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Institute for Neurobiology, Free University of Berlin, Koenigin-Luise-Str. 28-30, 14195 Berlin, Germany
Institute for Biology, Leipzig University, Talstr. 33, 04103 Leipzig, Germany
a r t i c l e
i n f o
Article history:
Received 23 May 2014
Revised 27 August 2014
Accepted 23 September 2014
Available online 28 September 2014
Keywords:
Agonistic behavior
Social behavior
Loser effect
Amine depletion
Behavioral depression
Octopamine
Tyramine
Subordinate behavior
Animal conict
Aggressive motivation
a b s t r a c t
Social defeat, i.e. losing an agonistic dispute with a conspecic, is followed by a period of suppressed aggressiveness in many animal species, and is generally regarded as a major stressor, which may play a role in psychiatric
disorders such as depression and post-traumatic stress disorder. Despite numerous animal models, the mechanisms underlying loser depression and subsequent recovery are largely unknown. This study on crickets is the
rst to show that a neuromodulator, dopamine (DA), is necessary for recovery of aggression after social defeat.
Crickets avoid any conspecic male just after defeat, but regain their aggressiveness over 3 h. This recovery
was prohibited after depleting nervous stores of DA and octopamine (OA, the invertebrate analogue of noradrenaline) with -methyl-tyrosine (AMT). Loser recovery was also prohibited by the insect DA-receptor (DAR) antagonist uphenazine, but not the OA-receptor (OAR) blocker epinastine, or yohimbine, which blocks receptors for
OA's precursor tyramine. Conversely, aggression was restored prematurely in both untreated and amine depleted
losers given either chlordimeform (CDM), a tissue permeable OAR-agonist, or the DA-metabolite homovanillyl
alcohol (HVA), a component of the honeybee queen mandibular pheromone. As in honeybees, HVA acts in
crickets as a DAR-agonist since its aggression promoting effect on losers was selectively blocked by the DARantagonist, but not by the OAR-antagonist. Conversely, CDM's aggression promoting effect was selectively
blocked by the OAR-antagonist, but not the DAR-antagonist. Hence, only DA is necessary for recovery of aggressiveness after social defeat, although OA can promote loser aggression independently to enable experience
dependent adaptive responses.
2014 Elsevier Inc. All rights reserved.
Introduction
Intra-specic aggression is common throughout the animal kingdom and a major hallmark of this behavior is that its expression is inuenced by a wide variety of experiences (Huntingford and Turner, 1987;
Archer, 1988; Hsu et al., 2006, 2009). In mammals, for example, experiences as diverse as physical exertion (Raichlen et al., 2011), the possession of a resource (Fuxjager et al., 2010) and winning (Hsu et al., 2006,
2009) can each promote the aggressiveness of an individual, whereas
losing leads to a pronounced reduction in the expression of aggressive
behavior (Hsu et al., 2006, 2009). Investigations of the consequences
of social defeat and its importance for understanding social behavior
and psychiatric disorders such as post-traumatic stress disorder are receiving increasing amounts of attention (Huhman, 2006). Comparatively
little, however, is known about the neuronal control mechanisms underlying the effects of experiences such as social defeat on aggressive
behavior.
Corresponding author at: Institute for Biology-II, Leipzig University, Talstr. 33,
D-04103 Leipzig, Germany. Fax: +49 341 9736848.
E-mail address: stevenson@rz.uni-leipzig.de (P.A. Stevenson).
http://dx.doi.org/10.1016/j.yhbeh.2014.09.012
0018-506X/ 2014 Elsevier Inc. All rights reserved.
697
Fight duration, from rst contact until conclusion, was measured to the
nearest second with a stopwatch. Very occasionally, the animals appeared
to lose contact with each other so that ghting paused for a brief period
before resuming when contact was regained. As in our previous studies,
we chose to deduct the duration of these pauses in the few cases they
occur in order to give a more representative measure of the actual
time spent ghting.
Pharmacological treatments
Various pharmacological treatments were performed to evaluate the
role of amines in loser recovery. To minimize variations due to random
differences in daily performances, we took the precaution of evaluating
single pairs of crickets from control and test groups in parallel and
accumulated data from multiple experimental sessions (three groups
per session, test sequence changed at each). The numbers of cricket
pairs for each test group is given in tables and gures.
Unless stated otherwise, all drugs were obtained from Sigma Aldrich
(Deisenhofen, Germany). Their effects were tested by injecting 10 l solutions into the hemocoel via the pronotal shield using a micro-syringe
(Hamiliton, Bonaduz, Switzerland). The most effective concentrations
that induced noticeable changes in aggressive behavior, but without
having any obvious detrimental effect on general motility were determined in pilot investigations.
Hydrochloride salts of native OA and DA were found to have no
obvious effect on aggression at concentrations as high as 20 mM,
which is due we suspect to the permeability barrier of the ganglion
sheath (cf. Schoeld et al., 1984). Contrasting this, the tissue permeable
OAR-agonist chlordimeform hydrochloride (CDM; cf. Roeder, 1995) and
the DAR-agonist homovanillyl alcohol (HVA: Beggs and Mercer, 2009)
were both effective at 1 mM in saline solution containing 1% DMSO
(dimethylsulfoxide; saline components in mmol L1: NaCl 140, KCl
10, CaCl2 7, NaHCO3 8, MgCl2 1, N-trismethyl-2-aminoethanesulfonic
acid 5, D-trehalose dihydrate, pH 7.4). The following amine receptor
antagonists were dissolved in the same solvent (saline, 1% DMSO) and
applied at the same concentration (10 mM): epinastine hydrochloride,
a selective OAR-blocker (Roeder et al., 1998), uphenazine dihydrochloride
a D1/D2 dopamine receptor (DAR) blocker in insects (Degen et al.,
2000) and yohimbine hydrochloride an insect tyramine receptor
(TAR) blocker (Roeder, 2005). Previous experiments have shown that
aminergic drugs injected into the hemocoel require about 30 min to
become effective, and that their effects last for up to 4 h (Stevenson
et al., 2005; Rillich et al., 2011; Rillich and Stevenson, 2011).
The roles of the amines OA, DA and TA in loser recovery were also
evaluated by applying the competitive synthesis inhibitor -methyltyrosine (AMT). We have previously shown that a comparatively high
dosage is required in order to effectively deplete OA and DA from the
cricket central nervous system as determined by immunocytochemistry
(Stevenson et al., 2000) and we followed the same protocol in this
study. Briey, each animal received two successive injections of
1.5 mg AMT in 20 l saline administered at 48 h intervals, and evaluated
aggressive behavior 48 h after the last injection. Controls received two
successive injections of saline only. Since AMT inhibits the conversion
of tyrosine to OA's precursor TA, this amine is probably also depleted
in addition to OA and DA by this treatment.
Experimental procedure
All experiments were performed during daylight hours, avoiding
times when aggression tends to be depressed (just after midday and
on generally dreary days; cf. Dixon and Cade, 1986; Stevenson et al.,
2000). Fights were rst staged in an initial ght to establish clear winners
and losers and the hierarchical relationship veried by re-matching the
same opponents 1 min later to assure that the designated loser retreated
immediately from the designated winner. To chart the time course of
loser recovery, the same opponents were re-matched 15, 30, 60 or
698
180 min after the initial ght, whereby different groups of animals were
tested for each time slot. In our current experiments all tested crickets
were drug treated 3060 min before any social interactions, to circumvent any effects of handling the losers, and their aggression was evaluated up until maximally 4 h after the injection. Since the effect of losing on
aggression is maximal 1530 min after defeat, this gave us ample time to
evaluate the effects of aminergic drugs on loser aggression. Although
both contestants were drug-treated, our experimental design still allows
conclusions concerning loser behavior. Firstly, the level and duration of a
ght are determined primarily by the subordinate, which normally
retreats, while winners are always aggressive (Rillich et al., 2007).
Secondly, even though aminergic receptor blockers, for example, can
reduce the aggressiveness of winners (Rillich and Stevenson, 2011),
rank reversals, in which the designated winners retreat from the
designated loser were less than 2% in our experiments (see also Rillich
et al., 2007), so that the scored level and duration of aggression still
reected the loser's decision to ght or ee.
Data analysis
All statistical tests were performed using standard commercial software (Prism 5, GraphPad Software Inc., La Jolla, CA, USA) running on a
Macintosh computer (Apple Computers, Cupertino, CA, USA). The median and the interquartile range (IQR) were calculated for non-parametric
data sets. Non-parametric tests were also performed on duration since
the data sets failed D'Agostino and Pearson omnibus normality tests,
even after log transformations. To evaluate whether loser recovery
Fig. 1. OAR- and DAR-agonist restore loser aggression. Bar graphs giving the level of aggression (i, top) and ght duration (ii, bottom) for ghts between pairs of socially naive crickets and
the resulting losers against their respective winners 15, 30, 60 and 180 min after defeat (different animals for each time slot; n is given above the x-axis in i). The animals received the
following treatments before the initial ght: A. Vehicle (1% DMSO in saline, white bars); B. OAR-agonist (CDM, blue bars); C. DAR-agonist (HVA, red bars). Circles give the medians
and boxes the interquartile ranges. The p(KW) gives error probabilities from KruskalWallis analyses for differences in the four loser vs. winner test periods as an indicator of loser recovery.
Asterisks indicate signicant differences between each test groups and vehicle for each time slot (U test, Bonferroni correction to alpha for three comparisons: *p b 0.025; **p b 0.005,
***p b 0.0005).
699
Table 1
The level of aggression (median and interquartile range, n in parenthesis) for ghts between socially naive crickets and the subsequent losers versus winners 15, 30, 60 and 180 min
after defeat for the following experimental groups: saline, DMSO, CDM, HVA, AMT, yohimbine, epinastine and uphenazine. Transient recovery of loser aggression is indicated by the
p(KW)-value that gives the error probabilities from KruskalWallis analyses for differences in the four loser vs. winner test periods (p N 0.05, not signicant for AMT and uphenazine).
Test group
Initial ght
w-l
15 min
w-l
30 min
w-l
60 min
w-l
180 min
Recovery
p(KW)-value
Saline
5, 35
(172)
5, 2.55
(93)
6,56
(70)
5,26
(76)
3,25
(80)
5,2.756
(72)
3,25
(102)
5,36
(97)
1, 12
(40)
1, 11.75
(20)
5, 15
(23)
1.5, 14
(28)
1, 11
(17)
1, 12
(24)
1, 13
(35)
1, 14
(23)
1, 12
(47)
1, 12
(24)
5, 3.55
(14)
4,15
(20)
1, 11
(16)
1, 14.75
(16)
1, 12
(19)
1, 13.75
(24)
3, 15
(36)
2.5, 15
(24)
5,4.56
(14)
5,3.756
(14)
1, 11
(16)
5, 1.755
(14)
3, 15
(30)
1, 13.5
(29)
5, 35
(37)
5, 2.55
(25)
6,56
(19)
5,46
(14)
1, 11
(20)
5, 1.755
(18)
5, 25
(18)
1, 15
(21)
p b 0.001
DMSO
CDM
HVA
AMT
Yohimbine
Epinastine
Fluphenazine
p b 0.001
p = 0.009
p = 0.009
p = 0.968
p b 0.001
p b 0.001
p = 0.853
to vehicle: p-level = 0.694 and p-duration = 0.712), and there was still
a clear transient increase of loserwinner aggression over the observation period of 180 min (Fig. 1C, Tables 1 and 2; KruskalWallis tests:
p-level = 0.0092; p-level = 0.0022). Nonetheless, as found for CDM,
HVA also led to an earlier loser recovery. For example, 15 min after
defeat losers interacted more aggressively with their previous winners
(median 1.5, IQR 14, n = 28) than the vehicle-treated group in ghts
that lasted signicantly longer (median 1 s, IQR 04.75; U test: plevel = 0.016, p-duration = 0.019). As for OA, DA itself (n = 12) produced no signicant changes in aggression at the highest dosage tested
(10 l, 20 mM) compared to vehicle (saline: n = 12, U-tests: initial
ght: p-level = 0.9465, p-duration = 0.6665; losers vs. winners,
15 min: p-level = 0.5912, p-duration = 0.5669, data not illustrated).
OA/DA depletion reversibly blocks loser recovery
Extending our earlier ndings (Stevenson et al., 2000), treatment
with -methyl-tyrosine (AMT) to selectively deplete OA and DA (and
probably TA) from the cricket nervous system reduced aggression at
the initial ght (AMT, n = 80, U test compared to saline control:
p-level b 0.001, p-duration b 0.001, Fig. 2), and completely blocked
the recovery of aggression throughout the 180 min observation period
(KruskalWallis test: p-level = 0.967, p-duration = 0.9428; Fig. 2B).
This effect of AMT was reversible and hence selective rather than generally detrimental. First, 24 h after defeat AMT-treated losers fought their
previous winners as aggressively and as long as at their initial ghts
(Wilcoxon signed rank tests: p-level = 0,545, p-duration = 0.129,
Fig. 1B). Second, additional administration of either the OAR-agonist
CDM or DAR-agonist HVA to AMT-treated crickets, each effectively
Table 2
The ght duration in s (median and interquartile range, n as in Table 1) for ghts between socially naive crickets and the subsequent losers versus winners 15, 30, 60 and 180 min after
defeat for the following experimental groups: saline, DMSO, CDM, HVA, AMT, yohimbine, epinastine and uphenazine. Transient recovery of loser aggression is indicated by the p(KW)value that gives the error probabilities from KruskalWallis analyses for differences in the four loser vs. winner test periods (p N 0.05, not signicant for CDM, AMT and uphenazine).
Test group
initial ght
w-l (s)
15 min
w-l (s)
30 min
w-l (s)
60 min
w-l (s)
180 min
Recovery
p(KW)-value
Saline
DMSO
CDM
HVA
AMT
Yohimbine
Epinastine
Fluphenazine
6.5, 310.75
7, 410
15,731
6.5,211
3, 15
7,2.7512
4,17
7,311.5
0, 03
0, 01.5
6, 09
1, 04.75
0, 00
0, 02
0, 01
0, 04
0, 02
0, 01
6, 3.58.25
5.5, 08.75
0, 00
0, 05.75
0, 01
0, 03.5
3, 05
3, 07
6, 430.75
7, 4.759.25
0, 00
4.5, 0.759.5
3.5, 06.5
0, 03
6, 3.58.5
6, 3.58
12, 528
9, 7.2512
0, 00
5.5, 1.58
6.5, 0.759
0, 05
p
p
p
p
p
p
p
p
b 0.001
b 0.001
= 0.201
= 0.002
= 0.943
b 0.001
b 0.001
= 0.883
700
Fig. 2. OA/DA depletion reversibly blocks loser recovery. Bar graphs, as in Fig. 1, giving the level of aggression (i, top) and ght duration (ii, bottom) for ghts between naive crickets and
losers versus winners 15, 30, 60 and 180 min after defeat (different animals for each time slot; n is given above the x-axis in i) for the following treatments: A. Vehicle (saline, white bars);
B. -Methyl-tyrosine (AMT, black bars), which depletes the CNS of DA and OA; C. AMT plus the OAR-agonist CDM (OARag, blue hatched bars) or the DAR-agonist HVA (DARag, red hatched
bars). Circles give the medians and boxes the interquartile ranges. The p(KW) gives error probabilities from KruskalWallis analyses for differences in the four loser vs. winner test periods.
Asterisks indicate signicant differences between test and vehicle groups for the same time slot (U test: **p b 0.01, ***p b 0.001).
Fig. 3. DAR- but not OAR-antagonist blocks loser recovery. Bar graphs, as in Fig. 1, giving the level of aggression (i, top) and ght duration (ii, bottom) for ghts between naive crickets and
losers versus winners 15, 30, 60 and 180 min after defeat (different animals for each time slot; n is given above the x-axis in i) for the following treatments: A. Epinastine (OAR-blocker,
blue hatched bars); B. Fluphenazine (DAR-blocker, red hatched bars); C. Yohimbine (TAR-blocker, yellow hatched bars). Circles give the medians and boxes the interquartile ranges. The
p(KW) gives error probabilities from KruskalWallis analyses for differences in the four loser vs. winner test periods. Asterisks indicate signicant differences between the interactions of
naive crickets, and interactions of the same animals as losers and winners 180 min after ghting (Wilcoxon signed rank test, *p b 0.05, **p b 0.01, n.s., not signicant).
701
Fig. 4. Selectivity of used agonists and antagonists. Bar graphs giving the level of aggression (i, top) and ght duration (ii, bottom) for ghts between losers and winners
15 min after defeat (different animals for each time slot; n is given above the x-axis in
i) for the treatments: A. Vehicle (DMSO in saline, white bar), the OAR-agonist CDM
(blue bars) or the DAR-agonist HVA (red bars) alone, with no antagonist (no blocker);
B. OAR-blocker epinastine followed by treatment with CDM (OARag, blue bars) or HVA
(OARag, red bars); C. DAR-blocker uphenazine followed by OARag (blue bars) or OARag
(red bars). The circles give the medians and the boxes the interquartile ranges. The
p(KW) gives error probabilities from KruskalWallis analyses for differences in the four
loser vs. winner test periods. Asterisks indicate signicant differences between HVA
and CDM for the same pretreatment with either epinastine or uphenazine (U test:
*p b 0.05, ***p b 0.001, except for A where *p b 0.025; **p b 0.005, ***p b 0.0005 to accommodate Bonferroni correction to alpha for three comparisons).
702
Fig. 5. Charts summarizing effects of amine agonists, depletion and antagonists on the recovery of aggression of losers matched against their previous winners. Each chart plots the mean
level of aggression (level 1 ghts were scored here as 0) exhibited by losers towards their previous winners as a percentage of the mean level at the initial ght at selected times after losing
on a log2 scale. The animals received the following treatments: A. Vehicle (1% DMSO with saline, white circles), the OAR-agonist CDM (OAR-ag, blue triangle) or the DAR-agonist
HVA (DAR-ag, red triangles); B. Vehicle (saline, white circle) or the semi-selective amine-depleting agent AMT (black circle); C. The OAR-blocker epinastine (OAR-bl, green circle), the
DAR-blocker uphenazine (DAR-bl, red circle) and the TAR-blocker yohimbine (TAR-bl, yellow circle).
aggressiveness in subordinate crickets, and that DA, but not OA, is actually even necessary for loser recovery. Hence our data suggest that DA
and OA have different roles in the control of aggression, even though
their net effects appear to be the same.
OA/DA depletion prohibits loser recovery
While the depletion of biogenic amines from the nervous system
leads to reduced levels of general excitability, escape responses and
aggression (Stevenson et al., 2000), it cannot completely prevent the
expression of aggressive behavior in ght inexperienced (naive) individuals. Extending an earlier study (Stevenson et al., 2005), we now
show that selective depletion of OA and DA (and probably TA) using
the competitive synthesis inhibitor AMT (cf. Sloley and Orikasa, 1988)
reversibly prohibits the recovery of aggression after social defeat for at
least 3 h (Fig. 2), which is the time span normally required for complete
recovery (Stevenson and Rillich, 2013). Experiments with selective
agonists and antagonist for DAR and OAR illustrate that this effect of
the monoamine synthesis inhibitor AMT on loser recovery is entirely
due to loss of DA rather than OA.
DA is necessary for loser recovery
The main problem in "whole-animal" behavioral pharmacological
studies such as ours, especially when the effects of closely related
amines are concerned, is to ensure selectivity of the drugs used. In honeybees, for example, DAR and OAR subtypes linked to calcium signaling
are phylogenetically and pharmacologically closely related (Beggs et al.,
2011), and hence their functions are difcult to tease apart. The problem
is exacerbated by the orthopteran ganglion sheath, a formidable blood
brain barrier even to the passage of ions (Schoeld et al., 1984), so that
exogenously applied native amines rst become effective only after
prolonged perfusion or at relatively high concentrations (Stevenson
and Kutsch, 1987; Stevenson et al., 2005; Buhl et al., 2008; Rillich
et al., 2013). It is hence not so surprising that injections of up to
20 mM DA (or OA) had no discernible effect on the expression of aggression as analyzed by us. In contrast, the structurally related DA-metabolite
homovanillyl alcohol (HVA) caused a signicant increase in the aggressive behavior of losers after defeat, and also restored aggressiveness
in amine depleted (AMT-treated) losers at the comparatively low
dosage of 1 mM (10 l). Given a total hemolymph volume of around
500 l, the effective concentration would be about 50 M, i.e. thus
just within the physiological range for natural amine effects in insects
(cf. Evans, 1985).
703
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