus, and W. Frank (1980) Cerebral larvae in the second intermediate host of
Dicrocoelium dendriticum (Rudolphi, 1819)
and Dicrocoelium hospes Looss, 1907 (Trematodes, Dicrocoeliidae). Z. Parasitenkd., 63:
277–286.
Salzet, M. (2000) Invertebrate molecular neuroimmune processes. Brain Res. Rev., 34: 69–79.
Schallig, H.D.F.H., M.J.M. Sassen, P.L. Hordijk,
and M. de Jong-Brink (1991) Trichobilharzia
ocellata: influence of infection on the fecundity
of its intermediate snail host Lymnaea stagnalis and cercarial induction of the release of schistosomin, a snail neuropeptide antagonizing female gonadotropic hormones. Parasitology,
102: 85–91.
Thompson, S.N., and M. Kavaliers (1994) Physiological bases for parasite-induced alterations of
host behaviour. Parasitology, 109: S119–S138.
Tierney, A.J., and L.A. Mangiamele (2001) Effects
of serotonin and serotonin analogs on posture
and agonistic behavior in crayfish. J. Comp.
Physiol. A, 187: 757–767.
Truman, J.W., W.S. Talbot, S.E. Fahrbach, and
D.S. Hogress (1994) Ecdysone receptor expression in the CNS correlates with stage-specific
responses to ecdysteroids during Drosophilia
and Manduca development. Development,
120: 219–234.
van Duivenboden, Y.A. (1984) Sexual behaviour of
the hermaphrodite freshwater snail Lymnaea
stagnalis. Ph.D. dissertation, Vrije Universiteit
te Amsterdam, Amsterdam, The Netherlands.
Webb, T.J., and H. Hurd (1999) Direct manipulation of insect reproduction by agents of parasite
origin. Proc. R. Soc. Lond. B, 266: 1537–1541.
Yoshino, T.P., J.P. Boyle, and J.E. Humphries
(2001) Receptor-ligand interactions and cellular signalling at the host-parasite interface. Parasitology, 123: S143–S157.
Zitnan, D., T. Kingan, S.J. Kramer, and N.E. Beckage (1995) Accumulation of neuropeptides in
the cerebral neurosecretory system of Manduca
sexta larvae parasitized by the braconid wasp
Cotesia congregata. J. Comp. Neurol., 356: 83–
100.
Brain Behav Evol 2002;60:370–377
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