Download http://www.utdallas.edu/~tres/papers/Wilmott&Thompson.2013.pdf

%HKDYLRXUDO3KDUPDFRORJ\
'RVHGHSHQGHQWIDFLOLWDWLRQRIPHPRU\IRUDQLQKLELWRU\DYRLGDQFHWDVNE\QLPRGLSLQH
0DQXVFULSW'UDIW
0DQXVFULSW1XPEHU
)XOO7LWOH
'RVHGHSHQGHQWIDFLOLWDWLRQRIPHPRU\IRUDQLQKLELWRU\DYRLGDQFHWDVNE\QLPRGLSLQH
$UWLFOH7\SH
5HVHDUFK5HSRUW
.H\ZRUGV
&DFKDQQHOV1LPRGLSLQH/W\SHFKDQQHOV,QKLELWRU\DYRLGDQFHWDVN
&RUUHVSRQGLQJ$XWKRU
/XFLHQ77KRPSVRQ3K'
8QLYRI7H[DVDW'DOODV
5LFKDUGVRQ7;81,7('67$7(6
&RUUHVSRQGLQJ$XWKRU6HFRQGDU\
,QIRUPDWLRQ
&RUUHVSRQGLQJ$XWKRU
V,QVWLWXWLRQ
8QLYRI7H[DVDW'DOODV
&RUUHVSRQGLQJ$XWKRU
V6HFRQGDU\
,QVWLWXWLRQ
)LUVW$XWKRU
/\QGD$:LOPRWW06
)LUVW$XWKRU6HFRQGDU\,QIRUPDWLRQ
2UGHURI$XWKRUV
/\QGD$:LOPRWW06
/XFLHQ77KRPSVRQ3K'
2UGHURI$XWKRUV6HFRQGDU\,QIRUPDWLRQ
0DQXVFULSW5HJLRQRI2ULJLQ
81,7('67$7(6
$EVWUDFW
,QIOX[RIFDOFLXPWKURXJK/W\SH&DFKDQQHOVSOD\VDFULWLFDOUROHLQOHDUQLQJDQG
PHPRU\,QFUHDVHVLQF\WRVROLF&DDUHDVVRFLDWHGZLWKLPSDLUHGOHDUQLQJLQDJLQJ
DQGVPDOOFKDQJHVLQLQWUDFHOOXODUFDOFLXPFRQFHQWUDWLRQVDOVRSOD\DQLPSRUWDQWUROHLQ
QHXUDOSODVWLFLW\LQ\RXQJEUDLQV,QWKHSUHVHQWVWXG\\RXQJDGXOWPDOHDQGIHPDOH
)LVKHU[%URZQ1RUZD\)%1K\EULGUDWVZHUHDGPLQLVWHUHGGLIIHUHQWGRVHVRI
QLPRGLSLQHRUPJNJLSDVSHFLILFGLK\GURS\ULGLQH/W\SH
&DFKDQQHOEORFNHULPPHGLDWHO\DIWHUDVLQJOHLQKLELWRU\DYRLGDQFHWUDLQLQJWULDO
:KHQWHVWHGKUODWHUQLPRGLSLQHGRVHGHSHQGHQWO\HQKDQFHGPHPRU\UHWHQWLRQ
FRPSDUHGWRFRQWUROVVLJQLILFDQWO\LQFUHDVHGODWHQF\WRHQWHUDGDUNFRPSDUWPHQW
SUHYLRXVO\SDLUHGZLWKDQDYHUVLYHVWLPXOXV7KHVHILQGLQJVPD\SURYLGHLQVLJKWVLQWR
FDOFLXPGHSHQGHQWPRGXODWLRQRIDYHUVLYHPHPRULHVDQGVKRXOGEHFRQVLGHUHGLQWKH
GHVLJQRIHIIHFWLYHWUHDWPHQWRSWLRQVIRUSDWLHQWVZLWKGHPHQWLDRUSUREOHPVLQYROYLQJ
PHPRULHVZLWKQHJDWLYHHPRWLRQDOYDOHQFH
Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation
0DQXVFULSW$OO0DQXVFULSW7H[W3DJHVLQFOXGLQJ7LWOH3DJH5HIHUHQFHVDQG)LJXUH/HJHQGV
!"
"
Title:
Dose-dependent facilitation of memory for an inhibitory avoidance task by
nimodipine
Running head:
L-type Ca2+ blocker enhances aversive memory
Authors:
Lynda A. Wilmott & Lucien T. Thompson
The University of Texas at Dallas
School of Behavioral & Brain Sciences
Corresponding & Reprint Request Author:
Lucien T. Thompson
The University of Texas at Dallas
School of Behavioral & Brain Sciences
800 W. Campbell Rd., Richardson TX 75080 USA
[email protected]
+1 (972) 883-4933
Conflicts of Interest and Source of Funding:
No conflicts of interest to declare. Funding was obtained through the Clark
Foundation.
"
"
#"
"
Abstract:
Influx of calcium through L-type Ca2+ channels plays a critical role in
learning and memory. Increases in cytosolic Ca2+ are associated with impaired
learning in aging, and small changes in intracellular calcium concentrations also
play an important role in neural plasticity in young brains. In the present study,
young adult male and female Fisher 344 x Brown Norway (FBN) hybrid rats were
administered different doses of nimodipine (0.0, 0.5, 1.0, 3.0, or 5.0 mg/kg, i.p.), a
specific dihydropyridine L-type Ca2+-channel blocker, immediately after a single
inhibitory avoidance training trial. When tested 48 hr later, nimodipine dosedependently enhanced memory retention compared to controls (significantly
increased latency to enter a dark compartment previously paired with an aversive
stimulus). These findings may provide insights into calcium-dependent modulation
of aversive memories, and should be considered in the design of effective
treatment options for patients with dementia or problems involving memories with
negative emotional valence.
Key Words: Ca2+ channels; Nimodipine; L-type channels; Inhibitory avoidance
task
"
"
$"
"
Introduction
Ca2+ regulation is critical for many neuronal processes, including synaptic
plasticity, and for the macroscopic processes based on them, including learning
and memory formation. Normally, cytosolic Ca2+ levels are tightly regulated by a
multitude of proteins, but during normal aging and dementia, intracellular Ca2+
becomes dysregulated (Foster and Kumar, 2002; Thibault et al., 2007). This
dysregulation is associated with impairments in learning and memory (Thibault et
al., 2001; Miyashita et al., 2008; Berridge, 2011). ,QSDWLHQWVZLWK$O]KHLPHU¶V
disease (AD), cytosolic Ca2+ levels and influx via L-type Ca2+-channels are
increased (Mattson et al., 1992; Thibault and Landfield, 1996; Forette et al., 2002).
Researchers have used Ca2+-channel blockers, such as nimodipine and
nitrendipine, in treatment of memory deficits in dementia (Forette et al., 2002;
López-Arrieta and Birks, 2002).
Ca2+ regulation is also critically important for young adult synaptic plasticity.
N-methyl-D-apartate glutamate receptors (NMDARs) and voltage-dependent Ca2+channels (ie L-type Ca2+-channels) are major transmembrane sources of neuronal
calcium influx contributing to neuronal plasticity (Wankerl et al., 2010). Calcium
entry via NMDARs are involved in long-term potentiation (LTP) (Bliss and
Collingridge, 1993; Nakazawa et al., 2002), and Ca2+ dysregulation impairs this
process (Shankar et al., 1998). Additionally, Ca2+ influx is involved in regulation of
Ca2+-dependent post-burst afterhyperpolarizations (AHPs); these AHPs are
enhanced, while neuronal excitability is decreased, in aging compared to young
"
"
%"
"
neurons in multiple neuronal populations involved in learning and memory
(Thompson et al., 1992; Foster and Kumar, 2002; Oh et al., 2010). Following
acquisition of a learning task in young or aging animals, AHPs in the amygdala
and hippocampus, two regions involved in multiple forms of learning and memory,
including the inhibitory avoidance task used in the present study, are transiently
decreased and excitability is increased (Moyer et al., 1996; Thompson et al.,
1996b; Farmer and Thompson, 2012). Notably, when L-type Ca2+-channels are
blocked with the dihydropyridine nimodipine, AHPs in both young and aging
animals are reduced in vitro (Moyer et al., 1992), and hippocampal excitability
(neuronal firing activity) is enhanced in young animals in vivo (Thompson et al.,
1990).
L-type high-voltage activated Ca2+-channels appear to be particularly
important for modulating memory (Moyer et al., 1992; Thompson et al., 1992;
Moyer and Disterhoft, 1994; Aradi and Holmes, 1999; Borde et al., 2000). L-type
calcium-channel blockers, including nilvadipine (Iwasaki et al., 2007; Bachmeier et
al., 2011), nifedipine (Quevedo et al., 1998; Barad et al., 2004; Cain et al., 2005;
Busquet et al., 2008; McKinney et al., 2008; Walteriet et al., 2008; Davis and
Bauer, 2012), isradipine (Gholamipour-Bodie et al., 2013), diltiazem (Quartermain
et al., 2001; Barad et al., 2004), verapamil (Davis and Bauer, 2012), and also
nimodipine (Levy et al., 1991; Taya et al., 2000; Quartermain et al., 2001) enhance
spatial learning in both young (Kane and Robinson, 1999; Quartermain et al.,
2001; Rashidy-Pour et al., 2009) and aged rats (McMonagle-Strucko et al., 1993;
"
"
&"
"
Norris et al., 1998) and rabbits (Deyo et al., 1989; Straube et al., 1990; Moyer et
al., 1992).
Numerous studies have assessed how L-type Ca2+-channel antagonists
affect appetitive spatial learning (which typically requires multiple trials for
acquisition) or aversive tasks that again require multiple training trials. None,
however, have assessed the impact of L-type blockade on memory for a singletrial task. To assess the role of calcium influx via L-type channels on consolidation
of inhibitory avoidance memory, rats were given a single training trial, then dosedependent effects of a single immediate post-trial injection of the L-type calciumchannel blocker nimodipine were assessed on memory retention 48 hr later. The
aim was to assess whether nimodipine improved memory consolidation for this
task, as has been shown previously in multiple trial learning tasks.
"
"
'"
"
Methods:
Subjects
At total of 86 locally bred young (~2-4 mo old) male and female Fisher 344
x Brown Norway hybrid (FBN) rats were socially housed in a temperaturecontrolled environment (~22oC) with a 12 hr light/dark cycle. Care followed
established protocols approved by the Institutional Animal Care and Use
Committee of the University of Texas at Dallas in accordance with NIH Animal
Welfare guidelines. Ad libitum access to both food and water were available in the
UDWV¶KRPHFDJHV. The experimenters were blind as to the identity of individual
rat¶VGUXJWUHDWPHQWVXQWLOGDWDwas collected and analyzed, with cohorts from
each litter pseudo-randomly assigned to each treatment group.
Inhibitory avoidance (IA) training
The apparatus used was a trough-shaped Plexiglas chamber (91 cm long,
15 cm deep, 20 cm wide at the top, and 6.4 cm wide at the bottom) with a sliding
guillotine door to separate a light compartment (30 cm long) from a dark
compartment (60 cm long, with two angled and divided metal plates serving as a
floor). A lamp (20 W) was placed over the light compartment so as to brightly
illuminate the light but not the dark compartment. All rats were handled for 5 d, 5
min/d, prior to undergoing a single training session.
For this training session, each rat was placed in the light compartment,
facing away from the dark compartment. When the rat turned around and escaped
fully into the dark compartment, the door was closed behind and its initial escape
"
"
("
"
latency was recorded. When the rat reached the end of the dark compartment and
turned around, a moderate footshock (0.18 mA, 1 s) was applied. Any rat that
failed to vocalize or jump in response to the footshock was eliminated from further
study. After another 15 s, the rat was removed from the apparatus and given an
immediate post-training injection of either vehicle or one of the doses of
nimodipine (detailed below). The rat was then returned to its home cage.
Memory retention testing
Forty-eight hr later the rat was returned to the light compartment of the
apparatus, and the time it took to fully enter the dark compartment (retention
escape latency) was measured. Longer escape latencies served as an indicator of
better memory for the previous aversive event.
Drug Treatment
Nimodipine treatment
Male and female FBN rats were divided into 5 treatment groups (see Table
1) and each was given an i.p. injection of either vehicle (65% polyethylene glycol
(PEG)/35% 0.9% saline) or nimodipine (0.5, 1.0, 3.0, or 5.0 mg/kg, i.p., dissolved
in 65% PEG/35% 0.9% saline; Tokyo Chemical Industry (TCI)).
Sensorimotor tests
To determine if administration of nimodipine affected rats¶ ability to perform
an escape from the light compartment during memory retention testing 48 hr posttrial, sensorimotor function was also assessed immediately following memory
retention testing. Each task below was assessed once per rat.
"
"
)"
"
Wire Hang
A wire-hang test was used to measure strength and endurance. The rat was
suspended grasping by its forelimbs a wire (200 mm thick) 40 cm above a foam
cushion, and the latency to drop was recorded. A greater latency was taken as an
indication of better strength or motor endurance.
Narrow Beam
A narrow beam test was used to measure balance/agility. The rat was placed
midway down a 1.2 m long x 2.5 cm beam that had 25 cm2 wooden escape
platforms on either end and was 80 cm above a foam cushion. The latency to
reach either end of the beam was recorded, with a shorter latency indicating better
balance or agility.
45° Incline
A 45° incline test measured vestibular processing. The rat was placed facing
downward on a 45° incline apparatus (33.5 cm long x 23.5 cm wide x 42 cm high)
and the latency to turn facing upward was recorded. Subjects that continuously
climbed down the 45϶ incline, rather than turning around, were excluded. A shorter
latency was considered a measure of better vestibular processing.
Blind Alley
Contextual processing was assessed using a blind alley test. The rat was
placed face first into an enclosed alley (29 cm long x 9.5 cm wide x 24 cm high)
with walls on three sides of the apparatus. The time it took the rat to turn around
and face the opening was recorded. Better contextual processing was inferred
"
"
*"
"
from a short latency.
Data analysis
Inhibitory avoidance task
To compare initial escape latencies to 48 hr retention escape latencies
across sex and dose of nimodipine, we used a 2-way ANOVA, followed by an unpaired t-test to compare sex differences and a paired t-test to compare dosedependent differences. To analyze the effect of nimodipine on retention escape
latencies, we used a one-way ANOVA with escape latency as the dependent
variable and nimodipine dose group as the independent variable (Fig. 2).
Significant interactions were further analyzed by Fisher post hoc analysis.
Sensorimotor tasks
To compare mean latencies on the 4 sensorimotor tasks (narrow beam,
wire hang, 45° incline, and blind alley), we used a one-way ANOVA with the task
latency as the dependent variable and drug treatment group as the independent
variable. Significant interactions were further analyzed by Fisher post hoc test."
"
"
!+"
"
Results:
Memory for inhibitory avoidance learning in male and female FBN rats
A 2-way ANOVA for retention latency yielded no significant drug x sex
interaction (F4,76=0.217, p=0.9284), and a series of planned comparisons were run
using un-paired t-tests for sex but yielded no specific difference when comparing
between males and females in any of the drug groups (0.0 mg/kg, t(11)=1.949,
p=0.0773; 0.5 mg/kg, t(18)=1.006, p=0.3279; 1.0 mg/kg, t(16)=1.296, p=0.2134;
3.0 mg/kg, t(14)=0.938, p=0.3643; 5.0 mg/kg, t(17)=0.621, p=0.5428); therefore,
the data for the two sexes were combined for all further analyses. As seen in
Figure 1, when collapsed across conditions and sexes, all rats tested 48 h later
exhibited longer retention escape latencies compared to initial escape latencies
(t(85)=8.012, p<0.0001), indicating all rats, regardless of sex, exhibited memory
for the earlier aversive experience. Drug treatment effects below are collapsed
across sexes.
Post-training nimodipine enhanced memory
As seen in Figure 2, rats in each treatment condition exhibited memory for
the aversive foot shocked paired with entry to the dark compartment, with
significantly longer retention escape latencies compared to their initial escape
latencies (paired t-test: 0.0 mg/kg, t(12)=2.657, p=0.0209; 0.5 mg/kg, t(19)=4.077,
p=.0006; 1.0 mg/kg, t(17)=4.317, p=0.0005; 3.0 mg/kg, t(15)=3.609, p=0.0026; 5.0
mg/kg, t(18)=4.689, p=0.0002).
"
"
!!"
"
The specific L-type Ca2+-channel blocker nimodipine enhanced memory for
the aversive IA task (Fig. 2). At all doses tested, nimodipine treatment increased
escape latencies, with the dose-response curve taking a general inverted-U
shape, typical of nootropic drugs. Forty-eight hr after acquisition of the inhibitory
avoidance task, nimodipine dose-dependently increased escape latencies
compared to those of control animals, as determined by one-way ANOVAs
(F4,81=2.609, p=0.0415). Significant increases in escape latencies were seen at
doses of 0.5 mg/kg and 1.0 mg/kg nimodipine (Fisher test; p=0.0077 and
p=0.0052, respectively; Fig. 2).
Nimodipine had no effect on sensorimotor performance by FBN rats
To verify that the nimodipine-induced enhancement of memory (increases
in retention latency) were not simply due to impairments in sensorimotor functions,
each rat was tested on four sensorimotor tasks immediately after retention testing.
Administration of nimodipine had no effect on performance of any of the
sensorimotor tasks in male rats, as determined by one-way ANOVAs (wire hang:
F4,36=0.66, p=0.62; narrow beam: F4,36=0.38, p=0.82; 45o incline: F4,33=0.67,
p=0.61; blind alley: F4,36=0.57, p=0.69). Similarly, administration of nimodipine had
no effect on any of the sensorimotor tasks in female rats, as determined by oneway ANOVAs (wire hang: F4,14=1.23, p=0.34; narrow beam: F4,14=0.33, p=0.85;
45o incline: F4,14=0.80, p=0.55; blind alley: F4,14=0.97, p=0.46).
"
"
!#"
"
Discussion:
FBN rats successfully remembered a single-trial aversive event in an
inhibitory avoidance task (see Fig. 1), with significantly increased escape latencies
when tested 48 hr after a single aversive foot-shock trial compared to initial
escape latencies. The specific L-type Ca2+-channel blocker nimodipine (Fig. 2)
dose-dependently increased these escape latencies compared to controls when
rats were retested 48 hr post-training, an operational measure of enhancement of
memory consolidation for the task.
Ca2+ regulation is critically important for synaptic plasticity, learning, and
memory. Ca2+ influx through voltage-gated Ca2+-channels during action potential
firing increases cytosolic Ca2+ (McAfee and Yarowsky, 1979; Freschi, 1983). In
hippocampal CA1 neurons, calcium entry via L-type Ca2+-channels can activate
sAHPs, which decrease neuronal excitability and impair learning and memory
(Landfield and Pitler, 1984; Disterhoft et al., 1996; Thibault et al., 2001; Forette et
al., 2002). Learning-dependent reductions in AHP amplitudes and durations have
been observed after learning numerous tasks (Moyer et al., 1996; Thompson et
al., 1996; Saar et al., 1998; Tombaugh et al., 2005; Farmer and Thompson, 2012).
Specifically, nimodipine has been used dose-dependently to enhance multi-trial
aversive learning (eyeblink conditioning: Deyo et al., 1989; Straube et al., 1990;
Thompson et al., 1992; Kowalska et al., 1994) and to enhance hippocampal
pyramidal neuron excitability in vivo (Thompson et al., 1990) and in vitro (Moyer et
al., 1992).
"
"
!$"
"
During normal aging and in dementias (including AD) learning is impaired;
this impairment is associated with increases in cytosolic Ca2+ levels (for review
see Zündorf and Reiser, 2011; Garwood et al., 2013). L-type Ca2+-channel
antagonists have been tested for use in alleviating dementia-like symptoms. When
Bachmeier et al. LQWUDFUDQLDOO\DGPLQLVWHUHGKXPDQ$ȕ1-42 into the caudateSXWDPHQRIPLFHWKH\IRXQGDQLQFUHDVHLQ$ȕ1-42 clearance from the brains of
mice treated with in vivo administration of the dihydropyridines nitrendipine,
nilvadipine, or cilnidipine compared to controls. These mice also showed greater
memory for the spatial Morris water maze task than controls (Bachmeier et al.,
2011). López-Arrieta and Birks (2002) found that administration of another L-type
calcium-channel antagonist, nimodipine, enhanced cognitive function in human
patients with dementia. Furthermore, Forette et al. (2002) found that elderly
human subjects administered nitrendipine for an average of 3.4 years had a 55%
decrease in incidence of dementia or AD compared to those administered a
placebo for an average of 3.8 years.
When drugs are administered prior to acquiring a behavioral task, both
acquisition and memory consolidation are affected, as McGaugh and Petrinovich
(1959) detailed in early studies. However, when a drug is administered within 30
minutes after acquisition, only consolidation memory is affected (McGaugh et al.,
1962; McGaugh and Krivanek, 1970; for review see McGaugh and Roozendaal,
2009). Similarly, we showed that nimodipine, an L-type specific Ca2+-channel
blocker, when administered immediately post-trial, enhanced single-trial aversive
"
"
!%"
"
memory, as evidenced by longer escape latencies 48 hr following training on a
single-trial inhibitory avoidance task. These findings are consistent with numerous
other studies demonstrating that the consolidation of learning and memory is
enhanced by calcium antagonists, with L-type channel blockers accounting for
most of the improvement (Deyo et al., 1989; Fanelli et al., 1994; Quartermain et
al., 2001; Schafe, 2008).
This enhancement of newly acquired memories, however, is contrary to
what has often been reported for extinction of aversive memories. Several studies
have found that L-type Ca2+-channel blockers impair extinction (Cain et al., 2005;
Busquet et al., 2008; McKinney et al., 2008; Waltereit et al., 2008; Milad et al.,
2009; Davis and Bauer, 2012). Waltereit et al. (2008) found that peripheral
injections of nifedipine impaired extinction for contextual or auditory fear tasks, and
Davis and Bauer (2012) found impaired extinction memory 24 hr after nifedipine
was infused into the BLA. While no studies have shown sex-differences in L-type
Ca2+-channel blockade on fear extinction, Milad et al. (2009) found that female rats
with low estradiol (E2) levels had lower extinction levels compared to females with
high E2 levels and males, and when the estrous cycle phases are not taken into
consideration, there were no differences in fear extinction in female rats. Our data
also indicate no sex-specific differences.
Our data are consistent with the hypothesis that L-type Ca2+-channel
blockers facilitate memory for an aversive inhibitory avoidance task. We found that
post-training injections of nimodipine (Fig. 2) dose-dependently enhanced memory
"
"
!&"
"
when retested 48 hr later. This is consistent with earlier studies showing that these
Ca2+-channel blockers decrease AHP amplitudes (Moyer and Disterhoft, 1994;
Borde et al., 2000) and facilitate memory (Deyo et al., 1989b; Shinnick-Gallagher
et al., 2003) in other tasks. In our hands, the dihydropryidine nimodipine
significantly enhanced escape latencies at doses ranging from 0.5-1.0 mg/kg.
While dihydropyridines (Ramdas et al., 2011) can produce side effects, no sensory
or motor effects that would affect retest (memory) performance were observed
across the range of doses tested here. It is likely that dihydropyridines or other Ltype blockers could have relatively fewer side effects in human studies, as much
lower doses would be needed, and should not affect the other voltage-gated Ca2+channel families. L-type blockers also would not interfere with NMDA receptor
function.
"
"
!'"
"
Conclusions:
Our data show the L-type Ca2+ channel blocker nimodipine dosedependently enhanced memory for a single-trial inhibitory avoidance task. These
results provide further insight into the role of calcium influx in learning and
memory."
"
"
!("
"
Acknowledgements:
This study was funded by the Clark Foundation. We thank Drs. E.J. Donzis
and J.R. McReynolds for their advice and commentary; M. Montgomery, A. Partin,
and A. Ho for their technical assistance; and Dr. C.K. McIntyre for helpful editorial
comments and for the use of the behavioral apparatus.
"
"
!)"
"
References:
Aradi I, Holmes WR (1999). Role of multiple calcium and calcium-dependent
conductances in regulation of hippocampal dentate granule cell excitability.
J Comput Neurosci 6:215-235.
Bachmeier C, Beaulieu-Abdelahad D, Mullan M, Paris D (2011). Selective
dihydropyiridine compounds facilitate the clearance of beta-amyloid across
the blood-brain barrier. Eur J Pharmacol 659:124-129.
Barad M, Blouin AM, Cain CK (2004). Like extinction, latent inhibition of
conditioned fear in mice is blocked by systemic inhibition of L-type voltagegated calcium channels. Learn Mem 11:536-539.
Berridge MJ (2011). Calcium signalling and Alzheimer's disease. Neurochem Res
36:1149-1156.
Bliss TV, Collingridge GL (1993). A synaptic model of memory: long-term
potentiation in the hippocampus. Nature 361:31-39.
Borde M, Bonansco C, Fernandez de Sevilla D, Le Ray D, Buno W (2000).
Voltage-clamp analysis of the potentiation of the slow Ca2+-activated K+
current in hippocampal pyramidal neurons. Hippocampus 10:198-206.
Busquet P, Hetzenauer A, Sinnegger-Brauns MJ, Striessnig J, Singewald N
(2008). Role of L-type Ca2+ channel isoforms in the extinction of conditioned
fear. Learn Mem 15:378-386.
"
"
!*"
"
Cain CK, Godsil BP, Jami S, Barad M (2005). The L-type calcium channel blocker
nifedipine impairs extinction, but not reduced contingency effects, in mice.
Learn Mem 12:277-284.
Davis SE, Bauer EP (2012). L-type voltage-gated calcium channels in the
basolateral amygdala are necessary for fear extinction. J Neurosci
32:13582-13586.
Deyo RA, Straube KT, Disterhoft JF (1989). Nimodipine facilitates associative
learning in aging rabbits. Science 243:809-811.
Deyo RA, Straube KT, Moyer JR jr, Disterhoft JF (1989b). Nimodipine ameliorates
aging-related changes in open-field behaviors of the rabbit. Exper Aging
Res 15:169-175.
Disterhoft JF, Thompson LT, Moyer JR jr, Mogul DF (1996). Calcium-dependent
afterhyperpolarization and learning in young and aging hippocampus. Life
Sci 59:413-420.
Fanelli RJ, McCarthy RT, Chisholm J (1994). Neuropharmacology of nimodipine:
from single channels to behavior. Ann NY Acad Sci 747:336-350.
Farmer GE, Thompson LT (2012). Learning-dependent plasticity of hippocampal
CA1 pyramidal neuron postburst afterhyperpolarization and increased
excitability after inhibitory avoidance learning depend upon basolateral
amygdala inupts. Hippocampus 22:1703-1719.
Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu S, Bossini
A, et al (2002). The prevention of dementia with antihypertensive treatment:
"
"
#+"
"
new evidence from the Systolic Hypertension in Europe (Syst-Eur) study.
Arch Intern Med 162:2046-2052.
Foster TC, Kumar A (2002). Calcium dysregulation in the aging brain.
Neuroscientist 8:297-301.
Freschi JE (1983). Membrane currents of cultured rat sympathetic neurons under
voltage clamp. J Neurophysiol 50:1460-1478.
Garwood C, Faizullabhoy A, Wharton SB, Ince PG, Heath P, Shaw PJ, Baxter
L, et al (2013). Calcium dysregulation in relation to Alzheimer-type
pathology in the ageing brain. Neuropathol Appl Neurobiol [Epub ahead of
print].
Gholamipour-Badie H, Naderi N, Khodagholi F, Shaerzadeh F, Motamedi F
(2013). L-type calcium channel blockade alleviates molecular and reversal
spatial learning and memory alterations induced by entorhinal amyloid
pathology in rats. Behav Brain Res 237:190-199.
Iwasaki K, Egashira N, Takagaki Y, Yoshimitsu Y, Hatip-Al-Khatib I, Mishima K,
Fujiwara M (2007). Nilvadipine prevents the impairment of spatial memory
induced by cerebral ischemia combined with beta-amyloid in rats. Biol
Pharm Bull 30:698-701.
Kane KA, Robinson GB (1999). Effect of chronic nimodipine on spatial learning
and on long-term potentiation. Behav Brain Res 98:95-101.
"
"
#!"
"
Landfield PW, Pitler TA (1984). Prolonged Ca2+-dependent
afterhyperpolarizations in hippocampal neurons of aged rats. Science
226:1089-1092.
Levy A, Kong RM, Stillman MJ, Shukitt-Hale B, Kadar T, Rauch TM, Lieberman
HR (1991). Nimodipine improves spatial working memory and elevates
hippocampal acetylcholine in young rats. Pharmacol Biochem Behav
39:781-786.
López-Arrieta JM, Birks J (2002). Nimodipine for primary degenerative, mixed and
vascular dementia. Cochrane Database Syst Rev 3:CD000147.
Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE (1992). BetaAmyloid peptides destabilize calcium homeostasis and render human
cortical neurons vulnerable to excitotoxicity. J Neurosci 12:376-389.
McAfee DA, Yarowksy PJ (1979). Calcium-dependent potentials in the mammalian
sympathetic neurone. J Physiol 290:507-523.
McGaugh JL, Petrinovich L (1959). The effect of strychnine sulphate on mazelearning. Am J Psych 72:99-102.
McGaugh JL, Thomson CW, Westbrook WH, Hudspeth WJ (1962). A further study
of learning facilitation with strychnine sulphate. Psychopharmacologia
3:352-360.
McGaugh JL, Krivanek JA (1970). Strychnine effects on discrimination learning in
mice: effects of dose and time administration. Physiol Behav 5:1437-1442.
"
"
##"
"
McGaugh JL, Roozendaal B (2009). Drug enhancement of memory consolidation:
historical perspective and neurobiological implications.
Psychopharmacology 202:3-14.
McKinney BC, Sze W, White JA, Murphy GG (2008). L-type voltage-gated calcium
channels in conditioned fear: a genetic and pharmacological analysis. Learn
Mem 15:326-334.
McMonagle-Strucko K, Fanelli RJ (1993). Enhanced acquisition of reversal training
in a spatial learning task in rats treated with chronic nimodipine. Pharmacol
Biochem Behav 44:827-835.
Milad MR, Igoe SA, Lebron-Milad K, Novales JE (2009). Estrous cycle phase and
gonadal hormones influence conditioned fear extinction. Neurosci 164:887895.
Miyashita T, Kubik S, Lewandowski G, Guzowski JF (2008). Networks of neurons,
networks of genes: an integrated view of memory consolidation. Neurobiol
Learn Mem 89:269-284.
Moyer JR jr, Thompson LT, Black JP, Disterhoft JF (1992). Nimodipine increases
excitability of rabbit CA1 pyramidal neurons in an age- and concentrationdependent manner. J Neurophysiol 68:2100-2109.
Moyer JR jr, Disterhoft JF (1994). Nimodipine decreases calcium action potentials
in rabbit hippocampal CA1 neurons in an age-dependent and
concentration-dependent manner. Hippocampus 4:11-17.
"
"
#$"
"
Moyer JR jr, Thompson LT, Disterhoft JF (1996). Trace eyeblink conditioning
increases CA1 excitability in a transient and learning-specific manner. J
Neurosci 16:5536-5546.
Nakazawa K, Quirk MC, Chitwood RA, Watanabe M, Yeckel MF, Sun LD, Kato A,
et al (2002). Requirement for hippocampal CA3 NMDA receptors in
associative memory recall. Science 297:211-218.
Norris CM, Halpain S, Foster TC (1998). Reversal of age-related alterations in
synaptic plasticity by blockade of L-type Ca2+ channels. J Neurosci
18:3171-3179.
Oh MM, Oliveria FA, Disterhoft, JF (2010). Learning and aging related changes in
intrinsic neuronal excitability. Front Aging Neurosci 2:1-10.
Quartermain D, deSoria VG, Kwan A (2001). Calcium channel antagonists
enhance retention of passive avoidance and maze learning in mice.
Neurobiol Learn Mem 75:77-90.
Quevedo J, Vianna M, Daroit D, Born AG, Kuyven CR, Roesler R, Quillfeldt JA
(1998). L-type voltage-dependent calcium channel blocker nifedipine
enhances memory retention when infused into the hippocampus. Neurobiol
Learn Mem 69:320-325.
Ramdas S, Riesenberg LA, Jasani N (2011). Drug overdose with refractory
bradycardia and hypotension. Del Med J 83:169-72.
Rashidy-Pour A, Vafaei AA, Taherian AA, Miladi-Gorji H, Sadeghi H, Fathollahi Y,
Bandegi AR (2009). Verapamil enhances acute stress or glucocorticoid-
"
"
#%"
"
induced deficits in retrieval of long-term memory in rats. Behav Brain Res
203:76-80.
Saar D, Grossman Y, Barkai E (1998). Reduced after-hyperpolarization in rat
piriform cortex pyramidal neurons is associated with increased learning
capability during operant conditioning. Eur J Neurosci 10:1518-1523.
Schafe GE (2008). Rethinking the role of L-type voltage-gated calcium channels in
fear memory extinction. Learn Mem 15:324-325.
Shankar S, Teyler TJ, Robbins N (1998). Aging differentially alters forms of longterm potentiation in rat hippocampal area CA1. J Neurophysiol 79:334-341.
Shinnick-Gallagher P, McKernan MG, Zie J, Zinebi F (2003). L-type voltage-gated
calcium channels are involved in the in vivo and in vitro expression of fear
conditioning. Ann NY Acad Sci 985:135-149.
Straube KT, Deyo RA, Moyer JR jr, Disterhoft JF (1990). Dietary nimodipine
improves associative learning in aging rabbits. Neurobiol Aging 11:659-661.
Taya K, Watanabe Y, Kobayashi H, Fujiwara M (2000). Nimodipine improves the
disruption of spatial cognition induced by cerebral ischemia. Physiol Behav
70:19-25.
Thibault O, Landfield PW (1996). Increase in single L-type calcium channels in
hippocampal neurons during aging. Science 272:1017-1020.
Thibault O, Hadley R, Landfield PW (2001). Elevated postsynaptic [Ca2+]i and Ltype calcium channel activity in aged hippocampal neurons: relationship to
impaired synaptic plasticity. J Neurosci 21:9744-9756.
"
"
#&"
"
Thibault O, Gant JC, Landfield PW (2007). Expansion of the calcium hypothesis of
EUDLQDJLQJDQG$O]KHLPHU¶VGLVHDVHPLQGLQJWKHVWRUHAging Cell 6:307317.
Thompson LT, Deyo RA, Disterhoft JF (1990). Nimodipine enhances spontaneous
activity of hippocampal pyramidal neurons in aging rabbits at a dose that
facilitates associative learning. Brain Res 535:119-130.
Thompson LT, Moyer JR jr, Disterhoft JF (1992). Cellular mechanisms for
nimodipine's reduction of aging-related learning deficits. Adv Behav Biol
40:241-256
Thompson LT, Deyo RA, Disterhoft JF (1996). Nimodipine enhances spontaneous
firing of hippocampal pyramidal cells in aging rabbits at a dose that
facilitates associative learning. Brain Res 535:119-130.
Thompson LT, Moyer JR jr, Disterhoft JF (1996b). Transient changes in excitability
of rabbit CA3 neurons with a time course appropriate to support memory
consolidation. J Neurophysiol 76:1836-1849.
Tombaugh GC, Rowe WB, Rose GM (2005). The slow afterhyperpolarization in
hippocampal CA1 neurons covaries with spatial learning ability in aged
Fisher 344 rats. J Neurosci 25:2609-2616.
Waltereit R, Mannhardt S, Nescholta S, Maser-Gluth C, Bartsch D (2008).
Selective and protracted effect of nifedipine on fear memory extinction
correlates with induced stress response. Learn Mem 15:348-356.
"
"
#'"
"
Wankerl K, Weise D, Gentner R, Rumpf JJ, Classen J (2010). L-type voltagegated Ca2+ channels: A single molecular switch for long-term
potentiation/long-term depression-like plasticity and activity-dependent
metaplasticity in humans. J Neurosci 30:6197-6204.
Zündorf G, Reiser G (2011). Calcium dysregulation and homeostasis of neural
calcium in the molecular mechanisms of neurodegenerative diseases
provide multiple targets for neuroprotection. Antioxid Redox Signal 14:12751288.
"
"
#("
"
Figure Legends:
Table 1. Number of male and female rats tested in the different nimodipine dose
treatment groups.
Figure 1. All rats showed significantly longer escape latencies 48 hr following a
single inhibitory avoidance learning trial (p<0.0001). All nimodipine doses have
been collapsed within genders. Values reported are means ± SEM; ***p<0.001.
Figure 2. Post-training nimodipine treatment enhanced memory consolidation for
the inhibitory avoidance task in FBN rats. No significant differences in escape
latencies were observed comparing between males and females at any of the drug
doses tested, so the data for the two sexes were combined. Rats that received
immediate post-training injections of nimodipine (0.5-1.0 mg/kg) had significantly
longer escape latencies than control rats (p<0.01). Values reported are means ±
SEM; *p<0.01.
"
"
7DEOH
Nimodipine treatment
number of rats
dose (mg/kg) males females
!
total
0.0
6
7
13
0.5
9
11
20
1.0
7
11
18
3.0
7
9
16
5.0
9
10
19
total
38
48
86
)LJXUH
!
)LJXUH
!