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Identification of a treatment-resistant, ketamine-sensitive genetic line in
the chick anxiety-depression model
Kenneth J. Sufka
a,b,c,
⁎, Stephen W. White
a
a
Department of Psychology, University of Mississippi, Oxford, MS 38677, USA
b
Department of Pharmacology, University of Mississippi, Oxford, MS 38677, USA
c
Research Institute of Pharmaceutical Sciences, University of Mississippi, Oxford, MS 38677, USA
abstractarticle info
Article history:
Received 12 August 2013
Received in revised form 8 October 2013
Accepted 12 October 2013
Available online 22 October 2013
Keywords:
Animal model
Preclinical screening
Antidepressants
Psychopharmacology
The introduction ofpharmacotherapies for treatment-resistant depression is hindered by translational challenges
with existing preclinical screening models that fail to adequately model the clinical features of this syndrome.
This research sought to screen antidepressants in two selected genetic lines previously identified as stress-
vulnerable and -resilient in the chick anxiety-depression model. Separate groups of socially-raised 5–6 day-old
Black Australorps (stress-vulnerable) and Production Reds (stress-resilient) were administered imipramine
(0–20 mg/kg), fluoxetine (0–10 mg/kg), maprotiline (0–10 mg/kg) or ketamine 0–15 mg/kg) IP (1 ml/kg) and
placed into isolation for 90 min. Distress vocalizations (DVoc) were recorded. Onset of behavioral despair and
Dvoc rates during the depression-like phase (30–90 min) were calculated. Black Australorps entered behavioral
despair approximately 25% faster than Productions Reds highlighting stress-vulnerability inthis Black Australorp
line. In the depression-like phase, Black Australorps were insensitive to imipramine and fluoxetine but sensitive
to ketamine, a finding that parallels stress-vulnerable, treatment resistant depressive disorder. The chick
anxiety-depression model using the Black Australorp line may prove useful in pre-clinical screening of novel
antidepressant targets for use in treatment-resistant depression.
© 2013 Elsevier Inc. All rights reserved.
1. Introduction
Major depression, oftentimes comorbid with anxiety, is a common
and debilitating neuropsychiatric condition with heavy social and
economic burdens. Current antidepressant therapies that target mono-
aminergic (MA) systems are problematic (Thase, 2008)astheyre-
quire 4–6 weeks of administration to achieve beneficial effects, are
accompanied by unpleasant side effects, possess modest efficacy rates
(45-65%) and display significant (N50%) relapse rates (Dobson et al.,
2008; Samuels et al., 2011). New work indicates that low-doses
of the N-Methyl-D-aspartate (NMDA) receptor antagonist ketamine
produce rapid antidepressant effects in treatment-resistant depression
(Berman et al., 2000; Zarate et al., 2006), defined as being insensitive
to two classes of Food and Drug Administration (FDA)-approved
antidepressants and depression with suicidal ideation (Price et al.,
2009).
Numerous validity concerns of rodent-based depression models
have been raised including screening paradigms that a) were reverse-
engineered to screen clinically effective antidepressants, b) produce
significant false positives rates and c) fail to model the diverse clinical
features of depression including co-morbidity with anxiety disorders
(Berton et al., 2012; Kalueff et al., 2007; Nestler and Hyman, 2010;
Pryce and Seifritz, 2011). Furthermore, to our knowledge, no
antidepressant-screening model has been designed around what is,
perhaps, the greatest need and that is in identifying clinically effec-
tive compounds in treatment-resistant depressive disorders (Samuels
et al., 2011).
Using an endophenotypic mapping validation strategy (van der Stay,
2006), the chick anxiety-depression simulation (Sufka et al., 2006)
displays numerous homologies to the clinical features of depression.
This behavioral despair paradigm entails measurement of separation-
induced distress vocalizations (DVoc) in socially-raised 5–6 day old
chicks during a 1–2 hr test period. Non-isolated chicks vocalize little, if
any, during the test session. Isolated chicks display high rates of DVocs
for the first 3–5 min that decline over the next 20–30 min to about
50% of the initial rate and remain stable thereafter. The high rate of
DVoc during the initial period has been shown to model a panic-like
state as anti-panic compounds attenuate DVoc rates in this phase
(Feltenstein et al., 2004; Warnick et al., 2006) whereas the latter period,
like other behavioral despair models, simulates the depression-like
phase as anti-depressants attenuate the decline in DVoc rates (Sufka
et al., 2006; Warnick et al., 2009).
The model displays endophenotypes in a) etiological mediators
of stress resilience via environmental enrichment (Kim and Sufka,
2011), b) alterations in stress (i.e., corticosterone) and depression (i.e.,
interleukin 6 and BDNF) biomarkers (Loria et al., 2013; Sufka et al.,
Pharmacology, Biochemistry and Behavior 113 (2013) 63–67
⁎Corresponding author at: Peabody Building, University of Mississippi, Oxford, MS
38677, USA. Tel.: +1 662 915 7728; fax: +1 662 915 5398.
E-mail address: pysufka@olemiss.edu (K.J. Sufka).
0091-3057/$ –see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pbb.2013.10.013
Contents lists available at ScienceDirect
Pharmacology, Biochemistry and Behavior
journal homepage: www.elsevier.com/locate/pharmbiochembeh
2006; Warnick et al., 2009), c) cognitive biases (i.e., more pessimism
and less optimism) in approach/avoidant behaviors (Hymel and Sufka,
2012; Salmeto et al., 2011), and d) pharmacological sensitivity in that
it correctly screens FDA-approved pharmacotherapies (Warnick et al.,
2006, 2009) and several novel compounds targeting non-MA-ergic
systems passing Phase II and III clinical trials as well as avoids two
false positives from rodent screening models that failed clinical efficacy
trials (Sufka et al., 2009).
Much of the endophenotypic validation work in the chick anxiety-
depression model used a White Leghorn strain. Recent research com-
paring nine diverse genetic lines in the model identified two strains in
which one displayed stress vulnerability (Black Australorp) and the
second stress resilience (Production Red) as measured by onset of
behavioral despair (Hymel et al., 2013). This current study sought
to explore whether these two lines display differential sensitivities
to separate classes of FDA-approved antidepressant compounds by
screening the tricyclic antidepressant (TCA) imipramine, the selective
norepinephrine reuptake inhibitor (SNRI) maprotiline and the selective
serotonin reuptake inhibitor (SSRI) fluoxetine. We also included in
our efficacy screening the NMDA receptor antagonist ketamine noting
this compound is used off-label for treatment resistant depression
and depression with suicide ideation. The goal of this project was to
determine whether the stress vulnerable line displays similar homol-
ogy to antidepressants as patients diagnosed with treatment-resistant
depression.
2. Methods
2.1. Subjects
Cockerels (Production Red or Black Australorp, Ideal Poultry, Inc.
Cameron, TX, USA) were received 2 days post-hatch and group housed
in 34 × 57 × 40 cm cages at 12 chicks per cage. Food and water were
available ad libitum. Daily maintenance included replacement of tray
liners, re-filling food and replacing water. Lights were operated on a
12:12 light dark cycle. Supplemental heating sources provided housing
temperatures at 32 ± 1 °C.
2.2. Apparatus
A six-unit testing apparatus containing Plexiglas chambers
(25 × 25 × 22 cm) surrounded by sound attenuating media was used
to record separation-induced vocalizations. Each unit was illuminated
by a 25-W light bulb, and ventilated by an 8-cm-diameter rotary fan
(Model FP-108AX S1, Commonwealth Industrial Corp., Taipei, Taiwan).
Miniature video cameras (Model PC60XP, SuperCircuits, Inc., Liberty
Hill, Texas, USA) mounted outside the observation chambers at floor
level and routed through a multiplexor (Model PC47MC, SuperCircuits,
Inc.) provided televised display of chicks for observation. Distress
vocalizations (DVocs) were detected via microphones [Radio Shack
Omnidirectional Model 33-3013 (modifiedforACcurrent)]mountedat
the top of the Plexiglas chamber and routed to a computer equipped
with custom designed software for data collection (continuous acquisi-
tion with sample rates N10/sec).
2.3. Procedure
Separate hatches or cohorts were used for each strain and dose
response study. At 5–6 days post-hatch, chicks were removed from
their home cage in squads of six and placed into an opaque plastic
transport container. Body weight was determined for each chick for
dosing and identification of outliers (i.e., low body weight). Chicks
received a single IP injection of a drug probe (imipramine: 5, 10, 15
and 20 mg/kg; fluoxetine: 1, 5 and 10 mg/kg; maprotiline: 2.5, 5 and
10 mg/kg; ketamine: 5,10 and 15 mg/kg) or vehicle in a volume of
1 mL/kg. Doses selected were based on previous studies in our
anxiety-depression model (Sufka et al., 2006, 2009). Following a
30 min injection-to-test interval, chicks were placed in isolation into
the test apparatus for a 90min test session.
For the ketamine dose response studies, a group of non-isolated
vehicle-treated chicks (one for each strain) were included as a control
for the isolation manipulation. These non-isolated chicks were placed
along with two conspecifics from a separate cage into the observation
chamber that contained mirrors positioned along the side-walls. Non-
isolated chicks vocalize little if any throughout the test session but
were included to highlight the robust social separation stress effect on
DVocs. To reduce the number of research animals, this group was not
included in the remaining dose response studies as vehicle isolated
chicks served as the comparison for detecting antidepressant drug
effects. Chicks were returned to their home cage following tests. These
procedures were approved by the University of Mississippi's IACUC
(Protocol # 12–021).
2.4. Statistical analysis
Data were screened for outliers before data analyses. This included
chicks with body weights 15–20% below mean. Such animals appear
developmentally delayed in motor activity, color, and/or in response
to the isolation stressor. This may be due to low hatch weight leading
to competition for food/water access under group housing. Average
body weights were 49.9 g and 48.8 g for Production Reds and Black
Australorps, respectively and these were not statistically different
from each other. The number of chicks removed prior to data analyses
was 2.4%.
Data were analyzed using one- (i.e., drug dose) and two- (i.e.,
isolation test condition × test session length or strain × behavioral
despair onset) analyses of variance (ANOVAs). Behavioral despair was
calculated using the time point at which each chick's DVoc rate (i.e.,
counts/min) from its anxiety-like phase (first 3 min block) declined by
25%, 50%, 75% and 95% to the rate during its depression-like phase
(30–90 min; Hymel et al., 2013; Kim and Sufka, 2011; Loria et al.,
2013). To determine whether drug probes possessed antidepressant
effects, DVoc rates for depression-like phase (30–90 min test period)
were analyzed via 1-way ANOVAs followed by Fisher's LSD post-hoc
tests. A dose that produced a statistically significant increase in DVoc
rate (pb0.05) compared to vehicle treated chicks was considered
to possess antidepressant effects (i.e., attenuated behavioral despair in
the model).
3. Results
Results highlightingthe isolation stress effect and behavioral despair
in Production Reds and Black Australorps are summarized in Fig. 1
panels A and B, respectively. In non-isolated chicks, DVoc rates were
relatively low and remained stable throughout the test session. In
contrast, isolated chicks displayed a robust increase in DVoc rates at
the start of the test session that declined about 50% over the next
20–30 min and remained stable thereafter. A 2-way ANOVA revealed a
significant main effect for Stress, F(1,19) = 50.06, pb0.0001, a sig-
nificant main effect for Test Session F(29,551) = 3.82, pb0.0001 and a
significant Stress × Test Session interaction term, F(29,551) = 1.66,
p= 0.018. Simple effect analyses revealed a significant effect of Test
Session in the Isolated group, F(1,232) = 2.75, pb0.0001) but not in
the non-isolated group (p= n.s.). This pattern in DVoc rates illustrates
the two phases of the Anxiety-Depression model.
Like in Production Reds,DVoc rates in non-isolated Black Australorps
chicks were relatively low and remained stable throughout the test
session. Isolated chicks displayed a robust increase in DVoc rates at
the start of the test session that declined about 50% over the next
10–20 min and remained stable thereafter. A 2-way ANOVA revealed a
significant main effect for Stress, F(1,21) = 65.11, pb0.0001 and a
significant main effect for Test Session F(29,609) = 3.84, pb0.0001.
64 K.J. Sufka, S. W. White / Pharmacology, Biochemistry and Be havior 113 (2013) 63–67
The Stress × Test Session interaction term failed to reach statistical
significance (p=0.15). A 1-way repeated measures ANOVA on isolated
chicks revealed a significant effect of Test Session, F(1,290) = 2.64,
pb0.0001). As before, this pattern in DVoc rates illustrates the two
phases of the Anxiety-Depression model.
Behavioral despair onset thresholds between strains for the vehicle-
isolated groups from the dose response studies (pooled data) are
summarized in Fig. 2. Five cohorts (hatches)/strain were used for dose
response studies (one dose response/drug except two dose responses
for ketamine). Separate 1-way ANOVAs on DVoc rates in each phase
(Anxiety-like phase: 0–5 min, Depression-like phase 30–90 min) of
the model were conducted within each strain to determine cohort
differences in base rates in vocalizations. These analyses revealed that
1 cohort in each strain displayed significantly different base DVoc
rates from their respective cohorts. These 2 cohorts, which showed
patterns of behavioral despair, were removed before calculating be-
havioral despair onset thresholds. In general, Black Australorps entered
into behavioral despair at each threshold sooner than Production Reds.
Consistent with theseobservations, 2-wayANOVA revealed a significant
main effect for Strain F(1,84) = 6.59, pb0.05 and a significant main
effect for behavioral despair onset Threshold, F(3,252) = 77.15,
pb0.0001. The Strain × Threshold interaction term was not statistically
significant.
To illustrate differential sensitivities to antidepressants between
Production Reds and Black Australorps, dose response curves for each
drug probe are summarized in Fig. 3A–D. Imipramine possessed
antidepressant activity as indexed by a significant increase in DVoc
rate in the Production Reds at the 5 mg/kg dose. However, imipramine
failed to alter DVoc rates in the Black Australorps at any dose tested
(Fig. 3A). Fluoxetine failed to show antidepressant effects at any dose
tested in either strain (Fig. 3B). Maprotiline produced an antidepressant
effect at 2.5 and 5.0mg/kg in Productions Reds and at 2.5mg/kg in Black
Australorps (Fig. 3C). Ketamine failed to affect DVoc rates in Production
Reds but did show significant antidepressant activity at the 10 mg/kg
dose in Black Australorps (Fig. 3D). A follow-up study with ketamine
at lower doses failed to see antidepressant activity in either strain
noting the highest dose tested produced transient (5–10 min) ataxia
(data not shown).
4. Discussion
In both strains, non-isolated chicks displayed few, if any, DVocs
across the test session. Isolation from social companions produced an
initial high DVoc rate in the first few minutes that we have previously
shown to model a panic-like state (Warnick et al., 2006). In both
strains, DVoc rates then declined over the first quarter to third of the
test session to about one-half the initial rate and remained stable
thereafter. This decline in DVoc rates resembles that of other behavioral
despair paradigms (e.g., forced swim and tail suspension tests) and
characterizes the depression-like phase (i.e., 30–90 min period) of
the anxiety-depression model (Willner, 1991). To highlight stress
vulnerability between strains, Black Australorps displayed quicker
onset of behavioral despair than Production Reds. This finding is con-
sistent with two earlier studies in which comparative onset curves to
behavioral despair showed the Production Reds to be stress resilient
and the Black Australorps to be stress vulnerable (Loria et al., 2013;
Hymel et al., 2013).
0
25
50
75
100
125
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84 87 90
Mean DVoc Rate
Time (3 Minute Blocks)
Non-Isolated (PR)
Isolated (PR)
Non-Isolated (BA)
Isolated (BA)
Fig. 1. The effects of S. divinorum and salvinorin A on place preference. Values represent mean change in time (seconds) spent in S+ (drug-paired) chamber between baseline and
preference trials. Solid horizontal line reflects the mean preference score for the vehicle group and is provided for comparative purposes. Scores significantly above and below baseline
reflect CPP and CPA, respectively. *indicates a significant difference from the vehicle group. Sample sizes were 9–10.
0
2
4
6
8
10
12
14
16
18
20
25% 50% 75% 95%
Mean Latency (m)
Behavioral Despair Onset Curves
Production Reds Black Australorps
*
Fig. 2. Mean latencies (± SEM) to behavioral despair in Production Red and Black
Australorp lines. * indicates significantly shorter latencies to behavioral despair (ANOVA
main effect for strain, pb0.05). Sample sizes were n=46–48 from pooled cohorts (i.e.,
vehicle-isolated treated chicks from the individual drug probe studies).
65K.J. Sufka, S. W. White / Pharmacology, Biochemistry and Be havior 113 (2013) 63–67
Previous research (Lehr, 1989; Sufka et al., 2006; Warnick et al.,
2009) has shown antidepressants to attenuate behavioral despair in
the chick social separation stress model as indexed by an increase in
DVoc rates during the depression-like phase. A summary of the current
study in Production Reds and Black Australorps alongside that of
previously published screening studies of the same drug probes in a
White Leghorn strain (Sufka et al., 2006; Warnick et al.,2009)isdetailed
in Table 1. The stress-resilient Production Red line displayed sensitivity
to two classes of FDA-approved antidepressants but was insensitive to
fluoxetine and ketamine. In contrast, the Black Australorp line only
screened positive maprotiline and ketamine. Like rodent depression
models, the dose ranges were broad enough in the positive screens to
show an inverted U-shaped response function. This dose response pattern
evident across species adds an important validation step in the model.
It is somewhat surprising that the Production Red line was insen-
sitive to fluoxetine and ketamine as we expected all four compounds
to screen positive given earlier findings that these same drug probes
within the same dose ranges possessed antidepressant activity in a
White Leghorn strain from a different vendor. We hypothesize that
the antidepressant effects of imipramine and maprotiline in this line
involves activity at the norepinephrine transporter (NET). That the
Production Red strain failed to respond to fluoxetine and ketamine
suggests this may not be a useful pre-clinical screening beyond com-
pounds that target the norepinephrine transporter. For the broadest
screening of antidepressants with diverse mechanisms of action, the
White Leghorn line appears to be the most useful.
In contrast to the Production Reds and White Leghorns, the stress-
vulnerable Black Australorp line failed to show antidepressant sensitivity
to imipramine and fluoxetine at the broad range of doses tested. The
Black Australorp line did show antidepressant sensitivity to maprotiline
at a limited dose range. This pattern of drug effects meets the clinical
criteria of being treatment-resistant because of the insensitivity to
two classes of antidepressants. Interestingly, this stress-vulnerable,
treatment-resistant Black Australorp line shows sensitivity to ketamine.
This finding parallels the clinical picture in that treatment resistant
Fig. 3. Mean distress vocalization rate/m (± SEM) as a function of drug dose duringthe depression-like phase of themodel (30–90 m) in isolated 5–6 day ol d chicks from the Production
Red and Black Australorp lines. * indicates significant increase in distress vocalizations via Fisher’s LSD (pb0.05; i.e., attenuate behavioral despair). Samples sizes were n=9–12.
Table 1
Efficacy test outcomes.
Drug probe White Leghorns
a
Production Reds
(stress-resilient)
Black Australorps
(stress-vulnerable)
Imipramine + + -
Fluoxetine + −-
Maprotiline + + +
Ketamine + −+
+= antidepressant activity detected; −= no antidepressant activity observed at doses
tested.
a
From Warnick et al., 2009.
66 K.J. Sufka, S. W. White / Pharmacology, Biochemistry and Be havior 113 (2013) 63–67
depression responds well to ketamine after a single administration. That
the Black Australorp strain is a) stress-vulnerable, b) treatment-resistant
(fails two drug probes) and c) ketamine sensitive suggests that this line
may prove useful in pre-clinical screening of novel antidepressants for
use in treatment-resistant depression.
The underlying mechanisms that differentiate drug response be-
tween chick genetic lines are unknown at this time. Like rodent models,
we hypothesize that insensitivity to fluoxetine involves altered ex-
pression of the serotonin transporter protein (Carneiro et al., 2009).
Such strain comparison research may not only identify CNS markers
that differentiate drug sensitivity but also stress-vulnerability/resiliency
in these lines. For example, recent research points to the SLC6A15 gene
that affects amino acid transporters and, interestingly, confers stress
vulnerability in animal models (Kohli et al., 2011). Further, studies in
the Black Australorp line could lead to the identification of new targets
for treatment-resistant depression.
A body of evidence argues that depression reflects stunted neuro-
genesis in homeostatic networks that respond to stress (Duman and
Aghajanian, 2012; Eisch and Petrik, 2012). Interestingly, ketamine's
rapid clinical effects are thought mediated by potentiation of α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that
elevate BDNF via the mammalian target of rapamycin (mTOR) pathway.
BDNF acts on tyrosine kinase B (TrkB) receptors to produce neuro-
genesis, specifically Arc-mediated expansion and stabilization of spines
and expression of glutamate A1 receptors, in a neural homeostatic
control system that respond to stress events (Eisch and Petrik, 2012;
Santos et al., 2010).Ourmostrecentresearch(Loria et al., 2013)
quantifying hippocampal BDNF in these two chick lines ties nicely into
this neurogenesis hypothesis of depression. No differences in BDNF
levels were observed prior to stress exposure. The resilient Production
Red line showed stable BDNF levels throughout the isolation stress
period whereas the vulnerable Black Australorp line showed elevated
BDNF that peaked at 90 minutes into the test period and declined
thereafter. We interpreted these findings to suggest that stress vul-
nerability reflects a loss of homeostatic control mechanisms involved
in synaptogenesis. Collectively, these earlier data and thatof the current
study suggest this line may perform well as an early preclinical
screening of novel glutamate targets for treatment resistant depression
(Lapidus et al., 2013).
5. Conclusions
Animal models have been useful in understanding the underlying
neurobiological mechanisms of depression. There exist a number of
modified rodent lines that show stress vulnerability and include, for
example, the inbred rat Wistar–Kyoto line (Lahmame and Armario,
1996) and the mouse val66met knock-in model of the human variant
loss-of-function BDNF gene (Gatt et al., 2009). The Wistar–Kyoto line
has also shown sensitivity to ketamine (Tizabi et al., 2012). Several
attempts to model treatment resistance in depression models have
also been reported (see Samuels et al., 2011 for review) but none
have yet demonstrated lack of antidepressant effects beyond one class
of FDA approved pharmacotherapies (Jayatissa et al., 2006; Samuels
et al., 2011). However, to our knowledge, no antidepressant screening
paradigm has shown to incorporate three important animal model
features in one assay. These are using a line that is stress-vulnerable,
treatment-resistant and ketamine-sensitive. If additional research
supports this claim, the Black Australorp line in the chick anxiety-
depression model would become an important screening tool for
identifying promising treatment strategies for individuals with major
depression who fail to respond to current therapies.
Competing financial interests
The authors declare no competing financial interests.
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