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Research Paper
Galantamine Facilitates Acquisition of a Trace-Conditioned Eyeblink Response in Healthy, Young Rabbits
1 Shirley L. Buchanan Neuroscience Laboratory, WJB Dorn VA Medical Center, Columbia, South Carolina 29209, USA 2 Department of Psychology, and 3 Department of Neuropsychiatry and Behavioral Science, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USA
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ABSTRACT |
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 TOP ABSTRACT RESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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).
Galantamine (GAL) functions both as a potentiating ligand and as a weak
acetylcholinesterase (AchE) inhibitor. As a potentiating ligand, GAL
facilitates Ach release by binding to presynaptic nAChRs and increasing the
number of open postsynaptic receptors during action potentials.
(Geerts et al. 2002). As an
AchE inihibitor, GAL prevents the breakdown of Ach in cortical tissue
(Sweeney et al. 1989;
Geerts et al 2002). GAL has
been found to significantly increase nicotinic receptor binding and decrease
brain levels of AchE in rabbits
(Woodruff-Pak et al. 2001).
This compound also increased nicotinic receptor density in the hippocampus and
prefrontal cortex in rats, leading to enhanced long-term potentiation of cells
in these areas (Barnes et al.
2000). It is believed that this dual action of GAL, both
facilitating Ach release and preventing the breakdown of Ach in the synapse,
offers greater efficacy than other cholinergic agonists for longer treatment
periods with less risk of tolerance in the treatment of cognitive dysfunction
due to Alzheimer's disease (Maelicke
2001; Geerts et al.
2002; Woodruff-Pak et al.
2002).
Animal studies have shown that GAL can reverse the cognitive deficits
caused by treatment with anticholinergic drugs (i.e., scopolamine or
mecamylamine) and brain lesions (Fulton
and Benfield 1996), as well as normal aging
(Woodruff-Pak and Santos 2000;
Woodruff-Pak et al. 2001).
Certain kinds of Pavlovian EB conditioning tasks have proven to be a sensitive
index of simple associative learning processes often disrupted in both aging
organisms (e.g., Powell 1999)
and various types of brain dysfunction including Alzheimer's disease (AD;
Solomon et al. 1991,
1995;
Woodruff-Pak and Papka 1996;
Woodruff-Pak et al.
1996a,b),
Korsakoff's disease (McGlinchey-Berroth et
al. 1995), schizophrenia
(Sears et al. 2000), and
post-traumatic stress disorder (PTSD;
Rasmusson and Charney 1997).
Previous studies have demonstrated that treatment with 3.0 mg/kg GAL can
significantly improve simple-delay eyeblink (EB) conditioning in older rabbits
(Woodruff-Pak and Santos 2000;
Woodruff-Pak et al. 2001).
Although simple-delay conditioning can be disrupted through aging and
following certain types of brain damage (i.e., cerebellar damage, e.g.,
Thompson 2000), trace
conditioning tasks, in which the CS and US are temporally distinct, are
typically much more difficult to learn, even in young, healthy organisms. Thus
the present experiment assessed the efficacy of GAL in healthy rabbits
performing this difficult task to assess whether GAL might provide benefit in
the treatment of learning or attention disorders in healthy, young organisms.
Previous studies by Woodruff-Pak and colleagues (e.g.,
Woodruff-Pak and Santos 2000;
Woodruff-Pak et al. 2001)
found that 3.0 mg/kg GAL facilitated acquisition of simple-delay conditioning
in both younger and aged animals, whereas lower (1.0 and 2.0 mg/kg) and higher
doses (4.0 mg/kg) did not. For example, Woodruff-Pak and Santos
(2000) demonstrated highly
significant decreases in the number of trials required to reach an EB learning
criterion (eight EB conditioned responses within nine consecutive trials).
Aged rabbits injected with 3.0 mg/kg GAL reached criterion in 233
(±176.9) trials, compared with an average of 1000
(±200–300) trials in untreated older animals. Studies from this
lab have also shown that, whereas other compounds facilitating Ach
transmission, including the 
7 nicotinic partial agonist GTS-21 and the
cholinesterase inhibitors donepezil and physostigmine, can significantly
increase learning; treatment with GAL yielded even greater improvement. A
second study further demonstrated that treatment with 3.0 mg/kg GAL
facilitated learning a simple delay (750 msec) EB conditioned response (CR) in
young (4–6 mo old) as well as older (15–43 mo old) rabbits
(Woodruff-Pak et al.
2001).
These findings are especially compelling because younger organisms
typically perform so well on this simple task that it is difficult to find
significant facilitation because of ceiling effects. We therefore tested the
optimal 3.0-mg/kg dose, as well as a lower 1.5-mg/kg dose, in younger animals
performing a difficult EB trace-conditioning task, where such ceiling effects
are not present. Evidence indicates that enhancement of cognitive function
with pharmacological agents is dependent on task demands (e.g.,
Hahn et al. 2002), such that
performance on simple tasks is typically not improved because of ceiling
effects, whereas performance on difficult tasks may not be facilitated because
organisms may not understand the task contingencies well enough to show
improvement. The objective of the present study was thus to assess the effects
of GAL on acquisition of the more difficult trace EB conditioning task, which
requires higher cognitive demands (Clark
and Squire 1998) to determine if this drug might be useful in the
treatment of attentional dysfunction in humans.
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RESULTS |
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TOPABSTRACTRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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A two-way ANOVA using only the data from the experimental animals compared the effects of the three doses of GAL on percentage of CRs during acquisition. This analysis indicated significant main effects of group (F(2, 159) = 4.26, p < 0.03) and session (F(9, 18) = 2.81, p < 0.004); however, the interaction was not significant. Post hoc analyses revealed that 3.0 mg/kg GAL produced significantly greater percentages of CRs throughout training than either a lower dose of 1.5 mg/kg GAL or vehicle controls (p < 0.05). There was no significant difference between vehicle and the lower dose GAL group (difference of means over training = 0.81, p > 0.05). Analyses of extinction data indicated that there was no significant difference in percentage of CRs between groups over extinction sessions (F(8, 51) = 1.15, p > 0.05; see Fig. 1).
Additional planned comparisons between doses for each training day for the conditioning groups indicated significant group differences on acquisition days 1, 3, and 5 (F(2, 24) = 11.0, 5.75, and 3.75, respectively; all ps < 0.05; see Fig. 1). Differences between the groups approached significance on training day 2 (F(2, 24) = 3.21, p = 0.0599) and day 4 (F(2, 24) = 3.28, p = 0.0567). Post hoc comparisons (Student–Newman–Keuls) indicated that treatment with 3.0 mg/kg GAL resulted in a significantly greater number of CRs than both 1.5 mg/kg GAL and vehicle on conditioning days 1 and 3, and significantly more CRs than 1.5 mg/kg GAL on conditioning day 5 (again, see Fig. 1).
An interesting aspect of the data shown in Figure 1 is that the differences between the conditioning groups occur during the initial session. Thus acquisition for the 3-mg/kg group appears to be relatively complete during session 1. To determine whether an acquisition function was apparent in this group, CR probability was assessed on a trial-by-trial basis as a function of the first 10 trials of session 1. These data are shown in Figure 2A. This figure indicates that, indeed, the actual acquisition of the EB CR occurs very rapidly during the first 10 trials of both drug groups, compared with the vehicle control group. In fact, as indicated in Figure 2B, which shows the mean number of EB CRs as a function of 10 trial blocks during session 1, acquisition in this latter group does not begin until late during this session, and as illustrated in Figure 1 remains well below that of the 3-mg/kg group throughout training. These data strongly indicate that the effects of GAL are on acquisition of the EB CR and not on possible nonspecific factors that may have increased reactivity to stimulation.
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Analyses of EB CR amplitude data over training sessions (shown in Fig. 3A) indicated a significant main effect of session (F(9, 18) = 4.34, p < 0.0001), but no significant group effect. Analysis of EB CR amplitude during extinction revealed no significant effects (all ps > 0.05). Analysis of EB UR amplitude during conditioning and extinction also revealed no significant effects (all ps > 0.05).
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Analysis of EB CR and UR latency data over training (shown in Fig. 3B) revealed that there were no changes in latency within or between groups over acquisition or extinction sessions for either CR or UR latencies (all ps > 0.05).
Analysis of the amplitude and latency data for CRs and URs during the pseudoconditioning tests also indicated no significant differences between groups on either of these measures (all ps > 0.05). These data are shown in Figure 4.
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Because stimulant drugs like nicotine, which is another cholinergic agonist, often have anorectic effects, animal weights were analyzed to assess the effects of GAL on weight gain over training and extinction sessions. Data from all experimental and control rabbits were analyzed together and can be seen in Figure 5. A 3 (group) x 13 (training and extinction day) ANOVA indicated that weights significantly increased in all animals over sessions (F(12, 24) = 2.81, p < 0.001), without a significant group-by-session interaction (F(12, 24) = 1.11, p = 0.33). Thus, galantamine does not appear to exert significant anorectic effects.
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DISCUSSION |
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TOPABSTRACTRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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),
which showed that a similar dosage of galanthamine facilitated acquisition of
a delay EB conditioning task in rabbits. This finding was, however, obtained
with a fairly long interstimulus interval (e.g., 750 msec), which also
produces slower conditioning than the more optimal 400-msec ISI
(Buchanan et al. 1997). It thus
appears that galanthamine, which is a cholinesterase inhibitor, as well as an
allosteric nictonic receptor agonist, facilitates EB conditioning under
conditions that make learning more difficult.
These data are also compatible with the general hypothesis that central
cholinergic systems play a large role in classical EB conditioning. It has
been determined, for example, that central cholinergic blockade with
scopolamine or atropine severely impairs acquisition of delay EB conditioning
(e.g., Kazis et al. 1973). The
role of acetylcholine in learning and memory has also been widely supported in
a number of other behavioral paradigms (for a recent review, see, e.g.,
Sarter and Bruno 1997). It has
been suggested that delay EB conditioning using optimal stimulus parameters is
not dependent on the hippocampus and is learned without awareness of the
stimulus contingencies, whereas successful trace conditioning requires
hippocampal processing and is dependent on conscious awareness
(Clark and Squire 1998). In
support of this conclusion are findings from rabbits showing that although
increases in hippocampal neuronal activity are elicited by both delay and
trace conditioning (Berger and Thompson
1978; Weiss et al.
1996), hippocampal damage does not produce deficits in delay
conditioning (Schmaltz and Theios
1972), but can dramatically impair trace conditioning
(Moyer Jr. et al. 1990).
Moreover, the findings by several investigators that humans with temporal lobe
or diencephalic damage can learn a delay EB conditioning task but have
difficulty learning a trace task provides further evidence for this conclusion
(Gabrieli et al. 1995;
McGlinchey-Berroth et al.
1997; Clark and Squire
1998).
These findings are especially important in the context of pharmacological
interventions for Alzheimer's disease, because the loss of cholinergic
function appears to be prevalent in this disorder, especially in the
hippocampal region (Bartus et al.
1982; Coyle et al.
1983; Nordberg
1992). The dependence of declarative learning and memory on the
hippocampus is also widely accepted (Clark
and Squire 1998). Thus, the use of the trace eye-blink
conditioning task is especially illuminating in this context, because it is
also dependent on the hippocampus, as well as cholinergic function. Finally,
EB conditioning is also impaired in patients with early Alzheimer's disease
(Woodruff-Pak et al. 1990;
Solomon et al. 1995;
Woodruff-Pak 2001). The
present results thus indicate that galantamine might be an especially good
therapeutic agent for delaying the onset of the devastating learning and
memory problems associated with Alzheimer's disease and mixed dementia
(Alzheimer's disease with cerebrovascular disease), and has in fact been shown
to be efficacious in this regard (e.g.,
Wilcock et al. 2000). These
findings illustrate the efficacy of using EB conditioning tasks as a
preclinical measure of associative learning and memory problems. Trace
eyeblink conditioning in the rabbit thus appears to provide a valid animal
model of the CNS dysfunctions that accompany the degenerative diseases of old
age such as Alzheimer's or Parkinson's disease.
Another important aspect of the present results is that they indicate that
treatment with GAL, and possibly other nonselective cholinergic agonists, may
provide benefit for learning new, difficult material in young, healthy
organisms. This is in contrast to traditional dopaminergic agonists, typically
used in the treatment of attentional dysfunction in humans, which, while known
to have benefit for aiding certain types of attentional focus in low doses
(e.g., Grilly and Simon 1994),
have been shown to have little benefit in improving acquisition of difficult
tasks (Grilly et al. 1998) or
even accuracy on tasks requiring certain forms of attention (e.g.,
Cole and Robbins 1987;
Ljungberg and Enquist 1987;
McGaughy and Sarter 1995).
Thus, cholinergic agonists may prove more beneficial than dopaminergic agents
for the treatment of attention-deficit/hyperactivity disorders. Indeed, work
from several laboratories including Robbins and colleagues (e.g., Muir et al.
1992,
1994,
1995; for review, see
Everitt and Robbins 1997) and
Sarter and colleagues (e.g., McGaughy et
al. 1996) have long indicated that basal forebrain and other brain
cholinergic systems are involved in attention, as lesions or chemical
inactivation of cholinergic systems typically result in deficits on several
animal models of attention including five-choice serial reaction time tasks
(5-CSRTT; e.g., Robbins et al.
1989; McGaughy et al.
2002; Risbrough et al.
2002; Hahn et al.
2003a,b)
and two-choice vigilance tasks (e.g.,
McGaughy and Sarter 1995;
Turchi et al. 1995). Moreover,
treatment with drugs that enhance Ach function such as physostigmine and
nicotine can reverse the effects of lesions (e.g.,
Muir et al. 1995) or
facilitate performance on tasks requiring sustained attention (e.g.,
Mizra and Stolerman 1998;
Grilly et al. 2000). A more
recent study further demonstrates the involvement of cortical Ach for tasks
requiring sustained attention. Rats were trained in a two-choice operant task
in which the correct lever was indicated by the position of a light; animals
had to pay attention and "track" the position of the light to
maximize water reinforcement. Microdialysis probes implanted in the
frontoparietal cortex were used to asses Ach efflux during performance of the
task. Results indicated significant increases in Ach levels that were directly
related to the attentional requirements of the task, and were not the result
of motor or motivational factors involved in task performance
(Arnold et al. 2002).
Additional neuroanatomical evidence indicates that the attentional
disruptions caused by decreases in cholinergic transmission are mediated at
least in part by medial prefrontal cortex (mPFC; for a recent review, see
Robbins 2002). Select lesions
to mPFC by direct infusions of excitotoxins including quisolinic acid and
-amino-2-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) disrupt
attention as measured by decreased performance on the five-choice serial
reaction time task (Robbins
2002). In addition, excitotoxic lesions to the nucleus basalis
magnollaris (nbm) result in decreased choline acetyltransferase (ChAT)
activity, a cortical cholinergic marker, in rat PFC, likely owing to the
lesion-induced disconnection between nbm and PFC
(Robbins 2002). Peripheral
(subcutaneous) administration as well as direct infusions of nicotine into PFC
but not dorsal hippocampus improved accuracy on the 5-CSRTT in rats (Hahn et
al. 2003). Thus, PFC appears to mediate at least certain forms of attention.
This is especially relevant for the present study in which a trace EB
conditioning task was used, a task also shown to be dependent on mPFC
(Powell et al. 2000). Several
studies from our laboratory have shown that both pre- and posttraining lesions
to mPFC disrupt performance on a trace conditioning task in rabbits (e.g.,
Powell et al. 2001;
McLaughlin et al. 2002),
whereas mPFC lesions typically do not disrupt performance on
simple-delay-conditioning tasks (Buchanan
and Powell 1982). Trace conditioning tasks, therefore, appear to
require attentional as well as other cognitive resources (e.g., working
memory), as animals need to attend to the initially neutral CS, and then hold
the memory for the CS through the trace period so that the CS may be
associated with the US. The present study indicates that increasing Ach
transmission can facilitate performance on this difficult associative learning
task in a manner similar to that observed for other tests of cognitive
function including the 5-CSRTT and two-lever vigilance tasks. Thus, trace
eyeblink conditioning in the rabbit may also provide a valid animal model of
attention.
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MATERIALS AND METHODS |
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TOPABSTRACTRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Animals were equal numbers of male and female New Zealand albino rabbits obtained from a USDA-licensed supplier (Robinson Services, Inc.) and maintained in an AAALAC-accredited animal facility. Food and water were freely available. All behavioral testing was conducted during the daylight portion of a 12:12 h light/dark cycle with lights on at 7 a.m. All USPHS regulations regarding animal welfare were followed. There were eight animals in each of three dosage groups including 0 mg/kg, 1 mg/kg, and 3 mg/kg galanthamine hydrobromide. An additional 15 rabbits served as pseudoconditioning control animals. Seven of these animals received the vehicle alone, and eight received 3 mg/kg GAL.
Drugs
Galantamine hydrobromide (4a,5,9,10,11, 12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol hydrobromide) was purchased from Tocris Cookson Inc. or was generously donated by Janssen Pharmaceuticals. GAL was dissolved in sterile DI H2O in a solution of 1 mg/0.25 mL. Fresh solutions were prepared every 2–3 d. All animals were weighed daily, and equal volumes of drug or vehicle according to animal weight were injected subcutaneously (sc) into the nape of the neck 30 min prior to conditioning sessions.
Apparatus
All experimental events (timing, delivery of stimuli, data collection, etc.) were controlled by microcomputer with user-written software, and interfaced with the animal chambers via TTL logic devices. Intertrial intervals (ITIs) were pseudorandomly programmed (range = 30–90 sec). All EB responses were recorded by the computer, and by a Grass Model 7 polygraph with appropriate preamplifiers.
During classical conditioning, the conditioned stimuli (CSs) were 1216-Hz,
75–80-db (SPL) tones delivered for 500 msec. The unconditioned stimulus
(US) was a puff of air to the cornea (3.0 psi) delivered for 100 msec. US
onset began 500 msec after termination of the CS. The airpuff was carried to
the eye via a plastic tube that was attached to a moveable wire arm mounted on
slightly modified Gormezano-type Plexiglas rabbit restrainers
(Gormezano 1966). The airpuff
tube was attached to an air source through an electrically operated valve. The
tube terminated on a 2-mm diameter plastic pipette tip attached with Velcro to
the moveable wire arm so that the pipette tip could be oriented for each
animal 1 cm in front of the right orbit. Rabbit restrainers were placed inside
sound- and light-deadened commercial chambers (Industrial Acoustics). Chambers
were equipped with 6-in. overhead speakers placed 
10 in. above the
animal's head, through which the computer-generated tone-conditioned stimuli
were presented. The EB leads were connected to Grass EMG preamplifiers with
integrators. Output of the driver amplifiers were input to the A-D card of the
computer, where A-D recording was done in real time. The Grass polygraph also
provided a permanent analog record of all data.
Conditioning Procedures
Prior to conditioning training, animals received three 1-h adaptation sessions to the experimental chamber, during which they were loosely restrained, but no stimuli were delivered. On day 3 of adaptation, all animals received vehicle injections 30 min prior to being placed in the testing chambers. Conditioning sessions and data collection began on day 4. Training and test sessions consisted of 100 trials of CS–US pairings with an ITI of 60 ± 30 sec. Sessions lasted 60 min and occurred once a day for 13 d, which included 10 d of trace conditioning and 3 d of extinction training, consisting of 100 CS-alone trials with an ITI of 60 ± 30 sec.
Pseudoconditioning tests were conducted following either vehicle or 3.0 mg/kg GAL in 15 naive rabbits (n = 7 in vehicle group, n = 8 in 3.0 mg/kg GAL group) to ensure that increases in EB CRs observed during conditioning were not caused by non-associative processes. Naive rabbits were habituated to the experimental situation as described above. Then, 30 min prior to pseudoconditioning sessions, animals were injected with either 3.0 mg/kg GAL or sterile DI H2O. Each daily session consisted of 200 trials, 100 CS-alone trials and 100 US-alone trials, with an ITI = 30 ± 15 sec presented in a pseudorandom order such that neither stimulus was presented more than three consecutive times. Sessions lasted 60 min and occurred for 13 d.
For recording the EB response, electrodes constructed of orthodontic wire
were acutely inserted beneath the upper and lower eyelids. These electrodes
allowed for simultaneous recording of eyelid closure and nictitating membrane
extension (VanDercar et al.
1969). Electrodes were connected to a Grass model 7P3 preamplifier
and integrator set in its integrator mode. The preamplifier was calibrated
such that a 100-µV change across the electrodes corresponded to a 1-mm
deflection of the oscillograph pen. The amplitude of the signal (integrated
over the CS interval) served as the EB measure. An EB CR was defined as a
potential change of 100 µV or greater, corresponding to 0.5 mm of
eyelid movement. EB latency was defined as the time interval from CS onset
until the CR exceeded 100 µV.
Data Analysis
Data on percent CRs were analyzed by two-way (group x session) mixed ANOVAs with group as a nonrepeated measure and session as a repeated measure. Training and extinction sessions were analyzed separately, and included all experimental and pseudoconditioning control animals (n = 39). Additional separate two-way ANOVAs compared percent CRs for experimental animals (n = 24) and control animals (n = 15) to assess dose effects. Additional separate one-way ANOVAs analyzed dose differences for each training or extinction day. Post hoc analyses used the Student–Newman–Keuls method to analyze group differences when the ANOVAs were significant. Separate three-way ANOVAs (group x session x trial) were used to analyze CR amplitude and CR latency data for all animals. Extinction and pseudoconditioning sessions counted CRs as any 100-µV change across the electrode for 1 sec following the onset of the CS tone.
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ACKNOWLEDGMENTS |
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The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
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FOOTNOTES |
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4 E-MAIL barbara.simon2{at}med.va.gov; FAX (803) 695-7942.
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corneal airpuff unconditioned stimulus on each trial. During
extinction, 100 CS-alone trials were presented.
