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First published online October 18, 2006
Journal of Experimental Biology 209, 4273-4282 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02520
Repeated cocaine effects on learning, memory and extinction in the pond snail Lymnaea stagnalis
1 Program in Neuroscience, Department of Veterinary and Comparative Anatomy,
Pharmacology and Physiology, Washington State University, Pullman, WA 99164,
USA
2 Department of Physiology and Biophysics, Neuroscience Research Group,
University of Calgary, T2N 4N1, Canada
3 Department of Chemistry, Washington State University, Pullman, WA 99164,
USA
* Author for correspondence (e-mail: sorg{at}vetmed.wsu.edu)
Accepted 4 September 2006
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Summary |
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Key words: cocaine, dopamine, reinstatement, Lymnaea stagnalis, long-term memory, snail
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Introduction |
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TOPSummaryIntroductionMaterials and methodsResultsDiscussionReferences |
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; Berke and Hyman,
2000; Wise, 2000;
Robinson and Kolb, 2004;
Wolf et al., 2004;
Hamilton and Kolb, 2005;
Liu et al., 2005). Changes
occur within dopaminergic brain regions that are similar to those found in
learning and memory studies, such as long-term potentiation and depression
(LTP and LTD, respectively) (Bonci and
Malenka, 1999; Thomas et al.,
2000; Liu et al.,
2005; Wolf et al.,
2004). Morphological alterations are observed in brain areas such
as the prefrontal cortex and nucleus accumbens after repeated psychostimulant
exposure (Ferrario et al.,
2005; Robinson and Kolb,
2004). Additionally, repeated exposure to these drugs produces
changes in intracellular signaling that influence learning and memory (for a
review, see Hyman, 2005).
Extinction training attenuates or reverses neuronal changes associated with
the memory of drug-related cues (Sutton et
al., 2003; Self et al.,
2004). Extinction training consists of exposure to the conditioned
stimulus, such as a drug cue, without the unconditioned stimulus, the drug.
After repeated extinction sessions, the original behavior can return with no
further stimulus [spontaneous recovery
(Pavlov, 1927)] or with
presentation of the unconditioned stimulus [reinstatement
(Myers and Davis, 2002)].
Although extinction appears to be forgetting, it is an active learning process
that occludes previously learned behavior but does not erase it
(Bouton, 1994;
Eisenberg et al., 2003;
Pedreira and Maldonado, 2003;
Suzuki et al., 2004). Thus,
the memory for extinction may critically impact the return, or reinstatement,
of behavior such as drug-seeking behavior. It is not known whether repeated
drug exposure produces a stronger initial memory of the trained behavior or if
it impairs extinction learning so that reinstatement occurs more readily or
easily, but distinguishing which pathways have been altered is especially
difficult in the complex mammalian brain. A first step toward addressing this
issue is to measure how drugs of abuse impact learning, memory and
reinstatement after extinction in a simpler neuronal circuit.
The pond snail, Lymnaea stagnalis, provides a relatively simple
model suitable for studying learning, memory and reinstatement behavior after
extinction (Lukowiak et al.,
1996) (for a review, see
Lukowiak et al., 2006).
Lymnaea are bimodal breathers via both cutaneous and aerial
systems. Aerial respiratory behavior is driven by a central pattern generator
consisting of three neurons: right pedal dorsal 1 (RPeD1), ventral dorsal 4
(VD4) and input 3 interneuron (Syed et
al., 1990; Syed et al.,
1992). Learning, memory and extinction have all been shown to be
dependent on RPeD1, which is dopaminergic
(Scheibenstock et al., 2002;
Spencer et al., 2002;
Sangha et al., 2004). Thus,
the circuitry involving RPeD1 may be susceptible to alteration after repeated
cocaine treatment. These changes can be measured by examining learning and
memory for operant conditioning of aerial respiration, and testing for the
memory of extinction during reinstatement of this conditioned behavior, which
appear to be RPeD1 dependent.
We tested the hypothesis that repeated cocaine exposure enhances learning and memory or impairs the memory for extinction during reinstatement of respiratory behavior. We first characterized dopamine uptake in Lymnaea stagnalis and measured the ability of cocaine to block this process using rotating disk electrode voltammetry and HPLC techniques. Second, we assessed whether repeated cocaine exposure enhanced learning and/or memory of operant conditioning of respiratory behavior. Third, we determined whether repeated cocaine exposure attenuated extinction memory during reinstatement of this conditioned behavior.
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Materials and methods |
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Drugs
Cocaine hydrochloride and dopamine were obtained from Sigma Chemical
Company (St Louis, MO, USA). Concentrations of cocaine (ranging from 0.03 to
10 µmol l-1 for HPLC studies) are reported as weight/volume of
the salt.
Voltammetry
To determine doses of cocaine that would effectively block dopamine uptake
from the extracellular space, we first characterized dopamine uptake using
rotating disk electrode (RDE) voltammetry to measure the kinetics of transport
and map the time course of dopamine uptake in isolated snail brain
suspensions. We note here that dopamine uptake is described as the clearance
of exogenously added dopamine from the extracellular space. As mentioned in
the results for Fig. 2 below,
we found a minor component of dopamine clearance that was not inhibited by
cocaine and, we attributed this effect to either an uptake mechanism that is
not sensitive to cocaine or to another mechanism unrelated to uptake, such as
monoamine oxidase-mediated metabolism of dopamine.
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Voltammetry was conducted at 22°C. The RDE (Pine Instruments, Grove City,
PA, USA) was lowered into the chamber and rotated at 2000 r.p.m. A potential
of 450 mV relative to a Ag/AgCl reference electrode was applied with a
potentiostat (LC-4B, Bioanalytical Systems Inc., Indianapolis, IN, USA). After
collecting a baseline signal, various amounts of dopamine were administered
using a constant-flow rate microsyringe. Increasing concentrations of dopamine
were added (in µmol l-1: 0.10, 0.15, 0.25, 0.5, 1.0). After each
addition, the disappearance of dopamine was monitored with a Nicolet 310
digital oscilloscope. The initial rate of dopamine disappearance was estimated
as described previously (Meiergerd et al.,
1997). The velocity of uptake was expressed as pmol s-1
g-1 wet mass.
High-pressure liquid chromatography
Use of the RDE technique allowed us to determine the time window over which
dopamine disappearance occurred. Because dopamine uptake occurred over a
matter of minutes rather than seconds, we could take advantage of measuring
dopamine uptake with high-pressure liquid chromatography (HPLC) to
unequivocally identify dopamine levels after cocaine addition to the tissue.
Brain tissue (five pooled brains per sample) was prepared in the same manner
as described for voltammetry, placed in the glass chamber and washed as
described above, and rotated at 2000 r.p.m. using the RDE as a stirring rod
only (i.e. not detecting changes in dopamine levels with this electrode).
Cocaine (0.03-10 µmol l-1) was added with a microsyringe and
allowed to incubate for 30 s before adding 0.5 µmol l-1
dopamine. After 2 min, the contents of the chamber were removed and
centrifuged at 10 000 g at 4°C for 1 min. The supernatant
was transferred to a tube containing 100 µl of 0.1 mol l-1
perchloric acid. Dopamine was measured by HPLC as described
(Wayment et al., 2001).
Drug exposure
All operant behavior experiments involving drug pretreatment were done in a
blinded fashion. Animals were randomly assigned to one of two treatment
groups: control or 0.1 µmol l-1 cocaine. Control animals that
were given training were conducted throughout the entire study, and the same
cumulative data for controls are shown in
Fig. 4C and
Fig. 5A. The treatments were
made by dissolving the appropriate amount of drug in 1 l of eumoxic pond water
(PO2 >75 mmHg). Animals were placed into 1 l of the
given treatment for 1 h daily. Immediately after the 1 h exposure, all animals
were returned to their home aquaria. Exposures were repeated once each day for
5 days. The exposure time was based on several studies examining the ability
of cocaine to produce locomotor sensitization in rats
(Kalivas and Stewart, 1991;
Robinson et al., 1998). At the
end of this exposure time, animals were given 2 days in their home aquaria
with no treatment to allow for complete wash-out of cocaine before beginning
the training sessions.
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Operant conditioning procedure
The protocol for sessions for Training, Memory Test, Extinction and Test
for Savings is shown in Table
1. A hypoxic environment (PO2 <7 mmHg) was
created by bubbling N2 through 800 mm of pond water at a rate of 2
ml min-1 for 20 min. Animals were given a 10 min acclimation
period, which ended by gently pushing each snail below the surface to signify
the beginning of the training period. Training consisted of gently touching
the open pneumostome with a sharpened wooden probe. This stimulus caused
immediate closure of the pneumostome but did not cause the snail to withdraw
into its shell. The time at which the pneumostome opened was recorded, and
total pneumostome openings over the training period were tabulated for
individual snails.
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The basic training module consisted of three 45 min sessions: Training 1,
Training 2, and the Memory Test. During these sessions, the conditioning
procedure was applied and the time of all pneumostome openings recorded.
Training 1 and Training 2 were separated by a 1 h inter-training interval,
during which the animals were housed in their home aquaria. The Memory Test
followed Training 2, 24 h later. This training protocol has been shown to
create a memory that lasts for up to 5 days
(McComb et al., 2002).
Yoked controls
We performed yoked control experiments to confirm that the decrease in
respiratory behavior was contingent upon application of the stimulus to the
open pneumostome. Yoked animals and their freely behaving partners were placed
into the same hypoxic conditions used in the operant conditioning procedure.
Yoked animals received a gentle tactile stimulus to their pneumostome area
whenever their yoked partner's pneumostome was open. This training was
repeated using the same training sequence as used in the operant conditioning
procedure. Pneumostome openings were also tabulated as in the operant
conditioning procedure.
Extinction training
Three extinction sessions of 45 min each were performed with the same
temporal sequence as the operant conditioning procedure and were done
according to the method of McComb et al.
(McComb et al., 2002). The
first extinction session was begun 1 h after the Memory Test, and the second
extinction session was given 1 h after the first session. The third extinction
session was given 24 h later. However, during extinction, no stimulus to the
pneumostome was given. Animals were allowed to freely perform aerial
respiration. The time of each pneumostome opening was recorded. To test for
the memory of extinction, tactile stimulation was given during a fourth
session, the Test for Savings, starting 2 h after the last extinction
session.
Definition of learning, memory, extinction memory/reinstatement
We defined learning as a significant decrease in pneumostome openings
compared with the previous session (McComb
et al., 2002). Demonstration of memory was determined by two
criteria: (1) the number of pneumostome openings during a session must be
significantly less than observed during Training 1 (T1), and (2) the number of
pneumostome openings must not be significantly more than on Training 2 (T2),
or the last training session. We defined extinction memory during the
reinstatement test as a violation of either criterion for memory after the
Test for Savings. Thus, for extinction memory to be present during the test
for reinstatement, (1) the number of pneumostome openings on the Test for
Savings must not be significantly less than on Training 1, or (2) the number
of pneumostome openings on the Test for Savings must be significantly more
than on the Memory Test.
Data analyses and statistical testing
Data obtained from RDE voltammetry experiments were plotted and fitted to
the Michaelis-Menten equation using non-linear regression (GraphPad Prism, San
Diego, CA, USA). The Km and Vmax
values were obtained from the Michaelis-Menten equation. Data obtained from
HPLC studies were plotted and the IC50 estimated by examining the
resultant line to determine the cocaine concentration at which dopamine uptake
was half-maximal. To determine the effect of training on respiratory behavior
for each treatment group, data from each set of cohorts was subjected to a
one-way analysis of variance (ANOVA) followed by a post-hoc Fisher's
least significant difference (LSD) test to compare sessions within groups. In
the case where two treatments were compared across days (Figs
3 and
8), a two-way ANOVA was
conducted followed by a Fisher's LSD test in the case of a significant
interaction. The level of significance was set at P<0.05.
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). This
characterization revealed a Km of 0.9 µmol
l-1 and a Vmax of 558 pmol s-1
g-1 wet mass for dopamine.
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For behavioral studies, we chose a dose of 0.1 µmol l-1
cocaine because this was the lowest dose that maximally inhibited dopamine
uptake. Previous work showed that respiration was significantly increased when
Lymnaea were acutely exposed to hydrogen sulfide
(Rossenegger et al., 2004). To
determine whether repeated cocaine exposure may have altered basal respiration
levels, we measured the behavior of snails before and after exposure to
cocaine. After measuring total breathing time of snails in hypoxic water for
45 min, animals were divided into two cohorts and received either water only
(control) or 0.1 µmol l-1 cocaine. Two days after the last
exposure, total breathing time was again recorded.
Fig. 3A indicates that snails
exposed repeatedly to 0.1 µmol l-1 cocaine significantly
increased the amount of time spent performing aerial respiration compared with
the pre-cocaine exposure session. The number of pneumostome openings is shown
in Fig. 3B. The number of
openings before and after cocaine exposure was not different across time when
performing a two-way ANOVA, but there was a trend toward an increase in
pneumostome openings in snails given repeated exposure to 0.1 µmol
l-1 cocaine.
We also confirmed that contingent application of a stimulus to the
pneumostome area during aerial respiration was necessary for operant
conditioning of the respiratory behavior. Three groups of snails were tested
under hypoxic conditions. Control animals were allowed to freely perform
aerial respiration. Yoked animals received a gentle tactile stimulus to the
pneumostome area when the animal they were yoked to opened its pneumostome.
Fig. 4A,B shows that animals
that did not receive the tactile stimulus or those yoked animals given the
stimulus but not paired with pneumostome openings did not alter their
respiratory behavior over the three sessions. However, contingently trained
animals that received a tactile stimulus to the pneumostome area each time
they opened their pneumostome significantly decreased aerial respiration per
session compared with Training Session 1
(Fig. 4C). Thus, the training
protocol produced associative learning in these animals, consistent with the
findings first reported by Lukowiak et al.
(Lukowiak et al., 1996).
To determine if cocaine affected learning and memory in Lymnaea, we exposed two cohorts of animals to pond water (controls) or 0.1 µmol l-1 cocaine. Animals were then given the same training regimen as shown in Fig. 4. Both groups showed significant learning in Training 2 (Fig. 5) because there were fewer pneumostome openings than during Training 1. Both groups also showed evidence of memory in the Memory Test 24 h later (significantly less than Training 1 but not significantly more than Training 2). A t-test conducted on Training 1 between the control and cocaine-exposed groups indicated that the total number of pneumostome openings on this day was higher in the cocaine-pretreated group compared with controls (P<0.013). Because of our previous findings when measuring total breathing time (Fig. 3A), we speculated that this was due to increased motivation or need for respiration in the 0.1 µmol l-1 cocaine pretreated snails compared with controls.
Each group of snails was then given extinction training, and performance was measured during the Test for Savings (Fig. 6). Control animals showed memory for the previous extinction sessions during the test for reinstatement (Test for Savings significantly higher than Memory Test). However, snails treated with 0.1 µmol l-1 cocaine did not demonstrate a memory for extinction sessions because their performance during the test for reinstatement was not significantly higher than that on the Memory Test, and in fact, they demonstrated a significantly lower number of pneuomostome openings than on the Memory Test. Thus, reinstatement was greater in cocaine-pretreated snails than in controls.
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We also normalized the performance on the Test for Savings as a percentage of the performance on Trial 1 the first day, and as a percentage of performance on the last extinction test. The reason for normalization was that the initial number of pneumostome openings was significantly higher in the cocaine-pretreated group compared with controls. Fig. 8 shows the comparison of normalized performance between groups on the Test for Savings, which is a demonstration of how well animals activate extinction memory during reinstatement when they are again given stimulation to the pneumostome. The cocaine-pretreated group demonstrated a significant decrease in extinction memory compared with controls, suggesting an increased reinstatement of the originally learned behavior after cocaine.
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Dopamine uptake in Lymnaea
The RDE studies indicate that dopamine uptake had a Km
value similar to the range of Km values for the rat
prefrontal cortex, nucleus accumbens and striatum (range 0.47-1.3 µmol
l-1) (McElvain and Schenk,
1992; Povlock and Schenk,
1997; Meiergerd et al.,
1997). The Vmax for dopamine uptake in the
snail was much closer to that of the nucleus accumbens or striatum (375-582
s-1 g-1 wet mass) than that reported for the prefrontal
cortex [31.7 pmol s-1 g-1 wet mass]. The IC50
for cocaine inhibition of dopamine uptake was lower (0.03 µmol
l-1) than the Ki or IC50 reported
for cocaine in brain tissue or heterologous expression systems for mammalian
dopamine transporter (range 0.14-2.0 µmol l-1)
(Kilty et al., 1991;
Jones et al., 1995;
Povlock and Schenk, 1997;
Wu and Gu, 1999). It is also
possible that the effects of cocaine on dopamine disappearance in the snail
could occur through uptake by the norepinephrine transporter, as in mammals
(Carboni et al., 1990;
Moron et al., 2002). Maximal
inhibition of dopamine uptake occurred in the presence of 0.1 µmol
l-1 cocaine, but a somewhat diminished inhibition was observed in
the presence of 0.3 µmol l-1 cocaine. The mechanism for this
reduced inhibition at intermediate cocaine concentrations is unclear, but the
effect may be related to a combined effect of cocaine on all three monoamine
transporters. Cocaine in the range of 1 nmol l-1 to 1 µmol
l-1 could alter the dynamics of dopamine and other
neurotransmitters because it significantly increases calcium influx in
Lymnaea neurons (Vislobokov et
al., 1993). However, at all doses tested, cocaine only partially
inhibited dopamine uptake (about 70%), even in the presence of 10 µmol
l-1 cocaine. This finding suggests the existence of a mechanism for
clearance of dopamine from the extracellular space that is not affected by
cocaine, similar to that reported elsewhere
(Wayment et al., 2001).
Cocaine effects on Lymnaea learning, memory and extinction/reinstatement
Snails receiving 0.1 µmol l-1 cocaine demonstrated learning
and memory similar to controls; however, extinction memory was less active or
impaired in cocaine-pretreated snails because they reinstated to a greater
extent than did controls. Three possibilities to explain this finding are
considered.
First, repeated exposure to 0.1 µmol l-1 cocaine may have altered metabolism, producing increased motivation for respiration early after `withdrawal', but at the time they were given the Test for Savings, their metabolic need was back to control levels. This would give the appearance of better reinstatement on the Test for Savings, because there would no longer be an increased need to surface breath. However, the respiratory behavior of snails exposed to 0.1 µmol l-1 cocaine and not operantly conditioned, did not alter pneumostome openings over a similar time course, so this is an unlikely explanation.
A second possibility is that repeated cocaine exposure increased the consolidation time for memory formation by increasing the time to produce new RNA transcripts. If cocaine is acting to delay the mechanisms responsible for altered gene activity, performing the Test for Savings at a later time might reveal a memory for extinction. This explanation however, seems unlikely because snails pretreated with cocaine demonstrated normal long-term memory on the Memory Test.
A third intriguing possibility is that repeated exposure to cocaine may
have decreased the plasticity of the respiratory central pattern generator in
Lymnaea by interfering with extinction memory. The lack of expression
of extinction memory might be due to a loss in the ability to adapt to a
changing environment after repeated cocaine. In rodents, the effects of
repeated cocaine and other drugs of abuse have been shown to reduce plasticity
at behavioral, morphological, electrochemical and neurochemical levels
(Kolb et al., 2003;
Robinson and Kolb, 2004;
Briand et al., 2005;
Hamilton and Kolb, 2005;
Goto and Grace, 2005;
Thompson et al., 2004). Briand
et al. found that a complex environment enhanced fearconditioned learning, but
that prior repeated exposure to amphetamine prevented this enhancement by the
complex environment (Briand et al.,
2005). Similarly, Kolb and coworkers
(Kolb et al., 2003;
Hamilton and Kolb, 2005) showed
that repeated drug exposure produced a resistance to modification of dendritic
branching in neurons that normally occurs in response to a complex
environmental exposure. This loss of plasticity may be responsible for the
long-lasting nature of addiction. Cocaine or other drugs of abuse may alter
inhibitory pathways activated during extinction such that reinstatement of the
originally trained behavior occurs more readily after presentation of the
original (unconditioned) stimulus.
Lymnaea is expected to provide a valuable model for exploring the
cellular, molecular and electrophysiological changes in neuronal pathways
important for extinction. In semi-intact preparations of Lymnaea,
central nervous system (CNS) neurons innervating the pneumostome and the
pneumostome itself are left intact so that electrophysiological properties of
the RPeD1 neuron can be compared before, during and after conditioning
(McComb et al., 2005). Operant
learning decreases rhythmic firing of the RPeD1 neuron and decreases the
ability of RPeD1 neurons to elicit pneumostome opening movements. This
decrease is directly correlated with the decreased pneumostome openings after
operant conditioning. It is unknown if extinction training causes a return to
pre-training levels of RPeD1 neuronal firing rate or the ability of this
neuron to produce pneumostome openings. However, the RPeD1 neuron is required
for extinction learning (Sangha et al.,
2004) and extinction behavior is thus expected to be reflected in
the firing properties of this neuron. Extinction of respiratory operant
conditioning requires altered gene activity and new protein synthesis in RPeD1
neurons in Lymnaea (Sangha et
al., 2003). Studies in rodents suggest that extinction involves a
change in glutamate receptors (Sutton et
al., 2003; Self et al.,
2004), and similar mechanisms may be present in
Lymnaea.
Increased respiratory behavior after cocaine
The increase in respiratory behavior observed in snails treated with 0.1
µmol l-1 cocaine could be a result of compensatory actions by
neurons to the cocaine challenge, essentially a withdrawal response from
cocaine. However, respiratory behavior did not change over the 5 days after
cocaine exposure in freely behaving animals. A similar effect of hydrogen
sulfide on respiratory behavior in Lymnaea was reversible
(Rossenegger et al., 2004),
but it is not clear if the same is true for the effect of cocaine on
respiratory behavior. The increased respiratory behavior may be a form of
behavioral sensitization. Snails immersed for 30 min day-1 for 5
days in 0.1-1.0 µmol l-1 cocaine do not demonstrate increased
locomotion on day 5 compared with day 1 (unpublished observations); therefore,
behavioral sensitization by repeated cocaine does not appear in the form of
increased locomotor activity as it does in rodents
(Wise and Bozarth, 1987).
In summary, these studies show for the first time that repeated cocaine exposure alters extinction memory during reinstatement of operant conditioning in Lymnaea. Our work provides a basis to further explore the impact of repeated cocaine on extinction and reinstatement processes occurring in a simplified and well-delineated neural circuitry. Lymnaea should provide an excellent model to further examine the fundamental processes underlying extinction learning, as well as extinction forgetting that may occur during spontaneous recovery and reinstatement of the originally learned behavior. Our findings suggest that repeated exposure to cocaine modifies the interaction between the original memory trace and active inhibition of this trace through extinction training. An understanding of these processes may have important implications for treatment strategies in cocaine addiction.
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