Bi-directional effect of increasing doses of baclofen on reinforcement learning.

Abstract

In rodents as well as in humans, efficient reinforcement learning depends on dopamine (DA) released from ventral tegmental area (VTA) neurons. It has been shown that in brain slices of mice, GABA(B)-receptor agonists at low concentrations increase the firing frequency of VTA-DA neurons, while high concentrations reduce the firing frequency. It remains however elusive whether baclofen can modulate reinforcement learning in humans. Here, in a double-blind study in 34 healthy human volunteers, we tested the effects of a low and a high concentration of oral baclofen, a high affinity GABA(B)-receptor agonist, in a gambling task associated with monetary reward. A low (20 mg) dose of baclofen increased the efficiency of reward-associated learning but had no effect on the avoidance of monetary loss. A high (50 mg) dose of baclofen on the other hand did not affect the learning curve. At the end of the task, subjects who received 20 mg baclofen p.o. were more accurate in choosing the symbol linked to the highest probability of earning money compared to the control group (89.55 ± 1.39 vs. 81.07 ± 1.55%, p = 0.002). Our results support a model where baclofen, at low concentrations, causes a disinhibition of DA neurons, increases DA levels and thus facilitates reinforcement learning.

Full text

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BEHAVIORAL NEUROSCIENCE
by haloperidol, participants learned slower and earned less money
compared to the control group. Interestingly, no shift of the learning
curves was observed when participants were in the loss condition,
which suggests that other processes are involved in aversive learning.
In a separate study using the Iowa gambling task, an activation of
the ventral striatum has also been shown by fMRI (Li et al., 2010).
The effect of DA on learning can be explained by a modulation
of the mesocorticolimbic system of circuits involved in action plan-
ning and decision-making. In many mammals, at least two systems
exist to predict the value of an action: the planning or explicit
system, which takes a given situation, predicts an outcome and
evaluates that outcome; and the habit or implicit system, which
takes a given situation and identifies the best remembered action to
take (Redish et al., 2008). The flexible planning system involves the
ventral and dorsomedial striatum, the prelimbic medial prefrontal
cortex and the orbitofrontal cortex, as well as the entorhinal cortex
and hippocampus, with an involvement of DA inputs from the VTA.
The habit system involves the dorsolateral striatum, the infralim-
bic medial prefrontal cortex as well as the parietal cortex, with an
involvement of DA inputs from the pars compacta of the substantia
nigra (SNc; Redish et al., 2008). The mesocorticolimbic system thus
has a central role in evaluating the value of predicted outcomes
during decision-making and planning. An over- evaluation of a pre-
dicted value by the DA system might alter the decision system lead-
ing to addictive behaviors (Redish et al., 2008). Another mechanism
leading to automatic decision-making and even addiction could be
the recruitment of the habit system by the NAc via feedback loops
to the dorsal striatum (Koob and Volkow, 2010). Understanding
how modulation of DA can alter valuation and decision-processing
therefore has profound implication for understanding motivated
IntroductIon
In his paper on “The Law of Effect,” Thorndike stipulated that:
“of several responses made to the same situation, those which
are accompanied or closely followed by satisfaction to the ani-
mal will, other things being equal, be more firmly connected with
the situation, so that, when it recurs, they will be more likely to
recur” (Thorndike, 1898). Since then, it has been suggested that the
mesolimbic dopamine (DA) system is involved in this learning by
coding for a “reward-prediction error” (Schultz et al., 1997). The
mesocorticolimbic DA system originates in the ventral tegmental
area (VTA), which projects to the nucleus accumbens (NAc) and
the prefrontal cortex. Under physiologic conditions, mesocorti-
colimbic projections release DA in response to natural rewards such
as food and sex, which are critical for the survival of the species.
This process reflects the fact that it is important for an organ-
ism to learn the circumstances under which rewards are obtained
(Balland and Lüscher, 2008). When an external reward is delivered,
DA neurons elicit a strong learning signal indicating whether the
value of the current state is better or worse than predicted (Schultz
et al., 1997), rather than euphoria or pleasure (Balland and Lüscher,
2008). This signal therefore allows rapid acquisition of predictive
cues and efficient behaviors that are successful in obtaining rewards
(Bechara et al., 1998).
Evidence that this system can be pharmacologically modulated
by changes in DA function has been provided by Pessiglione et al.
(2006). In their study, human volunteers carried out a learning task
that involved money gains and losses while functional magnetic
resonance images (fMRI) were collected. When mesocorticolimbic
DA was boosted by l-DOPA, the participants learned faster and
earned more money. Conversely, when DA signaling was inhibited
Bi-directional effect of increasing doses of baclofen on
reinforcement learning
Jean Terrier†, Andres Ort†, Cédric Yvon, Arnaud Saj, Patrik Vuilleumier and Christian Lüscher*
Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland
In rodents as well as in humans, efficient reinforcement learning depends on dopamine (DA)
released from ventral tegmental area (VTA) neurons. It has been shown that in brain slices of
mice, GABAB-receptor agonists at low concentrations increase the firing frequency of VTA–DA
neurons, while high concentrations reduce the firing frequency. It remains however elusive
whether baclofen can modulate reinforcement learning in humans. Here, in a double-blind study
in 34 healthy human volunteers, we tested the effects of a low and a high concentration of oral
baclofen, a high affinity GABAB-receptor agonist, in a gambling task associated with monetary
reward. A low (20 mg) dose of baclofen increased the efficiency of reward-associated learning
but had no effect on the avoidance of monetary loss. A high (50 mg) dose of baclofen on the
other hand did not affect the learning curve. At the end of the task, subjects who received 20 mg
baclofen p.o. were more accurate in choosing the symbol linked to the highest probability of
earning money compared to the control group (89.55 ± 1.39 vs. 81.07 ± 1.55%, p = 0.002). Our
results support a model where baclofen, at low concentrations, causes a disinhibition of DA
neurons, increases DA levels and thus facilitates reinforcement learning.
Keywords: instrumental learning, mesolimbic dopamine system, reward-prediction error, baclofen, bi-directional effect,
ventral tegmental area, anti-craving treatment
Edited by:
Riccardo Brambilla, San Raffaele
Scientific Institute and University, Italy
Reviewed by:
Carmen Sandi, École Polytechnique
Fédérale de Lausanne, Switzerland
Nicola Canessa, Vita-Salute San
Raffaele University, Italy
*Correspondence:
Christian Lüscher, Department of Basic
Neurosciences, Medical Faculty,
University of Geneva, CMU 1, Rue
Michel Servet, CH-1211 Geneva,
Switzerland.
e-mail: christian.luscher@unige.ch
†Jean Terrier and Andres Ort have
contributed equally to this work.
Frontiers in Behavioral Neuroscience www.frontiersin.org July 2011 | Volume 5 | Article 40 | 1
Original research article
published: 22 July 2011
doi: 10.3389/fnbeh.2011.00040

Page 2

behaviors and addiction. Here we propose to pharmacologically
modulate DA release with the GABAB-receptor agonist baclofen and
observe the effect of this modulation on an instrumental learning
task.
Baclofen (p-chlorophenyl-GABA) acts as a high affinity
g-aminobutyric acid type B (GABAB) receptor agonist. Its pri-
mary action as spasmolytic agent is mediated by increasing K+
conductance that results in postsynaptic inhibition (Cruz et al.,
2004; Katzung, 2009). In addition, baclofen causes presynaptic
inhibition by reducing Ca2+ influx and the release probability of
excitatory transmitters in the brain and spinal cord (Katzung,
2009). Interestingly, baclofen may also modulate DA release
in the mesocorticolimbic system by targeting VTA neurons
(Lomazzi et al., 2008). A recent model proposed by Cruz et al.
(2004) shows a bi-directional control of DA activity by increas-
ing doses of baclofen. In this model, low-dose baclofen prefer-
entially inhibits g-aminobutyric acid (GABA) neurons, which
control in part DA neuron activity, causing a disinhibition of
DA neurons. Conversely, high dose baclofen inhibits the firing
of DA neurons, resulting in a decrease of transmitter release to
the NAc in the ventral striatum. A possible explanation for this
phenomenon is based on a different coupling efficiency between
GABAB-receptors, G-proteins, regulator of G-proteins signaling
(RGS) proteins, and G-protein-gated inwardly rectifying potas-
sium channels (GIRK/Kir3), forming a macromolecular signal-
ing complex (Lomazzi et al., 2008). Indeed, it has been shown
that the concentration that produces 50% of the maximal effect
(EC50) of baclofen is one order of magnitude lower in GABA
neurons than in DA neurons. Therefore, low doses of baclofen
preferentially inhibit GABA neurons activity (Cruz et al., 2004;
Labouèbe et al., 2007).
In this study, the focus was on the question whether the pre-
diction error of reward signals (i.e., DA neurons firing) in healthy
human subjects can be modulated by increasing doses of baclofen.
We predicted that low-dose baclofen would disinhibit DA neu-
rons, eventually increase DA release, and thus make the behavioral
instrumental learning process more efficient. Conversely, high dose
would inhibit DA neurons and therefore reduce the learning rate.
MaterIals and Methods
experIMental procedure
The local ethics committee and Swissmedic approved the study
(CER 07-074, NAC 07-029, Swissmed: 2008DR2044). The present
experiments constituted a randomized, double-blind, placebo-
controlled study using low- and high-dose of baclofen. Informed
consent was obtained from all subjects.
A total of 36 healthy male subjects were recruited at the
University of Geneva. Exclusion criteria were an age below 18 or
above 35 years, weight below 60 or above 90 kg, regular consump-
tion of drugs or medications, regular gambling (≥1 time/week, i.e.,
Casino, lottery, poker), and history of psychiatric or neurological
disease. These 36 subjects were randomly split into three groups:
12 subjects received 20 mg of baclofen, 12 subjects received 50 mg
of baclofen, and 12 subjects received a placebo. The 50-mg group
took 10 mg on the first day and progressively increased the dosage
by 10 mg every day to reach 50 mg at day 5. The 20-mg group took
the placebo during the first 3 days, took the first 10 mg of baclofen
on day 4 and 20 mg on day 5. All groups had to take the last dose 1 h
prior to the instrumental learning task. All subjects had to take the
same number of compounds over 5 days. Over the 5-days, subjects
were asked to report their degree of alertness using the Stanford
Sleepiness Scale (SSS) in order to assess for adverse effects at dif-
ferent time points each day (10.00 am–1.00 pm–4.00 pm–7.00 pm)
and 30 min before the instrumental test (Hoddes et al., 1973). The
SSS is a rating scale measuring current level of subjective sleepi-
ness. It consists of seven statements describing different levels of
current sleepiness ranging from “feeling active and vital” (1 point)
to “almost in reverie” (7 points). In addition, subjects underwent
an auditory digit span test (in order and inversed order), to assess
for attention and vigilance just prior to the test.
Baclofen is usually used for its spasmolytic effects at a dosage
between 30 and 80 mg/day. Twenty milligram of baclofen there-
fore represent a low-dose (0.3 mg/kg p.o. respectively for a 70-kg
weighted person). At this dose, the predicted plasmatic concen-
tration is about 360 ng/ml after 0.5–1.5 h (=1.60 μM, baclofen
MW = 213 g/mol; Compendium Suisse des Medicaments, 2011).
In the CSF, the expected value is about 8.5 times lower than in the
plasma, which corresponds to 42 ng/ml for the 20-mg dose (nearly
0.20 μM; Compendium Suisse des Medicaments, 2011). These doses
theoretically correspond to the concentration activating VTA DA
neurons in vitro (Cruz et al., 2004). For 50 mg baclofen, the pre-
dicted plasmatic concentration is about 900 ng/ml after 0.5–1.5 h
(=4.2 μM, baclofen MW = 213 g/mol; Compendium Suisse des
Medicaments, 2011). In the CSF, the expected value corresponds
to 106 ng/ml for the 50-mg dose (nearly 0.50 μM; Compendium
Suisse des Medicaments, 2011). These doses theoretically corre-
spond to the concentration starting to inhibit the VTA DA neu-
rons in vitro (Cruz et al., 2004). Plasma elimination half-life of
baclofen is situated between 3 and 4 h (Compendium Suisse des
Medicaments, 2011).
The subjects had to perform one first practice session in order to
become acquainted with the instrumental learning task and three
subsequent experimental sessions of the same task adapted from
Pessiglione et al. (2006). Each session proposed three new pairs of
visual stimuli. Each of the pairs of stimuli (three conditions: “win”
to assess the effects of baclofen on the ability of reward learn-
ing, “loose” to learn from punishment, and “neutral” as a control)
was associated with three pairs of outcomes (“win” +1 CHF/nil,
“loose” −1 CHF/nil, “neutral” nil/nil), the two stimuli correspond-
ing to reciprocal probabilities (0.8/0.2 and 0.2/0.8). The neutral
pair was nil whatever the stimulus chosen.
The three conditions were randomly presented during each run
and the relative position of the visual stimuli was counterbalanced
across trials. Each item in the pairs belonged to the same semantic
field (e.g., animals, current life objects, transport vehicles etc.), in
order not to influence choices by stimulus meaning. In each of the
four test sessions, subjects first viewed the cues above and under
a central fixation cross (4 s), then indicated their choice by press-
ing a button on a separate keyboard that led to the appearance of
a red frame around the chosen item (1 s), and finally viewed the
outcome (1.5 s). A total of 60 trials were administered per session
(20 trials per condition, trial 0 was calculated as 0.495 ± 0.036 as
the mean and SEM across all starting points of the subjects). One
session lasted about 8 min each (Figure 1).
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Terrier et al. Baclofen modulates reinforcement learning

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in each individual were smoothed with a Gaussian filter (smooth-
ing: 3) using IGOR data analysis software (Wavemetrics, version
6.12A), and an average curve was then obtained for each group in
each condition. An ANOVA test and Dunnett’s test for comparisons
of the drug groups with the placebo group were used to analyze
the amount of money gain. For asymmetrically distributed values
(overall mean proportion of correct choices, proportion of correct
choices trial by trial, SSS scores), we used a Kruskal–Wallis test and
post hoc comparisons by Mann–Whitney test. All statistical tests
were performed with SPSS 17.0.
results
Data from the behavioral learning task was obtained from 34 indi-
viduals (11 each in the control and 20 mg baclofen group, 12 in
the 50-mg baclofen group). Out of the initial 36 participants, one
was excluded in the control group because of discontinuation of
substance taking for unknown reasons; and another was excluded
in the 20-mg group because of a history of psychiatric disease and
addictive behavior not previously detected during the initial exami-
nation. All participants had reached a university level and had a
mean age between 24 and 27 years. We specifically monitored for
the presence of tiredness as a potential side effect. No significant dif-
ferences were observed on the SSS between the three groups during
the whole week and just prior to the task (30 min before the test:
placebo group 1.7 ± 0.0.65 SD, 20 mg group 1.8 ± 0.61 SD, 50 mg
2.1 ± 0.67 SD points on the SSS). All subjects were able to repeat a
five numbers digit span in order and four numbers in reverse order.
In the experimental gambling task, we observed a significant
difference in choosing the correct stimulus between the groups,
specifically for the gain condition (Kruskal–Wallis test, χ2 = 14.56,
df = 2, p = 0.001) but not for the loss (Kruskal–Wallis test, χ2 = 5.38,
df = 2, p = 0.68) nor the neutral condition (Kruskal–Wallis test,
χ2 = 1.57, df = 2, p = 0.45). Comparisons with placebo showed a
significant difference for the 20-mg baclofen group for the gain
(89.55 ± 1.39 vs. 81.07 ± 1.55%, p = 0.002 with Mann–Whitney
test) but not for the 50-mg group (79.59 ± 1.63 vs. 81.07 ± 1.55%,
p = 0.734 with Mann–Whitney test, Figure 2). These results indicate
that subjects in the 20-mg baclofen group more often chose the
correct symbol associated with the highest probability of earning
money (gain pair).
Accordingly, the 20-mg baclofen group earned the highest
amount of money overall (20.82 ± 2.67 CHF), whereas the 50-mg
baclofen group received 18.08 ± 2.39 CHF and the placebo group
17.73 ± 2.08 CHF (Figure 2). However, the difference for the mon-
etary gain did not receive significance, in contrast to the proportion
of correct choice [ANOVA, F(2,31) = 0.488, p = 0.618].
Learning curves for the gain, loss, and neutral pairs were obtained
and plotted for each group (Figure 1). The 20-mg baclofen group
showed a faster learning rate over the first 10 trials for the gain
pair, with a significant difference in trial per trial comparisons for
trials 5 (p = 0.038), 7 (p = 0.046), 8 (p = 0.034), 9 (p = 0.025), 10
(p = 0.032), and 11 (p = 0.032; Mann–Whitney test for each trial
after Kruskal–Wallis test showing a significant difference between
the three groups). For the loss pair, in contrast, no significant dif-
ference was observed between the three groups (Kruskal–Wallis
test for each trial, data not shown). This was also the case for the
neutral pair (Kruskal–Wallis test for each trial, data not shown).
To earn money, the subjects had to learn, by trial and error, the
stimulus–outcome associations. Subjects were instructed to maxi-
mize their earnings. Each subject received the total amount earned
during the three experimental sessions. The task was coded using
the software e-PRIME.
data and statIstIcal analysIs
All statistical data were obtained from the three experimental ses-
sions (3 × 60 trials) and calculated for each condition (gain pair,
loss pair, and neutral pair, each 3 × 20 trials) and group (control,
20 mg baclofen, 50 mg baclofen). The overall mean proportion of
correct choices and money gain were calculated for each partici-
pant. Learning curves (proportion of correct choices across trials)
Figure 1 | A low dose of baclofen accelerates instrumental learning. (A)
Schematics of the gambling task. Subjects selected either the upper or lower
of two visual symbol stimuli presented on a computer screen and
subsequently observed the outcome. The correct symbol of the gain pair was
associated with 80% probability of winning 1 CHF , the correct symbol of the
loss pair was associated with 20% of loosing 1 CHF , the neutral pair served as
control. ms, Milliseconds. (B) Observed mean of behavioral choices over three
concomitant sessions of 20 trials per condition (gain and loss pair) for the
20-mg baclofen, 50 mg baclofen and control group. The learning curves show
the proportion of correct choices for each trial (1 means correct symbol
choosing for the gain pair, 0 means correct symbol choosing for the loss pair).
Trial per trial comparison between the 20-mg baclofen and the control group
showed statistical significance for trial 5, 7 , 8, 9, 10, and 11 (*p < 0.05). Trial
points were smoothed starting from trial 1 using Gaussian algorithm. Neutral
condition data not shown. ±SEM means standard error of mean.
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a reward predicting stimulus and the reward. This activation var-
ies monotonically with risk and could code for the discrepancy
between predicted and actual reward (Fiorillo et al., 2003). Such
data suggest that DA signals could have an important role in the
gain condition of our learning task for evaluating, confirming, and
finally learning the risk uncertainties associated with the different
reward cues. The effect of 20 mg of baclofen could be explained
by an enhancement of this process due to larger release of DA at
striatal synapses, acting as potent learning signal and by the involve-
ment of glutamate-dependent forms of plasticity in VTA neurons
(Ungless et al., 2001; Saal et al., 2003; Borgland et al., 2004), in the
NAc (Kourrich et al., 2007), and prefrontal cortex neurons (Sun
et al., 2005). Moreover, we have to remember that there are other
brain structures implicated in reward-coding than the mesocorti-
colimbic DA system. Additional discriminatory information could
be provided by the orbitofrontal cortex, striatum, and amygdala
(Schultz, 2010).
Besides enhanced learning by DA agonist, Pessiglione et al.
(2006) also reported a significant decrease in the learning curve
with the DA receptor antagonist haloperidol, which is known for
its strong depressant action on the VTA system (Pessiglione et al.,
2006). In a same manner, we expected a decrease in the learning
rate with a dosage of 50 mg of baclofen compared to 20 mg and
placebo. However, we did not observe such effect. This negative
result is most probably due to the fact that the concentration of
baclofen in the CSF may be too low (0.5 μM) to sufficiently inhibit
DA neurons. For complete abolition of firing, a concentration of
100 μM must be reached in vitro (Cruz et al., 2004). However, this
concentration virtually corresponds to nearly 10 g of baclofen
p.o., a dose that is two orders of magnitude higher than the usual
maximum dose (80 mg/day). Furthermore, these dosage-effect
relationships may also be strongly influenced by each individual’s
pharmacokinetics. To inhibit efficiently the VTA system, concen-
trations close to the maximum dose or even higher concentra-
tions may be necessary, which however can be confounded by the
occurrence of adverse effects such as tiredness, muscle weakness,
and headache.
dIscussIon
In this study, inspired by a rodent model of the effects of baclofen on
the VTA (Compendium Suisse des Medicaments, 2011), we could
demonstrate that the GABAB-receptor agonist baclofen causes a
significant modulation of reward-driven learning in young, healthy
male humans.
reward learnIng
Out of the two dosages used here, enhanced instrumental learning
was only observed in the low-dose baclofen group. Participants who
received 20 mg of baclofen chose the stimuli linked to the highest
probability of earning money significantly more often than the
other two groups. This effect is reflected by the greater steepness
of the learning curve for this group relative to the placebo group at
the first six trials, and a higher plateau thereafter. From this point
onwards, all groups reached a relatively stable performance but
with generally higher accuracy for the 20-mg group. In addition,
participants in the 20-mg baclofen group tended to earn more
money after the task completion, as compared to the other groups
(although this failed to reach significance). However, the overall
amount of money is not a reliable indicator of learning because
subjects can also earn money by choosing the wrong symbol in the
gain condition (0.2 probability of earning money).
These results are in agreement with those obtained in a recent
study using the nearly same learning task showing improvement of
learning with l-DOPA in the gain condition but not in the loss con-
dition (Pessiglione et al., 2006). This improvement was correlated
with an increase in striatal activity as measured with fMRI. A similar
effect was also described in a population with Parkinson’s disease
with problem gambling and shopping (Voon et al., 2010). The
implication of DA for reward processing is now well established.
According to the “prediction error hypothesis,” most DA neurons
encode a “reward-prediction error” (Schultz et al., 1997) indistinctly
responding to reward probability, magnitude, and the time when
the predicted reward is expected (Schultz, 2007). Moreover, one
third of DA neurons show a relatively slow, moderate, but signifi-
cant activation that increases gradually during the interval between
Figure 2 | Correct choice and money earned. (A) Percentage of correct choice after three concomitant sessions of 20 trials for the gain condition. There is a
statistical difference between the 20-mg baclofen and the control group (*p < 0.01). (B) Amount of money earned after three concomitant sessions of 20 trials for
each, the gain, loss, and neutral condition for the control, 20 mg baclofen and 50 mg baclofen groups. ±SD means standard deviation.
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As mentioned above, low-dose baclofen may have addictive
properties since it preferentially disinhibits DA neurons, which
increases the learning of reward signals. However, in contrast to
GHB, addictive behaviors are not widely observed for baclofen,
which is also a GABAB-receptor agonist (European Monitoring
Centre for Drugs and Drug Addiction, 2010). This apparent con-
tradiction can be explained by their difference in affinity for the
GABAB-receptor (high-affinity for baclofen, low-affinity for GHB;
Cruz et al., 2004). Thus, typical therapeutic doses of baclofen, par-
ticularly when given repetitively are most likely sufficient to sup-
press physiological DA firing and explain why baclofen is normally
not abused (Labouèbe et al., 2007), while concentrations obtained
with typical recreational use of GHB will preferentially affect VTA
GABA neurons.
In line with this interpretation, rodent studies show that baclofen
reduces self-administration of a number of drugs (Brebner et al.,
2002) and is considered a putative anti-craving compound in
humans (Cousins et al., 2002). A double-blind controlled study
with a relatively low dosage (30 mg/day) of baclofen has shown its
efficacy vs. placebo on sobriety and dropouts in alcohol-dependant
patients (Addolorato et al., 2007), while in most case-reports up to
120 mg/day was used in order to obtain the same effects (Ameisen,
2005; Agabio et al., 2007; Bucknam, 2007). Also well documented
is the reduction in cigaret consumption with a relatively high dos-
age of 80 mg/day (Franklin et al., 2009). However, the efficacy of
these regimens remains controversial, as other studies reported only
modest relief of symptoms (Garbutt et al., 2010). Patient adherence
(low half-life of baclofen) and disease heterogeneity (for example
anxious vs. non-anxious populations) may limit those studies. The
potential of baclofen as a putative anti-craving compound in aiding
the initiation, alleviation, and maintenance of drug abstinence is
therefore still a highly discussed topic and certainly needs further
clinical research.
conclusIon
Our randomized, double-blind, and placebo-controlled study
revealed a positive reinforcement in healthy subjects taking a sin-
gle dose of 20 mg of baclofen during an instrumental learning task
involving monetary reward. At this dosage, subjects were more
efficient in choosing the stimulus linked to the highest probability
of earning money, as compared with the placebo group. These
results suggest a reinforcement of prediction error learning signals
by baclofen for reward stimuli, and thus corroborate with in vitro
studies showing an enhanced activation of DA neurons with low-
dose baclofen. However, these mechanisms must be confirmed by
using fMRI or labeled baclofen with carbon-11, which will eventu-
ally correlate our findings with increased activity in the mesocor-
ticolimbic DA system and associated areas. In contrast, learning
was not affected by a higher dosage of 50 mg of baclofen. Such a
finding suggests that even higher dosages are needed to efficiently
inhibit the VTA reward system in vivo and to eventually serve as
an anti-craving treatment.
acknowledgMents
We thank the Lüscher and Vuilleumier labs for support and
discussion.
aversIon learnIng
We did not observe any differences between the three groups in the
loss condition, which is consistent with previous data (Pessiglione
et al., 2006). Dopaminergic neurons respond mostly with depressed
firing rates to aversive stimuli (Ungless et al., 2004; Schultz, 2007).
Recent studies however identified different subpopulations of DA
neurons that respond to aversive stimuli in being either excited or
inhibited (Brischoux et al., 2009; Matsumoto and Hikosaka, 2009).
Thus, the inhibited responding subpopulations might encode a
prediction error for aversive stimuli (Matsumoto and Hikosaka,
2009). Such neurons are situated in the ventromedial SNc and
VTA, projecting mainly to the ventral striatum, which is thought
to process reward values as classically assumed (Matsumoto and
Hikosaka, 2009). In addition, however, other structures like the
lateral habenula (Matsumoto and Hikosaka, 2008) and amygdala
(Paton et al., 2006) have neurons responding both to reward and
aversive stimuli. These other structures might subserve learning of
the loss condition without any impact of DA manipulation used
in the study of Pessiglione et al. (2006) and ours.
The importance of DA neurons in the aversive condition needs
to be considered and clarified in future studies. In humans, data
from fMRI in healthy subjects and patients with Parkinson’s disease
during a similar instrumental learning task, point to the impli-
cation of a distinct brain network including the anterior insula,
dorsal striatum, and orbitofrontal cortex, that influences the learn-
ing from negative outcomes (Pessiglione et al., 2006; Voon et al.,
2010). Although some DA neurons in VTA are activated by aver-
sive events, the largest DA activation is related to reward (Ungless
et al., 2004). Alternatively and more specifically, the addictive
behaviors in Parkinson’s disease may be associated with a shift of
the response to reinforcing cues from ventral (impaired) to dor-
sal striatum, so that the response itself becomes dominated from
stimulus–response rather than action–outcome representations
(Everitt and Robbins, 2005).
IMplIcatIon for addIctIon
The key role of the mesocorticolimbic system in the neurocircuitry
of addiction is generally accepted. (Koob and Volkow, 2010), and
these pathways could be implicated in addictive behaviors even
long after drug exposure (Lüscher and Bellone, 2008). Although
addictive drugs have very distinct molecular targets, they all cause
an increase in DA concentration in the mesocorticolimbic pro-
jection target structures (Lüscher and Ungless, 2006). Moreover,
there is strong evidence that drugs of abuse cause a potentiation of
excitatory synapses on the VTA DA neurons (Kauer and Malenka,
2007). Synaptic plasticity might therefore represent the cellular
mechanism underlying instrumental learning, which is pathologic
in addicts (Balland and Lüscher, 2008). Drugs that bind to the
G-protein coupled receptors (GPCR) belong to a first group of
addictive drugs, which includes morphine, delta-9-tetrahydrocan-
nabinol (THC), and the GABAB-receptor agonist g-hydroxy-butyric
acid (GHB; Lüscher and Ungless, 2006). The action of these drugs
is preferentially on GABA interneurons, which normally inhibit DA
neurons. Thus, inhibition of GABA neurons leads to a net activa-
tion of DA neurons and an increase of DA release, a mechanism
referred to as disinhibition.
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Received: 04 April 2011; accepted: 06 July
2011; published online: 22 July 2011.
Citation: Terrier J, Ort A, Yvon C, Saj
A, Vuilleumier P and Lüscher C (2011)
Bi-directional effect of increasing doses
of baclofen on reinforcement learning.
Front. Behav. Neurosci. 5:40. doi: 10.3389/
fnbeh.2011.00040
Copyright © 2011 Terrier, Ort, Yvon, Saj,
Vuilleumier and Lüscher. This is an open-
access article subject to a non-exclusive
license between the authors and Frontiers
Media SA, which permits use, distribution
and reproduction in other forums, provided
the original authors and source are credited
and other Frontiers conditions are complied
with.
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