Administration of the phosphodiesterase type 4 inhibitor rolipram
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Brief Communication
Administration of the phosphodiesterase type 4
inhibitor rolipram into the amygdala at a specific
time interval after learning increases recognition
memory persistence
Aline Werenicz,1,2,3 Raissa R. Christoff,1,2,3 Martina Blank,1,2,3 Paulo F.C. Jobim,1,2,3
Thiago R. Pedroso,1,2,3 Gustavo K. Reolon,1,2,3 Nadja Schro¨der,3,4 and
Rafael Roesler1,2,3,5
Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences,
Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS, Brazil; 2
Cancer Research Laboratory, University Hospital Research
Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, Brazil; 3
National Institute for Translational
Medicine (INCT-TM), 90035-003 Porto Alegre, Brazil; 4
Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences,
Pontifical Catholic University, 90619-900 Porto Alegre, RS, Brazil
Here we show that administration of the phosphodiesterase type 4 (PDE4) inhibitor rolipram into the basolateral complex
of the amygdala (BLA) at a specific time interval after training enhances memory consolidation and induces memory persistence for novel object recognition (NOR) in rats. Intra-BLA infusion of rolipram immediately, 1.5 h, or 6 h after training
had no effect on retention tested at 1, 7, and 14 d later. However, rolipram infused 3 h post-training promoted memory
persistence for up to at least 14 d. The findings suggest that PDE4 inhibition in the BLA can enhance long-term memory
formation when induced specifically 3 h after learning.
The basolateral complex of the amygdala (BLA) is involved in enhancing the consolidation of memories for emotionally arousing
events (for review, see McGaugh 2004). Recent evidence suggests
that the BLA may also modulate memories for low-arousing tasks,
including novel object recognition (NOR), a task based on the natural preference toward novel objects displayed by rats and mice
(Roozendaal et al. 2006, 2008; Okuda et al. 2004).
Phosphodiesterase type 4 (PDE4), an enzyme that catalyzes
hydrolysis of cAMP, plays a critical role in regulating the activity
of protein kinase A (PKA). The cAMP/PKA/cAMP regulatory
element-binding protein (CREB) signaling pathway in the BLA is
involved in regulating memory for fear-motivated tasks (Schafe
and LeDoux 2000; Roozendaal et al. 2002). The specific PDE4
inhibitor rolipram enhances synaptic plasticity and memory formation in rodents, particularly when animals are given a mild
training, and also ameliorates memory deficits in models of cognitive impairment (Barad et al. 1998; Bourtchouladze et al. 2003;
Rutten et al. 2006; for review, see Tully et al. 2003). However, to
our knowledge previous studies have not verified whether PDE4 inhibitors affect memory when given into the amygdala. Moreover,
although systemic administration of rolipram has been shown to
rescue deficits in rat and mouse models of memory dysfunction
(Bourtchouladze et al. 2003; Rutten et al. 2006; de Lima et al.
2008), the possible effects of amygdalar PDE4 inhibition on NOR
memory have not been investigated. In this study, we examined
the effects of administration of rolipram into the BLA at different
time intervals after training on long-term retention of NOR memory in rats.
Male adult Wistar rats (age 3–4 mo; weight 270–330 g) were
obtained from our institutional breeding colony (CREAL-UFRGS).
The animals were housed five to a plastic cage with sawdust bedding and were maintained on a 12-h light:12-h dark cycle (lights
on at 7 a.m.) with room temperature of 22+18C. Food and water
were available ad libitum. Behavioral procedures were conducted
between 9 a.m. and 7 p.m. All experimental procedures were performed in accordance with the NIH Guide for the Care and Use of
Laboratory Animals (NIH publication number 80-23, revised
1996) and approved by the institutional animal care committee
under protocol number 10–0552.
Animals were bilaterally implanted under ketamine (75 mg/
kg) and xylazine (25 mg/kg) with a 14.0-mm, 22-gauge guide cannula aimed 1.0 mm above the BLA (Roesler et al. 2003, 2004b).
Stereotaxic coordinates were according to the atlas of Paxinos
and Watson (2007): A 2.8 mm, L+4.8 mm, V 7.5 mm. Rats given
at least 5 d to recover before the experimental procedures.
NOR training and testing was conducted in a 40-cm × 50-cm
open field surrounded by 50-cm-high walls made of plywood with
a frontal glass wall, placed in a dimly illuminated room. The floor
was covered with sawdust. The stimulus objects used in training
and tests presented distinctive colors and shapes and were made
of metal, glass, or plastic. In pilot experiments, all objects were
behaviorally irrelevant and equally distinguished for the rats.
Between trials, the objects were washed with a 70% ethanol solution. Exploration was defined as sniffing or touching the object
with the nose and/or forepaws. Sitting on the object was not considered exploration. Training and tests procedures followed the
general methods described in previous reports (Roesler et al.
2004a; de Lima et al. 2008; Reolon et al. 2011). Before training,
the animals were habituated to the experimental arena by allowing
them to freely explore it for 2 min in the empty arena. Twenty-four
Corresponding author
E-mail [email protected]
Article is online at http://www.learnmem.org/cgi/doi/10.1101/lm.026997.112.
19:495 –498 # 2012 Cold Spring Harbor Laboratory Press
ISSN 1549-5485/12; www.learnmem.org
495 Learning & Memory
Downloaded from learnmem.cshlp.org on November 8, 2012 – Published by Cold Spring Harbor Laboratory Press
hours after habituation, training was carried out by placing the rats in the open
field containing two identical objects (objects A1 and A2) and leaving them to free
explore for 5 min. The objects were positioned in two adjacent corners, 9 cm
from the walls. The rats were trained to a
criterion of 30 sec of total time exploring
both objects. Five rats were excluded from
the experiment because they did not accumulate 30 sec of object exploration
during the 5-min training. On retention
test trials given 1, 7, and 14 d after training, each rat was placed in the open field
for 5 min and left to freely explore. One
of the objects (A) was exchanged for a
novel object (B, C, or D). The new object
was placed in the same location of objects
as stimuli during the training trial. To reduce potential bias due to the preference
of the animal for a specific location or object, all combinations
and positions of objects were used in a balanced manner. Object
exploration was measured by one experimenter blind to group
treatment assignments. To measure retention, a discrimination
index (DI) was calculated [DI ¼ (tnovel – tfamiliar)/(tnovel + tfamiliar ×
100)] (Roozendaal et al. 2006, 2008).
Immediately, 1.5 h, 3 h, or 6 h after training, a 30-gauge infusion cannula was fitted into the guide cannula. The tip of the infusion needle protruded 1.0 mm beyond the guide cannula and
was aimed at the BLA. The animals received a bilateral 0.5-mL infusion of vehicle (20% dimethylsulfoxide [DMSO] in saline) or
rolipram (7.5 mg/side dissolved in vehicle; Sigma-Aldrich) via
the infusion cannula. The dose of rolipram was chosen on the
basis of previous pilot experiments performed in our laboratory.
Drug or vehicle was infused over a 30-sec period. All behavioral
sessions and drug infusions were performed during the light phase
of the light/dark cycle.
Twenty-four hours after the 14-d behavioral testing, a 0.5-mL
infusion of a 4% methylene blue solution was given into the BLA.
Rats were killed by decapitation 15 min later for post-mortem verification of infusion placements based on the dye diffusion. The
brains were removed and stored in 10% formalin for at least
72 h. The extension of the methylene blue dye was taken as indicative of diffusion of the drugs previously given to each rat (Roesler
et al. 2003, 2004b). Rats with incorrect infusion placements were
excluded from the analysis.
All data are expressed as the mean+SEM. Total exploration
time of both objects during NOR training and retention test trials
was compared using one-sample t-tests. The normality distribution was assessed using Shapiro-Wilk Statistics. A generalized linear model repeated-measures analysis (generalized estimating
equations [GEE]) was used for comparisons between all variables
and experiments. In all cases, if statistically significant interaction
was found, additional pairwise comparisons were made using the
Bonferroni post-hoc test. Normality distribution and identity as a
link function was always used. In all cases, the significance of the
effects was determined by Wald x2 statistics; P , 0.05 was considered to indicate statistical significance.
Table 1 summarizes the mean total time exploring both objects during NOR training and retention test trials. No significant
differences were found between groups. Infusion of rolipram immediately after training did not significantly affect NOR retention
measured 1, 7, or 14 d later (Fig. 1A), in spite of the apparent enhancement observed at 1 and 7 d. There were no differences between groups in training or any of the retention test trials. Both
groups showed a significantly higher discrimination index in
the 24-h test trial compared to training (Wald x2
(3) ¼ 130.886,
P’s , 0.001) but not in tests carried out at 7 and 14 d. The results
indicate that PDE4 inhibition in the BLA shortly after training
does not significantly affect NOR memory retention.
Intra-BLA rolipram infused 1.5 h after training did not affect
NOR retention (Fig. 1B). There were no differences between
groups in training or any of the retention test trials. Both groups
showed a significantly higher discrimination index in the 24-h
test trial compared to training (Wald x2
(3) ¼ 111.294, P’s ,
0.001) but not in tests carried out at 7 and 14 d. The results suggest
that infusions of a PDE4 inhibitor into the BLA 1.5 h after training
does not affect consolidation of NOR memory.
When given 3 h after training, rolipram enhanced NOR retention at all three retention test trials (Fig. 1C). The analysis revealed significant effects of treatment (Wald x2
(1) ¼ 24.479, P ,
0.001), trial day (Wald x2
(3) ¼ 76.686, P , 0.001), and interaction
treatment versus trial day (Wald x2
(3) ¼ 10.932, P ¼ 0.012). There
were significant differences between rats treated with vehicle and
rolipram in the retention test trials carried out 1, 7, and 14 d after
training (P , 0.035; P , 0.001; P , 0.025) but not in the training
trial. Comparisons between training and test trials in each group
showed that rats given vehicle demonstrate significant memory
retention 1 d (P ¼ 0.001) but not 7 or 14 d after training (P’s ¼
0.286 and 1.0, respectively). In contrast, rats infused with rolipram showed significantly higher discrimination indexes in all retention test trials (all P’s ≤ 0.001). The results indicate that
intra-BLA rolipram at 3 h post-training enhances consolidation
of NOR memory and, unexpectedly, promotes its persistence up
to at least 14 d after training.
Rolipram administered 6 h after training had no effect on
NOR retention. (Fig. 1D). There were no differences between
groups in training or any of the retention test trials. Both groups
showed a significantly higher discrimination index in the 24-h
test trial compared to training (Wald x2
(3) ¼ 35.145, P , 0.01),
and rats treated with vehicle showed a higher discrimination index also in the 7-d test (P , 0.05), but there was no difference between training and the 14-d test in any of the groups. The results
suggest that inhibition of amygdalar PDE4 6 h after training does
not significantly alter NOR memory.
Figure 2 shows a schematic drawing of the extent of the dye
spread within the BLA of rats in which infusion placements were
considered correct. Eleven rats were excluded because of incorrect
infusion placements.
Because (1) all animals were trained to the same criterion of
total object exploration, (2) no differences between groups in total
exploration were observed in any of the trials, and (3) drug
Table 1. Total time exploring both objects during NOR training and retention test trials in
rats given infusions of vehicle or rolipram into the BLA
Mean +SEM total time(s) exploring both objects
Group n Training 1-d test 7-d test 14-d test
Immediately post-training infusions
Vehicle 8 42.19+3.63 45.66+4.65 41.49+3.19 28.60+2.34
Rolipram 9 38.21+2.72 46.76+3.94 31.36+3.20 27.75+1.74
1.5 h post-training infusions
Vehicle 10 40.96+2.35 37.56+2.71 36.86+2.14 41.29+4.57
Rolipram 10 41.31+2.26 35.94+1.45 29.84+1.95 33.07+2.36
3-h post-training infusions
Vehicle 11 41.40+1.87 38.44+3.18 45.04+3.04 33.22+3.00
Rolipram 12 40.05+1.58 49.53+3.84 49.69+3.85 38.94+4.31
6-h post-training infusions
Vehicle 9 50.39+3.22 45.42+4.13 41.28+6.45 40.30+4.02
Rolipram 9 51.84+2.66 49.02+5.87 42.85+4.25 41.18+4.20
∗) P , 0.05 compared to the previous trial within the same group.
Amygdalar PDE4 and recognition memory persistence
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infusions were given after training, the differences between rats
treated with vehicle and rolipram observed are unlikely to be related to drug-induced alterations in acquisition, locomotion, motivation, sensorial function, or anxiety. Moreover, the possibility
that rolipram infusions induced long-term effects that affected
memory retrieval or nonspecific behavioral parameters during
retention test trials can be ruled out because rolipram given at
all post-training intervals except 3 h had no effect on test
performance.
The main finding of the present study was that rolipram given into the BLA 3 h after training, but not at other post-training
intervals, induced memory enhancement that persisted for at
least 14 d. The results indicate for the first time that inhibition
of PDE4 in the BLA at a specific later time point after learning
can induce a persistent enhancement of NOR memory.
Previous evidence has indicated a role for cAMP/PKA in the
BLA in memory formation. Thus, intra-BLA infusion of a PKA inhibitor impairs fear conditioning (Schafe and LeDoux 2000) and
blocks glucocorticoid-induced enhancement of fear memory
(Roozendaal et al. 2002). Conversely, administration of a PKA activator into the BLA enhances memory for rewarding conditioning
(Jentsch et al. 2002). A late phase (around 3 h after induction) of
long-term potentiation (LTP) in the amygdala requires PKA as
well as protein synthesis and mitogen-activated protein kinase
(MAPK) and is regulated by agonists of ß-noradrenergic receptors
(which act upstream of cAMP/PKA signaling) (Huang et al.
2000). Recent evidence suggests that PDE4 in the BLA interacts
with ß-arrestin to negatively influence PKA activity and formation
of memory for fear conditioning (Li et al. 2009). In studies using
the NOR task, post-training pharmacological stimulation of noradrenergic receptors in the BLA enhanced 1-d retention of NOR
(Roozendaal et al. 2008), and systemic injection of adrenaline immediately after training produced persistence of NOR memory at
least up to 4 d (Dornelles et al. 2007). However, previous studies
have not directly examined the role of PDE4 or other intracellular
components of the cAMP/PKA/CREB pathway in the BLA in NOR
memory. The finding that rolipram had an effect when given specifically 3 h after training is consistent with previous evidence
that rolipram injected systemically at 3 h, but not at 1 or 6 h, after
training enhanced the consolidation of NORmemory (Rutten et al.
2007). Our results suggest that stimulation of cAMP/PKA signaling
in the BLA can significantly enhance memory formation at a time
point in which PKA activity is required to promote enduring LTP in
the amygdala and support the view that the BLA regulates the consolidation of memories for tasks involving low-arousing stimuli.
Although many aspects of the molecular basis of memory
formation have been uncovered, much less is known about the
mechanisms underlying long-term memory persistence, or maintenance, one of the main attributes of long-term memories (Dudai
2002; Bekinschtein et al. 2007). Evidence indicates that persistence of memory for a fear-motivated task can be selectively produced by administration, at a late interval (12 h) after training, of
brain-derived neurotrophic factor (BDNF) into the hippocampus
and disrupted by hippocampal protein synthesis inhibition at
the same time point (Bekinschtein et al. 2007, 2008). Since treatment with rolipram can increase BDNF levels in the rat brain
(Nibuya et al. 1996; DeMarch et al. 2008), and the late phase of
rolipram-induced LTP is dependent on BDNF (Navakkode and
Korte 2012), an increase in amygdalar BDNF levels emerges as a
candidate mechanism involved in mediating memory persistence
induced by intra-BLA rolipram. Importantly, increases in amygdalar BDNF levels might be involved in mediating long-term
memory persistence (Ou et al. 2010). Moreover, since pharmacological stimulation of the BLA results in increased expression
of genes related to memory formation in other brain regions
such as the hippocampus (McIntyre et al. 2005), it is also possible
Training 1 day 7 days 14 days
Discrimination index (%)
Vehicle
Rolipram
Figure 1. Recognition memory in rats infused with rolipram into the BLA at different time intervals after training. Rats were given NOR training and
infused with vehicle or rolipram (7.5 mg/side) immediately (A), 1.5 h (B), 3 h (C), or 6 h (D) after training. Retention test trials were carried out 1, 7,
and 14 d later. Data are expressed as mean+SEM discrimination indexes; n ¼ 8 –12 animals per group. (∗) P , 0.05; (∗∗) P , 0.01 compared to
control rats in the same trial; (#
) P , 0.05; (##) P , 0.01 compared to the training trial within the same group.
Amygdalar PDE4 and recognition memory persistence
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that intra-BLA rolipram leads to enhanced BDNF levels in other
areas, which might be involved in mediating the enhanced NOR
memory observed in the present study. Further experiments
should address these possibilities.
In conclusion, the present findings provide the first evidence
suggesting that PDE4 inhibition in the BLA after learning can
enhance memory formation and produce long-term memory
persistence. Experiments aimed at further characterizing the relationship between amygdalar cAMP/PKA/CREB signaling and
memory persistence, as well as detailing the molecular mechanisms underlying the effects of PDE4 inhibition on long-term
memory maintenance, are warranted.
Acknowledgments
This research was supported by the National Council for Scientific
and Technological Development (CNPq) grant 303703/2009-1
to R.R., National Institute for Translational Medicine (INCT-TM),
Coordination for the Improvement of Higher Education Personnel (CAPES; fellowships to M.B., P.F.C.J., and T.R.P.), and the
HCPA Institutional Research Fund (FIPE/HCPA).
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Received May 8, 2012; accepted in revised form May 30, 2012.
Figure 2. Infusion placements into the BLA. Schematic diagrams of
coronal sections of the rat brain, adapted from the atlas of Paxinos and ZK-62711
Watson (2007) with permission from Elsevier # 2007, depicting the diffusion of methylene blue in the BLA for rats included in the statistical analysis.
Amygdalar PDE4 and recognition memory persistence
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