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First published online December 26, 2008
Journal of Experimental Biology 212, 163-168 (2009)
Published by The Company of Biologists 2009
doi: 10.1242/jeb.025361
Effects of cocaine on honey bee dance behaviour
1 ARC Centre for Molecular Genetics of Development, Research School of
Biological Sciences, Australian National University, Canberra, ACT 2601,
Australia
2 Department of Entomology and Neuroscience Program, University of Illinois at
Urbana-Champaign, 505 S. Goodwin Avenue, Urbana, IL 61801, USA
* Author for correspondence at present address: Centre for the Integrative Study of Animal Behaviour, Macquarie University, Sydney NSW 2109, Australia (e-mail: andrew.barron{at}mq.edu.au)
Accepted 22 November 2008
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Summary |
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 TOP Summary INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Key words: cocaine, Apis mellifera, reinforcement, dance language, drug abuse, dopamine, octopamine
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INTRODUCTION |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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). In
humans, cocaine is also highly toxic at medium to high doses but highly
rewarding and reinforcing at low doses and potentially addictive
(Kelley and Berridge, 2002;
Sullivan et al., 2008). Why
should a chemical that evolved to protect plants from herbivory be rewarding
to humans and other mammals? This has been called the `paradox of drug reward'
(Sullivan et al., 2008).
Solutions to this paradox often propose that cocaine evolved to deter
insect and not mammalian herbivores and that fundamental differences exist in
the responses of mammals (especially humans) to cocaine compared with those of
arthropods (Nathanson et al.,
1993). Seemingly in support of this view is the observation that
while there is abundant evidence for cocaine disruption of insect motor
systems (Hardie et al., 2007;
McClung and Hirsh, 1997;
Nathanson et al., 1993;
Wolf and Heberlein, 2003), it
has not previously been shown to be rewarding to insects
(Wolf and Heberlein,
2003).
New data, however, have revealed many similarities in neurochemical systems
and cocaine's mode of action between insects and mammals that call into
question this solution to the paradox of drug reward. In both mammals
(Kelley and Berridge, 2002;
Wise, 2004) and insects
(Roeder, 2005;
Wolf and Heberlein, 2003),
cocaine operates by blocking biogenic amine reuptake transporters
(Corey et al., 1994;
Gallant et al., 2003), thereby
disrupting biogenic amine signalling
(Bainton et al., 2000;
McClung and Hirsh, 1999;
Nathanson et al., 1993). In
mammals, the biogenic amine systems disrupted by cocaine [principally dopamine
(DA)] modulate both motor control and reward processing
(Cenci, 2007;
Uhl et al., 2002;
Wise and Rompre, 1989;
Wise, 2004). In insects,
biogenic amines [principally DA and octopamine (OA)] also modulate motor
control (Fussnecker et al.,
2006; Hardie et al.,
2007; Roeder et al.,
2003), arousal (Adamo et al.,
1995; Kume et al.,
2005; Stevenson et al.,
2005) and reward processing
(Barron et al., 2007b;
Hammer and Menzel, 1998;
Schwaerzel et al., 2003;
Unoki et al., 2005). Given
these mechanistic similarities we revisited the question of whether cocaine
could be rewarding to insects.
We used the dance language of the honey bee (Apis mellifera) as a
natural bioassay to study the effect of cocaine on reward assessment. On
return to the hive, forager honey bees may perform highly stereotyped
movements (dances) to signal the location and value of floral resources to
their nest mates (Seeley,
1995). The function of the dance is to advertise profitable
resources to improve the foraging efficiency of the colony. For resources
close to the hive, bees perform `round dances', and the likelihood and rate of
round dancing are related to the value of the resources
(Waddington, 1982). Resource
value is influenced by several factors including the costs and benefits of the
foraging trip and the nutritional needs of the colony
(Seeley, 1995;
Waddington, 1982). Bees use
these factors to develop a gestalt estimate of the value of collected floral
resources to the colony (Seeley,
1994; Seeley,
1995; Waddington,
1982). Dance thus provides a unique, natural and quantifiable
assay for a forager bee's assessment of the value of collected floral
resources. Here, we used the dance response of forager bees to sucrose and
pollen feeders as an assay to assess the effects of cocaine on honey bee
reward processing. We examined the effects of chronic and acute treatment with
low doses of cocaine on honey bee behaviour and found honey bee responses that
paralleled those of mammals.
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MATERIALS AND METHODS |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Pharmacological treatments
In these experiments, bees were treated with freebase cocaine, OA
hydrochloride or mianserin hydrochloride by applying the compounds dissolved
in 1 µl dimethylformamide (DMF) to the dorsal thorax of forager bees using
a glass microcapillary while they fed at sucrose or pollen feeders. DMF is a
solvent that can penetrate bee cuticle and act as a `vehicle' to allow
administered compounds to pass into the haemocoel and reach the brain
(Barron et al., 2007a).
Experiment 1: effects of cocaine and mianserin hydrochloride treatment on dance behaviour
Dances were observed using colonies of 
8000 bees housed in a
glass-walled observation hive. Individually paint-marked foragers were trained
to a 1.5 mol l–1 sucrose feeder 10 m from the hive, and their
round dances (Seeley, 1995;
Waddington, 1982) were video
recorded during a 50 min period. We compared the round dance behaviour of bees
treated with a single acute treatment of 3 µg, 6 µg or 12 µg cocaine
dissolved in 1 µl DMF. Control groups were sham-treated (simply touching
the bee's back with an empty glass microcapillary) or treated with 1 µl DMF
only. Inclusion of both sham- and DMF-treated control groups allowed us to
determine whether DMF itself was affecting behaviour. Bees treated with 2
µg OA in 1 µl DMF were included as a positive control, since OA is known
to modulate bee dance behaviour (Barron et
al., 2007b). Dance observations began 20 min after treatment.
During the observation period, the number of visits by each bee to the feeder
was also recorded. Videos were later analysed to score how many feeder visits
caused dances on return to the hive (dance likelihood) and the rate of dancing
(number of dance circuits per minute).
Mianserin hydrochloride is a biogenic amine antagonist
(Degen et al., 2000;
Roeder, 1999). To test whether
cocaine influenced dance behaviour by affecting biogenic amine signalling, we
examined whether mianserin treatment could reduce the effects of cocaine on
dance behaviour. In a separate experiment using a different bee colony we
compared dance behaviour in bees treated topically with 3 µg cocaine or 3
µg cocaine + 2 µg mianserin. We have shown previously that this dose of
mianserin does not make bees sick or reduce dance performance on its own but
is an effective antagonist of biogenic amine treatments
(Barron et al., 2007b). Control
groups were sham, DMF or OA treated.
Cocaine could affect dancing by stimulation of motor pathways or by
changing forager sensitivity to the floral rewards they collected. Experiments
2 and 3 tested which of these alternatives is more likely. Cocaine is known to
affect motor activity in Drosophila
(McClung and Hirsh, 1997), and
the honey bee dance is obviously a locomotor behaviour. Experiment 2 tested
whether cocaine generally increased locomotor behaviour in honey bees by
studying the effects of cocaine on activity in a simple locomotor assay.
Experiment 3 tested whether cocaine increased responsiveness to sucrose in the
proboscis extension response (PER) assay to examine whether cocaine affected
responses to rewarding stimuli in a non-dance assay.
Experiment 2: effect of cocaine on locomotor behaviour
Forager bees were caught at a sucrose feeder and chilled briefly to
immobility by 2 min exposure to –20°C in a domestic freezer.
Individual bees were treated topically with 3 µg cocaine, or DMF as a
control. Bees were placed individually in 9 cm-diameter Petri dishes. Each
dish was placed over a simple radial grid and we recorded the number of times
the bee walked across a line in the grid during a 5 min observation period.
Each bee was observed twice at 30 and 60 min post-treatment. This assay has
been used previously to detect activity differences in pharmacologically
treated bees (Beggs et al.,
2007).
Experiment 3: effect of cocaine on sucrose responsiveness
Cocaine could influence dance behaviour by changing responsiveness to
floral rewards. To explore this possibility we studied the effect of cocaine
treatment on responsiveness to sucrose using the PER assay. Bees were
harnessed in metal tubes following previously published methods
(Si et al., 2004) and starved
for 4 h. One hour prior to testing, bees were treated topically with 3µg
cocaine in DMF. DMF- and sham-treated bees were control groups. 20µl drops
of seven different sugar solutions (0.1%, 1%, 2.5%, 10%, 30%, 60% sucrose and
honey) were touched briefly to the antennae of each bee in order of ascending
sucrose concentration and ending with honey. Water was presented to bees
between each sucrose presentation. The first concentration eliciting proboscis
extension was the sucrose sensitivity index. An index of 1 meant a bee
responded to 0.1% sucrose, while 7 meant a bee responded to honey only. Bees
that responded to water more than twice were judged to have sensitised to
antennal stimulation and were excluded from analyses comparing sucrose
responsiveness across experimental groups.
Experiment 4: effect of cocaine on dances for pollen
To test whether cocaine affected dances for resources other than sucrose we
examined the effects of cocaine on dances for pollen. Pollen is the bees'
protein and lipid source. Unlike nectar it is not ingested by foragers: it is
carried in `baskets' on the hind legs. In this experiment, individually marked
bees collected freeze-dried pollen from a dish 10 m from the hive. Bees were
treated topically with 3 µg cocaine or sham or DMF treatments. At the time
of our experiment (May 2006; late Autumn in Canberra, Australia) dances for
pollen were rare and short; therefore, for each experimental group we compared
the proportion of bees that danced at least once for the pollen dish during a
50 min observation period beginning 20 min post-treatment.
Experiment 5: effect of chronic cocaine treatment and cocaine `withdrawal' on learning
Rats show disruptions in learning and memory on abrupt cessation of chronic
cocaine exposure (Calu et al.,
2007), which is considered a model for human cocaine withdrawal.
To examine whether bees exhibit something similar to withdrawal, we tested the
performance of bees in a two-odour discriminant learning task using PER
(Si et al., 2004). Bees were
reared from adult emergence in groups of 60 in cages in a humidified incubator
at 32°C for 6 days. Bees were given chronic oral drug treatments by being
fed excess 1.5 mol l–1 sucrose containing either 0.66 mmol
l–1 cocaine hydrochloride (a non-toxic dose) or 10.54 mmol
l–1 OA hydrochloride or plain sucrose as a control. Training
occurred on Day 6.
For PER training, commercial lemon essence (4 µlml–1)
in 1 mol l–1 sucrose solution was the rewarding stimulus,
while natural vanilla essence (4 µlml–1) in saturated NaCl
solution was the non-rewarding stimulus. Bees were given three training
sessions at 10 min intervals. During each training session, bees were exposed
to the odour of the rewarding stimulus for 5 s, following which one antenna
was touched with the stimulus, leading to the extension of the proboscis and
tasting of the sugar. This was repeated with the non-rewarding stimulus. The
responses of bees to vanilla and lemon odour were tested 20 h after training,
and the presence or absence of proboscis extension was noted
(Si et al., 2004). A `correct'
response was proboscis extension to lemon (sugar associated) but not vanilla
(salt associated).
Bees were held in their harnesses during the 20 h between training and testing. During this period the cocaine-treated and OA-treated bees were assigned to either `withdrawal' or `chronic' treatment groups. The `withdrawal' bees were all fed 20 µl of plain 1.5 mol l–1 sucrose solution 1, 3 and 7 h after training, giving 20 h without oral cocaine or OA treatment immediately before testing. The `chronic-treated' bees were fed 20 µl cocaine- or OA-containing sucrose 1, 3 and 7 h after training so that drug treatments were consistent throughout the training and testing period. The sucrose control group was fed 20 µl plain sucrose in both chronic and withdrawal experimental conditions. By comparing learning performance relative to sucrose control bees across these two experimental conditions, we could assess the effect of chronic oral cocaine treatment on learning performance and also the effect of cessation of chronic cocaine treatment on learning.
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RESULTS |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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;
Hammer and Menzel, 1998;
Schwaerzel et al., 2003). The
effects of cocaine on bee dance were eliminated by simultaneous treatment with
the biogenic amine antagonist mianserin
(Fig. 2), suggesting that
cocaine modulated dance performance by interfering with biogenic amine
signalling.
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Cocaine-treated foragers only danced when they were interacting socially within the hive. Foragers treated with cocaine but held in small vials isolated from the hive never performed any movements resembling dances (N=240 bees, doses 3–50µg, each observed for 1.5 h). This indicates that cocaine stimulates dancing only in the appropriate social context of a forager returning resources to the colony.
Experiment 2: effect of cocaine on locomotor behaviour
There was no sign of motor malfunction or locomotor hyperactivity in
isolated bees treated with the 3 µg cocaine dose
(Fig. 3). Since we observed no
effect of cocaine on simple locomotor activity we argue it is unlikely that
cocaine modulates dance behaviour via a general stimulation of motor
pathways.
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Experiment 3: effect of cocaine on sucrose responsiveness
Cocaine increased responsiveness to sucrose in the PER assay
(Fig. 4) but did not increase
the number of bees that sensitised to water presentation (number of bees
responding to two or more of seven water presentations: 3 µg cocaine 9/80,
DMF 11/80, untreated 17/80; 
2=3.323, d.f.=2,
P=0.189). This suggests that cocaine specifically increased
responsiveness to sucrose reward rather than a general sensitisation of reflex
motor responses to antennal stimulation in this assay.
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2=6.867, d.f.=2,
P=0.032). This indicates that cocaine modulated responses to
collected resources other than ingested sucrose.
Experiment 5: effect of chronic cocaine treatment and cocaine `withdrawal' on learning
Learning performance in cocaine-treated bees did not differ from that in
untreated or OA-treated control groups if drug treatments were maintained
during the 20 h between training and testing (`chronic treatment';
Fig. 5A). If cocaine and OA
treatment ceased during the interval between training and testing (giving the
OA and cocaine groups 20 h without drug exposure), the cocaine-treated group
performed only half as well as the control or OA-treated groups (`withdrawal
treatment'; Fig. 5B). This
demonstrates a significant learning deficit that manifests on cessation of
prolonged cocaine exposure, suggestive of a withdrawal-like phenomenon in
bees.
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DISCUSSION |
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TOPSummaryINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The behavioural function of the dance is to advertise profitable resources
to nest mates, and the effects of cocaine on dance behaviour are consistent
with cocaine increasing responsiveness to floral rewards. Hence, we argue that
our experiments present the first evidence for cocaine modulating reward
processing systems in an insect brain. However, cocaine is known to modulate
motor systems in insects (McClung and
Hirsh, 1997; Nathanson et al.,
1993; Wolf and Heberlein,
2003), and, in Drosophila, treatment with medium to high
cocaine doses can sometimes release looping locomotor stereotypies
(McClung and Hirsh, 1997).
Therefore, an alternative interpretation of our findings could be that cocaine
affected dance behaviour by stimulating motor and not reward pathways in the
insect brain.
We do not believe the dance response observed in bees is a simple
stereotypy or hyperkinesia for the following reasons. First, forager bees do
not automatically dance on return to the hive; the decision of whether or not
to dance and how to dance depends on the relative profitability of their
foraging trip (Seeley, 1995).
Cocaine increased the likelihood of an individual bee dancing
(Fig. 1) but did not make bees
dance every time, demonstrating that cocaine did not simply release dance
behaviour in every treated bee. Second, within the cocaine dose range that was
most effective in stimulating dancing, treated bees continued to forage
normally. Their foraging rate was not hyperactive and they did not show any
gross motor deficits that interfered with flight or navigation. This argues
against cocaine releasing an abnormal motor stereotypy of the kind observed in
Drosophila. Third, cocaine-treated bees only danced when in the
appropriate social environment of the dance floor, indicating that the
expression of dance behaviour in cocaine-treated bees remained sensitive to
the colony social environment. This would not be predicted for a motor
stereotypy. Fourth, in a locomotion assay
(Fig. 3), we observed no
evidence for general motor hyperactivity in bees treated with the cocaine dose
most effective in stimulating dancing.
In a PER assay, cocaine increased sucrose responsiveness (Fig. 4) but did not increase sensitisation to water, implying that cocaine modulated behavioural responses to stimulation by sucrose but did not increase the general motor reactivity of the proboscis reflex to antennal stimulation. These data support our interpretation that cocaine affected dance behaviour by modulation of brain reward systems. Cocaine increased dances for pollen also, indicating that cocaine increased dance responses to general floral rewards and that the effects of cocaine on dance cannot be explained solely by cocaine modulation of peripheral sucrose sensitivity.
While we certainly do not rule out the possibility of cocaine affecting
motor systems in honey bees [as it does in other insects
(Nathanson et al., 1993) and
mammals (Antoniou et al.,
1998)], we argue that the sum of our results cannot be explained
by cocaine stimulation of motor pathways alone at the doses used here. Rather
we favour the interpretation that our results demonstrate cocaine stimulation
of pathways for reward assessment and processing.
As a further parallel between honey bee and mammalian responses to cocaine,
we observed a withdrawal-like response in honey bees following cessation of
chronic cocaine treatment (Fig.
5). Cocaine withdrawal has been reported in rodents, which show
disruptions in learning and memory (Calu et
al., 2007), but this has not been shown previously in insects. In
honey bees, we observed poor performance in a learning task that manifested
only on cessation of chronic oral cocaine treatment and not with continued
chronic cocaine treatment. Hence, our result is unlikely to be due to cocaine
making bees sick. Whether the poor performance we observed was due to deficits
in learning, recall or attention remains to be explored.
The effects of cocaine on dance behaviour were eliminated by mianserin
treatment (Fig. 2). Since
mianserin is an antagonist of biogenic amine receptors, this result implies
that cocaine influences dance by interaction with biogenic amine pathways,
consistent with the known mode of action of cocaine in mammals
(Kelley and Berridge, 2002;
Wise and Rompre, 1989;
Wise, 2004) and insects
(Nathanson et al., 1993;
Wolf and Heberlein, 2003). In
mammals, cocaine blocks biogenic amine reuptake transporters, with highest
affinity for the dopamine reuptake transporter
(Kelley and Berridge, 2002).
Cocaine-sensitive dopamine and serotonin transporters have been cloned from
Drosophila (Corey et al.,
1994; Demchyshyn et al.,
1994; Porzgen et al.,
2001), and cocaine sensitivity in flies is modulated by
manipulation of dopamine and serotonin levels
(Bainton et al., 2000;
Li et al., 2000).
Cocaine-sensitive dopamine transporters have also been cloned from
Trichoplusia ni (Gallant et al.,
2003).
Presently, it is unclear how cocaine acts to influence dance behaviour and
reward processing in the honey bee. Dance behaviour has been shown to be
influenced by pharmacological manipulation of OA levels
(Barron et al., 2007b), and OA
has also been shown to modulate reward learning in honey bees
(Hammer and Menzel, 1998). One
plausible scenario is that cocaine interferes with bee reward processing by
disrupting OA signalling. While this interpretation is consistent with known
behavioural effects of OA in honey bees, presently we do not know which
biogenic amine systems in bees are most sensitive to cocaine. Four putative
biogenic amine transporters have been identified from the honey bee genome
based on sequence similarity to the Drosophila dopamine transporter
DAT; however, none of these genes has been functionally characterised
and their sensitivity to cocaine is also unknown. Some insects
(Drosophila) have transporters for DA and serotonin only whereas
others (Trichopusia ni) have distinct OA, DA and serotonin
transporters (Gallant et al.,
2003; Malutan et al.,
2002). Until the honey bee biogenic amine transporters have been
characterised we will not know what complement of transporters the bee
possesses and which are most sensitive to cocaine.
In both mammals and bees, the biogenic amines function as modulators of
reward processing and motor control. In mammals, both motor control and reward
processing are regulated by DA (Kelley and
Berridge, 2002; Wise and
Rompre, 1989; Wise,
2004). In bees, both DA and OA have been implicated in motor
control systems and reward processing
(Barron et al., 2007b;
Beggs et al., 2007;
Hammer and Menzel, 1998).
Since the behavioural functions of the biogenic amine systems disrupted by
cocaine are similar between insects and mammals, our findings imply a
parsimonious explanation for the paradox of cocaine reward. Cocaine is a
potent plant defence because it causes catastrophic failure of insect motor
control by disrupting biogenic amine signalling
(Nathanson et al., 1993). But
because biogenic amine systems regulating motor function also modulate reward
processing it is almost unavoidable that cocaine impacts reward systems.
Despite its reinforcing properties, cocaine remains an effective plant defence
because the concentrations naturally occurring in coca leaves are such that
herbivorous insects very rapidly ingest a toxic dose
(Nathanson et al., 1993). From
an evolutionary perspective, the reinforcing properties of cocaine can be
considered a `side effect' resulting from cocaine targeting neurochemical
systems regulating multiple aspects of behaviour.
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Footnotes |
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