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Neuroscience Letters 398 (2006) 328–332
The mGlu2/3 receptor agonist LY354740 suppresses immobilization
stress-induced increase in rat prefrontal
cortical BDNF mRNA expression
Younglim Lee 1, Ronald S. Duman, Gerard J. Marek ∗
Yale School of Medicine, Department of Psychiatry, Ribicoff Research Facilities of the Connecticut Mental Health Center,
34 Park Street, New Haven, CT 06508, USA
Received 17 October 2005; received in revised form 4 January 2006; accepted 12 January 2006
Abstract
Both a 5-hydroxytryptamine2A (5-HT2A) agonist and immobilization stress previously have been shown to differentially alter brain-derived
neurotrophic factor (BDNF) mRNA expression in the neocortex and hippocampus. Both 5-HT2A receptor activation and immobilization stress also
increase glutamate release in the rat prefrontal cortex. Given that the metabotropic glutamate2/3 receptor (mGluR2/3) agonist (1S,2S,5R,6S)-2-
aminobicyclo[3.1.0] hexane-2,6-dicarboxylate monohydrate (LY354740) suppressed electrophysiological, behavioral and biochemical effects of
5-HT2A receptor activation in the medial prefrontal cortex (mPFC), we assessed the efficacy of the mGluR2/3 agonist in suppressing the stress-
induced increase in BDNF mRNA expression. LY35740 (10 mg/kg, i.p.) attenuated the immobilization stress-induced increase in BDNF mRNA
expression in the rat mPFC. This result is consistent with the hypothesis that mGlu2/3 agonists may be an efficacious treatment for stress-induced
neuropsychiatric syndromes.
© 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Brain-derived neurotrophic factor; Immobilization stress; Restraint stress; Medial prefrontal cortex; Metabotropic glutamate receptors
Stress is known to be a precipitant to major neuropsychiatric ill-
ness including major depression, anxiety disorders, schizophre-
nia, and substance abuse disorders. Furthermore, genetic factors
may influence individuals to select “high risk” versus “low
risk” environments with respect to environmental stress [9]. The
most serious clinical sequelae to stress in vulnerable individuals,
beyond playing an etiological role in initiating a chronic remit-
ting or unremitting illness, is suicide. Thus, pharmacological
treatments which can mitigate the effects of stress would play a
major role in diminishing clinical morbidity and mortality.
Traditional treatments for major neuropsychiatric syn-
dromes generally have been based on the modulation of
monoamines serotonin, norepinephrine and dopamine. Going
beyond monoamine transporter blockade, subtle modulation of
∗Corresponding author. Present address: Eli Lilly and Company, Lilly Cor-
porate Center, Mail Drop 0510, Indianapolis, IN 46285, USA.
Tel.: +1 317 651 4776; fax: +1 317 276 7600.
E-mail address: gerard j marek@lilly.com (G.J. Marek).
1Present address: Department of Psychiatry, Indiana University School of
Medicine, Indianapolis, IN 46202, USA.
glutamate in the limbic systems by activating metabotropic
glutamate2/3 (mGlu2/3) receptors is now possible [25]. The
mGlu2 receptor functions as an autoreceptor controlling glu-
tamate release from presynaptic glutamatergic terminals in
the limbic forebrain. A wealth of preclinical evidence and
initial studies in humans suggest that the mGlu2/3 recep-
tor agonist (1S,2S,5R,6S)-2-aminobicyclo[3.1.0] hexane-2,6-
dicarboxylate monohydrate (LY354740) is a drug representing a
promising new approach for the treatment of anxiety and stress-
related disorders [21,24].
Since both 5-HT2A receptor activation and immobilization
stress increase glutamate release [1,19,22] and brain-derived
neurotrophic factor (BDNF) mRNA expression [7,20] in the rat
medial prefrontal cortex (mPFC), and BDNF mRNA is regulated
in an activity-dependent manner, we sought to determine the
effects of the mGlu2/3 receptor agonist LY354740 and immo-
bilization stress on BDNF mRNA expression in the rat mPFC.
Given that LY354740 was without a significant effect on BDNF
mRNA expression in the mPFC from a previous experiment [8],
the a priori expectations were that (1) the restraint-vehicle group
would have higher BDNF mRNA expression in the mPFC than
0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.neulet.2006.01.021
Y. Lee et al. / Neuroscience Letters 398 (2006) 328–332 329
Fig. 1. Effects of stress and the mGlu2/3 receptor agonist LY354740 on BDNF mRNA expression. LY354740 (10mg/kg, i.p.) resulted in a slight, non-significant
decrease in BDNF mRNA expression in the prelimbic region of the mPFC (bottom left) from a rat remaining in its home cage. A 2-h period of immobilization stress
increased BDNF mRNA expression (top right). LY354740 blocked the effect of stress-induced increase of BDNF mRNA expression in the mPFC (bottom right). An
arrow points to the prelimbic region (Cg3) of the mPFC in the brain section of a home cage control/vehicle-treated rat (upper left).
the home cage/vehicle group, and (2) the stress/LY354740 group
would have lower BDNF mRNA expression in the mPFC than
the stress/vehicle treated group.
Male Sprague–Dawley rats (200–250 g, Harlan, Indianapo-
lis, IN, USA) were group housed and maintained on a 12-h
light–dark cycle (lights on at 07:00 h, lights off at 19:00 h) with
access to food and water ad libitum. The animals were treated
in accordance with the guidelines of the National Institutes of
Health Guide for the Care and Use of Laboratory Animals, and
were approved by the Yale University Animal Care and Use
Committee.
All experiments were begun and completed between 10:00
and 14:00 h. Two experiments were conducted. The first exper-
iment compared the effects of LY354740 (10 mg/kg, i.p., neu-
tralized to a pH ∼7.4) or vehicle (0.9% saline neutralized to
pH ∼7.4) in rats remaining in their home cages or rats exposed
to 2 h of immobilization stress in plastic cones (n=7, cage con-
trol/vehicle; n= 7, cage control/LY354740; n= 6, stress/vehicle;
n= 6, stress/LY354740). The second experiment compared two
lower LY354740 doses (1 and 3 mg/kg, i.p.) or vehicle in rats
exposed to a 2-h period of immobilization stress to rats treated
with vehicle in their home cages (n= 4 for all groups). All ani-
mals were injected with either LY354740 (graciously supplied
by Dr. James A. Monn, Eli Lilly and Company, Indianapolis, IN)
or vehicle 15 min prior to being placed in plastic cones with the
open end securely closed. All immobilized rats were placed in
plexiglass chamber with animal bedding on the bottom; brought
to a quiet room outside of the animal colony; and immediately
placed in a plastic cone. Two hours after being placed in the
plastic containers, the rats were decapitated. The 2 h latency pre-
viously had been found to allow for maximal changes of BDNF
mRNA expression in the neocortex following administration of
a 5-HT2A receptor agonist [29]. The brains were removed and
frozen on dry ice, and stored at −80 ◦C.
In situ hybridization for BDNF mRNA was carried out as
described previously [23]. In brief, coronal sections of 14 m
thickness were cut on a cryostat and thaw-mounted onto RNase
free Probe-on (+) slides (Fisher). Tissue sections were fixed
in 4% formaldehyde, acetylated and dried. Levels of BDNF
mRNA were examined by probing with 35S-labeled antisense
riboprobes to the coding exon (V) that does not distinguish
among different BDNF transcripts. Rat BDNF cDNA clones
were obtained from Regeneron (Tarrytown, NY). The sections
were hybridized with 2 ×106cpm/section for 18 h at 55 ◦Cin
hybridization buffer (50% formamide, 0.6 M NaCl, 10mM Tris,
1×Denhardt’s solution, 2mM EDTA, 10 mM DTT, 10% dex-
tran sulfate, 50 g/ml salmon sperm DNA, 250 mg/ml tRNA).
After hybridization, section were washed in 2 ×SSC (0.15 M
NaCl, 0.015 M sodium citrate, pH 7.0) at 25◦C and then treated
with 20 g/ml Rnase A for 30 min in RNase buffer (0.5 M NaCl,
10 mM Tris, 1 mM EDTA). The sections were then washed for
10 min in 2×SSC at room temperature and twice for 20min on
0.2 ×SSC at 55 ◦C. The sections were then rinsed in 0.2 ×SSC,
dried and exposed to BioMax Film (Kodak, Rochester, NY) for
5 days. Previous work in this laboratory using the same proce-
dures did not yield any significant hybridization with 35S-labeled
sense BDNF riboprobes, indicating that the signal observed with
the antisense riboprobe is specific [29].
Levels of BDNF mRNA were analyzed using the Macintosh-
based National Institutes of Health Image Analyzer program,
version 1.57 (Bethesda, Maryland). A portion of the prelimbic
area of the medial prefrontal cortex (within an area 2.7–4.2 mm
anterior to bregma) was analyzed for in situ hybridization. The
region was analyzed by outlining the area of interest; an equiv-
alent area was outlined for each sample. For each animal, the
optical density measurements from both sides of four individ-
ual sections were analyzed, yielding eight measurements, from
which the mean was calculated. Both sides of the tissue section
were used since laterality differences were not observed previ-
ously for the effects of 5-HT2receptor agonists or the mGlu2/3
receptor agonist LY354740 on BDNF mRNA expression in the
mPFC [7]. To correct for nonlinearity, 14C step standards were
330 Y. Lee et al. / Neuroscience Letters 398 (2006) 328–332
Fig. 2. Summary effects of stress and the mGlu2/3 receptor agonist LY354740
(10 mg/kg) on BDNF mRNA expression in the mPFC. A 2-h period of immobi-
lization stress significantly increased BDNF mRNA expression while LY354740
significantly attenuated this effect of stress. Results are normalized to the cage
control/vehicle condition and are expressed as the mean ±S.E.M. (n= 7 for
both cage control groups; n= 6 for both immobilization stress groups). *p< 0.05
compared to the home cage/vehicle control condition. #p< 0.05 compared to the
combined effects of immobilization stress and vehicle.
used for calibration. The results were then subjected to statistical
analysis, using between-subjects analysis of variance (ANOVA)
followed by the post hoc Newman–Keuls test.
A 2 h immobilization stress treatment increased (F(1,22) =
11.74, p< 0.01), while the mGlu2/3 receptor agonist LY354740
(10 mg/kg) attenuated the stress-induced increase in BDNF
mRNA expression in the rat mPFC (Figs. 1 and 2). Overall,
a significant decrease in BDNF mRNA was observed for the
drug condition (F(1,22) = 5.28, p< 0.05). The interaction term
was not significant (F(1,22) = 0.92). Planned post hoc testing,
based on previous results, with the Newman–Keuls test found
that the stress/vehicle condition was significantly greater (140%
of control, p< 0.05) than the cage control/vehicle condition.
Furthermore, the stress/LY354740 condition was significantly
lower than the stress/vehicle condition (p< 0.05). In the cage
control/LY354740 group there was a tendency for reduced lev-
els of BDNF mRNA expression in the mPFC, but congruent with
past results [7], this effect was not significant. Unplanned anec-
dotal observations revealed that 6 of the 7stress/vehicle-treated
rats appeared to have greater sympathetic arousal (greater fecal
boli, urination and discharge from the mucous membranes) than
5 of the 6 stress/LY354740-treated rats.
In a second experiment examining the effects of two lower
doses of LY354740 (1 and 3 mg/kg, i.p.), a 2 h immobiliza-
tion stress increased BDNF mRNA expression in the rat mPFC
as revealed by a significant treatment effect (F(3,12) = 5.36,
p< 0.05). The stress/vehicle, stress/LY354740 (1 mg/kg), and
the stress/LY354740 (3 mg/kg) groups all had a signifi-
cantly greater density of BDNF mRNA expression (164±14,
154 ±16, and 150 ±12% of control, mean ±S.E.M., respec-
tively) than the cage control/vehicle group (100±1%). Neither
of the stress/LY354740 conditions were significantly different
than the stress/vehicle group.
The first main finding of the present study is that acute immo-
bilization stress induces an increase in prefrontal cortical BDNF
mRNA expression. This is the first report of an increase in BDNF
mRNA expression in the prefrontal cortex immediately follow-
ing a 2 h exposure to immobilization stress. However, the present
findings are consistent with an earlier report of increased BDNF
mRNA in the rat PFC (Cg1, Cg3, and infralimbic subregions)
following a 2 h exposure to restraint stress and an additional 1-h
period prior to sacrifice [20]. Thus, the present protocol differed
from that of Molteni et al. by the termination of the experiment
2 h, rather than 3 h following the beginning of a 2 h restraint
stress exposure.
Immobilization stress previously was found to down-regulate
BDNF mRNA expression in the hippocampus [27,29,30].
The differential brain region effect of immobilization stress
on BDNF mRNA is interesting in light of opposing direc-
tional effects of the 5-HT2receptor agonist and phenethyl-
amine hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-amino-
propane (DOI) on BDNF mRNA expression [29]. Namely,
both immobilization stress and DOI increase and decrease
BDNF mRNA expression in the neocortex/prefrontal cortex
and hippocampus, respectively. This similarity between the
effects of immobilization stress and DOI is important given
that the effects of both manipulations in the hippocampus (CA3
and the dentate gyrus) depend, at least in part, upon 5-HT2A
receptor activation [29,30]. Concordant with previous evidence
for stress-induced increases in serotonin release and turnover
and potentially increased 5-HT2A receptor mediated responses,
the combined administration of both the non-selective MAO
inhibitor tranylcypromine plus the serotonin precurser trypto-
phan increased BDNF mRNA expression in the prefrontal cortex
[31].
The second major finding was that the mGlu2/3 receptor ago-
nist LY354740 suppressed the immobilization stress-induced
increase in BDNF mRNA expression in the mPFC. Further
work is required to examine whether the alterations by stress
and mGlu2/3 receptor agonists on BDNF mRNA are reflected
in changes at the protein level. However, the primary reason
for investigating BDNF mRNA expression in this study were
some similarities to immediate early gene expression observed
for BDNF mRNA following a number of pharmacological or
environmental perturbations. Thus, attenuation by the mGlu2/3
receptor agonist on the stress-induced change in neurotrophin
mRNA is consistent with preclinical evidence that mGlu2/3
receptor agonists suppress the electrophysiological, biochemical
and behavioral activating effects of 5-HT2A receptor agonism in
the prefrontal cortex [8,10,16,32] via an autoreceptor function
on glutamatergic terminals [25]. Evidence suggests that a major-
ity of the cell bodies of these glutamatergic terminals appear to
be from the thalamus [11,12,15,26].
Recent work suggests that the prelimbic region of the mPFC
plays a critical role in modulating the effects of stress on the dor-
sal raphe with respect to evaluating the stressor as uncontrollable
versus controllable stress [2]. Acute inescapable stress has also
been found to increase c-fos and BDNF mRNA expression in the
mPFC of male rats [3]. Evidence for increased serotonergic tone
in the prefrontal cortex during immobilization stress [4–6,17]
Y. Lee et al. / Neuroscience Letters 398 (2006) 328–332 331
and potentially increased 5-HT2A receptor activation in suicide
victims [4–6,13,14,17] would be consistent with the hypothe-
sis that an increased serotonergic tone in the prefrontal cortex
(leading to 5-HT2A receptor activation), in part, may underly the
interaction of LY354740 and stress on prefrontal cortical BDNF
mRNA expression. This suppressant effect of LY354740 also
would be consistent with the known activity-dependent modu-
lation of BDNF mRNA expression in the mPFC/neocortex.
The suppressant effects of the mGlu2/3 receptor agonist
LY354740 on immobilization stress-induced increases in pre-
frontal cortical BDNF mRNA expression would seem consistent
with other preclinical and clinical data suggesting utility for
mGlu2/3 receptor agonists in stress/anxiety disorders [24].For
example, LY354740 appears to have efficacy in both rodent
and human models of conditioned fear. Similarly, LY354740
has demonstrated efficacy in experimentally induced panic-like
effects in both rodents and human patients with panic disor-
der. It should be noted that LY354740 doses of 10 mg/kg or
more have been required to block the stress-induced increase in
extracellular norepinephrine or dopamine in the rat mPFC [28].
Finally, mGlu2/3 receptor agonists appear to represent a truly
novel therapeutic given evidence for efficacy in the treatment
of generalized anxiety disorder and subjective reports of better
toleration of the mGlu receptor agonist compared to the ben-
zodiazepine lorazepam from double-blind, placebo-controlled
clinical research trials [18,24]. The effects of mGlu2/3 recep-
tor agonists in a variety of other stress-induced neuropsychiatric
conditions remains to be characterized.
Acknowledgments
Supported by PHS Grants K08 MH01551 and R01 MH62186
(GJM), R01 MH45481 (R.S.D.), P01 MH25642 (R.S.D.), a
NARSAD Young Investigator Award (G.J.M.), a VA National
Center Grant for PTSD (R.S.D.) and the State of Connecticut.
We thank Allyson Abo for technical assistance. A portion of this
work was previously presented at the 2002 Society for Neuro-
science Meeting.
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