Bidirectional Modulation of Goal-Directed
Actions by Prefrontal Cortical Dopamine
Paul K. Hitchcott, Jennifer J. Quinn and Jane R. Taylor
Department of Psychiatry, Division of Molecular Psychiatry,
Yale University School of Medicine, New Haven, CT 06508,
Instrumental actions are a vital cognitive asset that endows an
organism with sensitivity to the consequences of its behavior.
Response--outcome feedback allows responding to be shaped in
order to maximize beneficial, and minimize detrimental, outcomes.
behavior in several human psychopathologies. Such insensitivity to
habits: responses that are controlled by antecedent stimuli rather
than goal expectancy. Little is known regarding the neurochemical
substrates mediating this sensitivity. The present experiments used
sensitivity to posttraining outcome devaluation to index the action--
habit status of instrumental responding. Infusions of dopamine into
the ventral mPFC (vmPFC), but not dorsal mPFC, restored outcome
sensitivity bidirectionally—decreasing responding following out-
come devaluation and increasing responding when the outcome
was not devalued. This bidirectionality makes the possibility that
these infusions nonspecifically dysregulated vmPFC dopamine
transmission unlikely. VmPFC dopamine promoted instrumental
responding appropriate to outcome value. Reinforcer consumption
data indicated that this was not a consequence of altered sensitivity
to the reinforcer itself. We suggest that vmPFC dopamine reengages
attentional processes underlying goal-directed behavior.
Keywords: action, attention, dopamine, habit, instrumental, prefrontal
Acquiring knowledge about the relationship between behavior
and its consequences is a vital cognitive asset that permits
responses to be acquired and/or modified in the pursuit of
specific goals (Balleine and Dickinson 1998). This ‘‘response--
outcome association’’ is one of many encoded during instru-
mental conditioning (Colwill 1994). Clearly, dysfunction of the
neural substrates that encode or process this information may
result in maladaptive behavior (Toates 1998).
Instrumental responses controlled by knowledge of their
specific consequences are termed ‘‘actions.’’ The goal-directed
nature of actions is reflected by their sensitivity to posttraining
changes in outcome value. Thus, the performance of an action
spontaneously tracks changes in the value of its specific
outcome (Dickinson 1985). Continuous monitoring of the
response--outcome relationship requires allocation ofprefrontal
cortex (PFC)-dependent, limited-capacity cognitive processes
(Gehring and Knight 2000; Miller and Cohen 2001). This can
become redundant once responding has been shaped to pro-
duce the optimal behavioral outcome. Thus, extended, stable
response--outcome conditions promote a shift in the control of
instrumental responding from being goal directed to being
stimulus elicited. Instrumental responses triggered by environ-
mental stimuli are termed ‘‘habits.’’ The stimulus--response na-
ture of habits is reflected by their insensitivity to posttraining
changes in outcome value (Dickinson 1985). This action--habit
shift allows efficient responding to be maintained while permit-
ting the reallocation of cognitive resources to other demands
(Gehring and Knight 2000). Conversely, the inability to shift
from habit to action leaves an organism unable to readily adapt
to changing environmental conditions. This deficit is apparent
in various human psychiatric populations in whom general
cognitive functions are intact; yet, they compulsively perform
maladaptive behaviors that are primarily stimulus elicited
(Lhermitte 1986; Toates 1998; Montague and Berns 2002).
Studies in animals indicate that medial PFC (mPFC) integrity
is necessary both for the initial acquisition of task-relevant
responses and the suppression of task-irrelevant, especially
prepotent, responses (Balleine and Dickinson 1998; Coutureau
and Killcross 2003; Killcross and Coutureau 2003; Clark et al.
2004; Ostlund and Balleine 2005). Whereas these studies help
delineate the anatomical substrates mediating the balance
between actions and habits, the neurochemical substrates that
specifically influence this balance are not well understood.
Dopamine is one likely candidate because activation of dopa-
mine neurons increases during response acquisition but de-
clines following extended training under stable (i.e., habit
promoting) conditions (Ljungberg et al. 1992). The preferential
cortical targets of these dopaminergic neurons are precisely
those areas implicated in outcome sensitivity, namely, the
ventral mPFC (vmPFC) (Van Eden et al. 1987; Smiley et al. 1992).
Whereas striatal dopamine has been implicated in habitual
instrumental responding (Faure et al. 2005), there have been no
investigations of mPFC dopamine modulation of actions and/or
habits. Here, we tested the hypothesis that infusions of
dopamine into the vmPFC would promote goal-directed behav-
ior by increasing the sensitivity of instrumental responding to
the value of its outcome. Accordingly, we examined whether,
following habit formation, vmPFC infusions of dopamine would
promote responding appropriate to outcome value, which we
manipulated using a devaluation procedure that we and others
have previously shown to reduce the performance of an
instrumental action (e.g., Dickinson et al. 2002; Miles et al.
2003; Hitchcott et al. 2005; Quinn et al. 2006). Because the
vmPFC is implicated in the production of adaptive behavior
(e.g., Dalley et al. 2004), and dopamine has been suggested to
exert a permissive effect on this function (Hollerman et al. 2000;
Sullivan 2004; Fletcher et al. 2005; Floresco et al. 2006), we
hypothesized that dopamine infusions would promote adaptive
behavioral adjustments appropriate to current outcome value
Cerebral Cortex December 2007;17:2820--2827
Advance Access publication February 24, 2007
? 2007 The Authors.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
by guest on June 12, 2013
(i.e., enhance responding for a valued outcome and reduce
responding for a devalued outcome).
General Procedural Outline
We conducted 2 experiments looking at the role of dopamine in the
vmPFC on the expression of an instrumental habit. We first trained all
animals using procedures intended to generate an instrumental habit.
Subsequently, half of each group underwent a posttraining associative
reinforcer devaluation procedure by pairing the reinforcer that was
used during instrumental training with lithium chloride (LiCl). A
common procedure was then used to probe whether instrumental
performance was an action or a habit. Because actions are determined
by knowledge of their outcomes, their performance spontaneously
tracks outcome value such that posttraining devaluation of the outcome
results in decreased performance of the action. By contrast, habits are
directly elicited by antecedent environmental stimuli. As a result,
posttraining associative devaluation does not affect the performance
of habits. Hence, sensitivity to posttraining changes in outcome value
provides an objective criterion for distinguishing actions from habits. In
these experiments, the impact of an intra-vmPFC dopamine infusion on
instrumental performance was assessed. Finally, in experiment 2, all rats
underwent a reinforcer consumption test immediately following the
instrumental test session. This was done to test whether dopamine
infusions directly affected reinforcer value.
Subjects and Apparatus
Experimentally naive male Sprague-Dawley rats (Charles River Labora-
tories, Wilmington, MA), weighing 300--420 g at the time of surgery,
to acclimate to the colony room for at least 1 week prior to surgery.
Training and testing was conducted in 8 Med-Associates (St Albans, VT)
operant chambers housed within sound-attenuating boxes. Each cham-
ber was equipped with a liquid dipper that delivered 0.06 mL of 20%
(w/v) sucrose solution into a recessed magazine located in one of the
endwallsofthechamberwhenactivated. Aretractable leverwaslocated
of the top wall opposite the magazine provided illumination. Each
sound-attenuating chamberwas fitted with a fan and a speaker to deliver
white noise to mask sounds from outside. A PC equipped with the MED-
PC software controlled the equipment and recorded lever presses.
treated with the non-steroidal anti inflammatory drug carprofen (5 mg/
kg subcutaneously), and placed in a stereotaxic frame. Small holes were
drilled into the skull, and a bilateral guide cannula (22 gauge) was
lowered into either the vmPFC specifically targeting 1 mm above the
infralimbic (IL) cortex (+3.0 mm anterior-posterior, ±0.5 mm medial-
lateral (ML), and –4.2 mm dorsal-ventral (DV) relative to bregma) or the
dorsal mPFC (dmPFC) specifically targeting 1 mm above the cingulate
(CG1) cortex (+3.0 mm AP, ±0.5 mm ML, and –2.0 mm DV relative to
bregma) (Paxinos and Watson 2005). Subsequent infusions were
performed using a bilateral injection cannula (26 gauge) that projected
stainless steel screws and acrylic cement. Not less than 1 week after
g/dayof theirmaintenancedietuntil body weightswere reducedto 85%
of their preoperative, free-feeding level. Once training began, they were
fed sufficient food, at least 1 h after the training session, to maintain this
body weight. Access to water in their home cage was ad libitum.
Experiment 1: vmPFC Dopamine and Instrumental Performance
Rats (n = 40) were first given a single session of magazine training in
which sucrose solution was delivered (32 presentations) on a variable
time 60-s schedule with the lever removed. Next, lever-press training
was initiated during a single session of continuous reinforcement that
terminated once 30 reinforcers were earned. For all subsequent training
sessions (once daily), a random interval (RI) schedule of reinforcement
was used. Sessions ended after 90 min or the delivery of 100 reinforcers.
Sucrose was initially delivered on a RI 15-s schedule that was incre-
mented in steps of 15 each day until RI 60 s was reached. Training
continued for a further 4 sessions using a RI 60-s schedule. All animals
successfully acquired the lever-press response during the initial fixed
ratio1session,andthe rateofrespondingonthe finalRI 60-ssessionwas
12.4 ± 1.4 responses per minute. Animals were matched for their final
rate of responding prior to group assignment. Final group sizes were
(value/infusion) the following: valued/vehicle, n = 12; valued/dopamine,
n = 12; devalued/vehicle, n = 6; and devalued/dopamine, n = 10.
Experiment 2: Dissociation between vmPFC and dmPFC
In experiment 1, infusions of dopamine into the vmPFC produced
bidirectional effects on responding depending upon the outcome value.
Asecondexperimentwas conductedto assess the anatomical specificity
of these effects. This consisted of a replication of experiment 1 that
included additional groups of animals that received infusions of vehicle
or dopamine into the dmPFC. The training procedures were identical to
those used in experiment 1. All animals acquired the instrumental
response, and no differences were observed between vmPFC and
dmPFC cannulated groups either in the rate at which this response
was acquired or in the final rate of responding (responses per minute:
dmPFC = 15.2±1.5; vmPFC = 17.7± 2.0).Animalswere matchedfor their
final rate of responding prior to group assignment. Final group sizes
were vmPFC (value/infusion): valued/vehicle, n = 4; valued/dopamine,
n = 7; devalued/vehicle, n = 5; devalued/dopamine, n = 6; dmPFC (value/
infusion): valued/vehicle, n = 7; valued/dopamine, n = 6; devalued/
vehicle, n = 7; devalued/dopamine, n = 8.
Experiments 1 and 2: Outcome Devaluation by Conditioned Taste
In experiment 1, over the 3 consecutive days following the final
instrumental training session, the sucrose reward was devalued using
a conditioned taste aversion procedure. For the devaluation sessions,
each rat was allowed 30 min free access to a drinking tube containing
20% (w/v) sucrose (i.e., the reinforcer used during instrumental
training) in a novel context. Immediately thereafter, half of the animals
received an i.p. injection of lithium chloride (LiCl; 0.6 M, 5 mL/kg),
whereas the remaining half received sodium chloride (0.6 M, 5 mL/kg).
During these 3 days, conditioned taste aversion training was conducted
at least 4 h in advance of daily feeding. In experiment 2, the outcome
devaluation phase was modified such that animals in the valued and
devalued groups received equivalent exposure to LiCl, except that the
LiCl was paired with sucrose only in the devalued groups. Thus, over the
6 consecutive days following the final instrumental training session, all
animals received 3 injections of LiCl (0.6 M, 5 mL/kg) once every 2 days.
Subjects assigned to the ‘‘devalued’’ subgroups received this injection
immediately following 30 min access to sucrose as in experiment 1 (i.e.,
the sucrose and LiCl were paired). Subjects assigned to the ‘‘valued’’
subgroups received nothing following sucrose access. On the alternate
day ofeach 2-day cycle,valued subgroups receivedLiCl (0.6M, 5 mL/kg)
in the home cage (i.e., the sucrose and LiCl were unpaired), whereas
devalued subgroups received nothing. The order of treatment was
counterbalanced such that half the subjects received LiCl on days 1, 3,
and 5 and half on days 2, 4, and 6.
Experiments 1 and 2: Habit Test
In experiments 1 and 2, the day following the final outcome devaluation
session, each rat was lightly restrained and over 2 min received bilateral
intracranial infusions (0.25 lL/min) of dopamine (total dose 0 or 20 lg
in 1 lL) dissolved in phosphate-buffered saline containing 0.1% w/v
ascorbic acid. Selection of the dose of dopamine was based on data
showing that higher doses produced a nonspecific suppression of
responding (Hitchcott PK, Taylor JR, unpublished observations). Ten
minutes after this infusion, all animals received a 5-min test of
instrumental performance conducted in extinction. This test began
with the illumination of the house light and insertion of the lever and
ended with lever retraction and offset of the house light. No rein-
forcement was delivered during this test to establish that responding
Cerebral Cortex December 2007, V 17 N 12 2821
by guest on June 12, 2013
is determined solely by the information encoded during the previous
training phases and, in addition, a short test session was employed to
obviate any influence of extinction (Dickinson 1985). In experiment 2,
a brief (5 min) sucrose consumption test was conducted immediately
following the habit test. The purpose of this was to establish whether
the observed effects of dopamine infusions might be due to altered
sensitivity to the outcome per se.
Upon completion of behavioral testing, animals were anesthetized using
pentobarbital (>90 mg/kg i.p.) and perfused transcardially with 0.9%
saline followed by 10% formalin. Brains were extracted and placed in
10% formalin. Twodayspriorto being sliced,thebrainswere transferred
to a 10% formalin/30% sucrose solution. Brains were then sliced in 50-
lm-thick coronal sections using a cryostat. Sections at the level of the
infusion site were mounted on microscope slides and subsequently
stained using Cresyl Violet Acetate (Sigma, St. Louis, MO). Infusion sites
were identified under low-power light microscopy and their location
recorded using the atlas of Paxinos and Watson (2005).
Consumption data derived from the outcome devaluation phase of each
experiment were analyzed using a 3-way mixed-design analysis of
variance (ANOVA). Devaluation treatment (experiment 1: sodium
chloridevs. lithiumchloride;experiment2: LiClpaired orLiCl unpaired)
and infusion (experiments 1 and 2: vehicle or dopamine, which would
be administered before the final test) were included as between-subject
factors and day as a within-subject factor. Lever-press data from the final
instrumentaltest were analyzedusing a 2-waybetween-subjects ANOVA
using devaluation treatment and infusion (vehicle or dopamine) as
factors. Where indicated by a significant interaction of these factors,
post hoc t-tests were performed. In experiment 2, posttest sucrose
consumption data were not normally distributedin the devaluedgroups;
therefore, these data were further analyzed using nonparametric
statistics (Mann--Whitney U).
In experiment 1, all animals had infusion sites located within the
vmPFC (these were distributed throughout the entire dorsal--
ventral limits of IL cortex and within 0.5 mm of the intended
coronal plane i.e., AP+3.0± 0.5 mm) and weretherefore included
in the statistical analyses (see Fig. 1a). In experiment 2, a similar
distribution of infusion sites was observed in the vmPFC group,
whereas animals in the dmPFC group had infusion sites located
of the intended coronal plane i.e., AP +3.0 ± 0.5 mm, see Fig. 1b).
Experiment 1: vmPFC Dopamine and Instrumental
Performance following Devaluation
The data from the outcome devaluation phase are presented in
Figure 2a. The conditioned taste aversion was acquired rapidly
in those groups receiving lithium chloride but not in animals
receiving sodium chloride (devaluation: F1,36= 34.4, P < 0.001;
devaluation 3 day interaction: F2,72= 59.63, P < 0.001).
As seen in Figure 2b, rats infused with vehicle did not differ in
responding whether or not the reinforcer had been devalued,
confirming that the training procedures resulted in the de-
velopment of an instrumental habit. The effect of vmPFC
dopamine infusion was dependent upon outcome value (de-
valuation 3 infusion interaction: F1,36= 25.26, P < 0.01). In
comparison with vehicle-infused controls, dopamine infusions
reduced responding for a devalued outcome (P < 0.001) and
increased responding for a valued outcome (P < 0.05).
Experiment 2: Dissociation between vmPFC and dmPFC
The data from the outcome devaluation phase are presented in
Figure 3a,b. It is evident that the conditioned taste aversion was
acquired rapidly in the groups receiving sucrose--lithium
chloride pairings (devalued) but not in animals receiving
unpaired (valued) sucrose and lithium chloride (vmPFC de-
valuation: F1,18= 16.98, P < 0.01; devaluation 3 day interaction:
F2,34= 23.51, P < 0.001; dmPFC devaluation: F1,24= 22.75, P <
0.001; devaluation 3 day interaction: F2,46= 34.87, P < 0.001).
The data from the final habit test session are shown in Figure
3c,d. Separate analyses were performed on the data obtained
from vmPFC- and dmPFC-infused groups. There was no effect of
outcome devaluation in either vmPFC or dmPFC vehicle-infused
rats, confirming that the training procedures produced an
instrumental habit. Figure 3c shows the effect of dopamine
infusions into the vmPFC on instrumental performance. Statis-
tical analysis of the data replicated those of experiment
1.Dopamineexerted adifferentialeffectonresponding depend-
ing on outcome value (infusion 3 devaluation interaction: F1,18=
12.48, P < 0.01). Post hoc analyses indicated that dopamine
enhanced responding in valued animals (P <0.05) and reduced
responding in devalued animals (P < 0.05). The latter effect
Figure 1. Simplified schematic (adapted from Paxinos and Watson 2005) of the rat
PFC showing the location of the sites at which dopamine or vehicle was infused in
experiment 1 (a) and experiment 2 (b).
Prefrontal Dopamine and Instrumental Habit
Hitchcott et al.
by guest on June 12, 2013
reflected a reversal of the instrumental habit that was observed
in the vehicle-infused subjects. Figure 3d shows the effect
of dopamine infusions into the dmPFC on instrumental
performance. Dopamine nonspecifically reduced responding
regardless of outcome value (infusion: F1,24= 6.23, P < 0.05;
infusion 3 devaluation interaction: F1,24< 1).
Data from the consumption test are shown in Figure 3e,f.
Separate analyses were performed on the data obtained from
vmPFC- and dmPFC-infused groups. Figure 3e shows the effect
of dopamine infusions into the vmPFC on sucrose consumption.
Prior outcome devaluation was clearly effective in reducing
sucrose consumption (devaluation: F1,14 = 9.74, P < 0.01).
However, dopamine infusions had no significant effects on
sucrose consumption in either the valued or the devalued
groups (both F values <1). A very similar pattern of results was
observed in animals that received dopamine infusions into the
dmPFC (Fig. 3f). Again, prior outcome devaluation reduced
sucrose consumption (devaluation: F1,24= 11.44, P < 0.01), and
this effect was unaltered by dopamine infusion (both F values
<1). The near complete suppression of sucrose consumption
following devaluation resulted in a violation of normality within
those groups. The consumption data were, therefore, further
analyzed using the nonparametric Mann--Whitney U test. This
analysis entirely supported the ANOVA results. Prior outcome
devaluation was clearly effective in reducing sucrose consump-
tion inthe vmPFC group inboth vehicle- (U = 20.0, P <0.01) and
dopamine- (U = 40.0, P <0.01) infused rats. However, dopamine
had no significant effects on sucrose consumption in either the
valued or the devalued (P values >0.05) groups (Fig. 3e). An
dopamine infusions into the dmPFC (Fig. 3f). Prior outcome
devaluation reduced sucrose consumption in both vehicle-
(U = 49.0, P <0.01) and dopamine- (U = 48.0, P <0.01) infused
groups, and these effects were unaltered by dopamine infusion
in both the valued and the devalued (P values >0.05) groups.
The present study demonstrates that when animals are trained
using procedures that produce an instrumental habit, vmPFC
dopamine infusions produce opposite effects depending on
whether the reinforcer has been devalued by pairings with
lithium chloride. When devalued, dopamine reduces respond-
ing. When not devalued, it enhances responding. Therefore,
vmPFC dopamine increases the sensitivity of instrumental
responding to the value of its outcome leading to adaptive
bidirectional changes in performance. This bidirectionality
makes the possibility that vmPFC dopamine nonspecifically
disrupted behavior unlikely. Consistent with the anatomical and
functional heterogeneity of the mPFC, dopamine infusions into
the vmPFC, but not the dmPFC, produced this bidirectional
modulation of performance. The mechanism by which perfor-
mance was affected appeared not to involve changes in the
primary motivational properties of the reinforcer. First, dopa-
mine infusions into either region failed to alter posttest re-
inforcer consumption. Second, in a separate study, identical
vmPFC dopamine infusions suppressed, rather than enhanced,
responding for a valued reinforcer as assessed by progressive
ratio performance. Taken together, our data indicate that
dopamine in the vmPFC can modify the sensitivity of behavior
to its consequences generating instrumental responding that is
appropriate to current reinforcer value. These data demonstrate
a specific neurochemical substrate that determines whether
instrumental responding is expressed as an action or a habit.
It is possible that the present data showing bidirectional
effects of vmPFC dopamine on instrumental performance
reflect 2 dissociable underlying processes: one subserving the
decrease in responding in devalued animals and another
contributing to the increase in responding in valued animals.
If this is the case, then the general decrease in responding
following dmPFC dopamine infusions might suggest that both
vmPFC and dmPFC dopamine contributes to a reversal of
instrumental habit (promoting goal-directed behavior) as in-
dicated by a decrease in responding following devaluation.
However, the decrease in responding in valued animals is
counterintuitive to this interpretation because goal-directed
behavior should track current reinforcer value (Dickinson
1985). Thus, there would be no reason for responding in valued
animals to have changed. Therefore, we believe that dmPFC
dopamine generally decreases responding though it is unclear
what process this general suppression may reflect.
Figure 2. (a) Sucrose consumption during outcome devaluation in rats receiving
saline (open symbols) or lithium chloride (closed symbols) and that would sub-
sequently receive intra-vmPFC vehicle (circles) or dopamine (squares) prior to test. (b)
Instrumental performance during the 5-min habit test following infusion of vehicle or
dopamine. *P\0.05 and **P\0.01. yyP\0.01 versus respective valued group.
Cerebral Cortex December 2007, V 17 N 12 2823
by guest on June 12, 2013
Given that the posttraining reinforcer devaluation by condi-
tioned taste aversion was conducted in a separate context
that this devaluation training may transfer to the instrumental
context differentially among dopamine- and vehicle-infused
animals. Whereas this could potentially account for dopamine-
induceddifferences indevaluedanimals, thiscannot account for
the dopamine-induced differences observed in valued animals.
It is interesting that vmPFC dopamine appears to have the
direct opposite effect in modulating goal-directed behavior
compared with striatal dopamine. Faure et al. (2005) showed
that lesions of the nigrostriatal dopamine system disrupt the
development of an instrumental habit. Thus, generally speaking,
it appears that decreased dopamine function in striatum and
increased dopamine transmission in vmPFC both promote goal-
directed behavior. It will be interesting to see whether infusions
of dopamine directly into dorsal striatum and dopamine de-
pletion (or antagonism) within the vmPFC have similar effects
in promoting habitual responding. Future studies will need to
address how dopamine transmission is differentially regulated in
these 2 regions across training and/or how these 2 systems
compete for control over performance.
vmPFC Dopamine Amplifies the Sensitivity of Behavior to
In humans, lesions of the vmPFC increase control over behavior
by external stimuli at the expense of internally generated goals
(Lhermitte 1986; Bechara et al. 1994). This shift is hypothesized
to bias the expression of instrumental responding in animals
toward habit (Balleine and Dickinson 1998)—objectively
Figure 3. (a) Sucrose consumption during outcome devaluation in rats receiving unpaired (open symbols; valued) or paired (closed symbols; devalued) presentations of sucrose
andLiCl andthatwouldsubsequentlyreceiveintra-vmPFCvehicle(circles) ordopamine(squares) priortotest.(b)Sucroseconsumptionduringoutcomedevaluationinratsreceiving
unpaired (open symbols; valued) or paired (closed symbols; devalued) presentations of sucrose and LiCl and that would subsequently receive intra-dmPFC vehicle (circles) or
dopamine (squares) prior to test. (c) Instrumental performance during the 5-min habit test following vmPFC infusion of vehicle or dopamine. *P \ 0.05 and **P \ 0.01.
yyP\0.01versusrespectivevaluedgroup. (d) Instrumentalperformanceduringthe5-minhabit testfollowingdmPFC infusionof vehicleor dopamine. *P\0.05and**P\0.01.
yyP\0.01 versus respective valued group. (e) Posttest sucrose consumption following vmPFC infusion of vehicle or dopamine. (f) Posttest sucrose consumption following dmPFC
infusion of vehicle or dopamine.
Prefrontal Dopamine and Instrumental Habit
Hitchcott et al.
by guest on June 12, 2013
defined by insensitivity to posttraining changes in reinforcer
value (Dickinson 1985). We found that in rats trained to express
an instrumental stimulus--response habit, vmPFC infusions of
dopamine restored the spontaneous sensitivity to altered re-
inforcer value. That is, animals that had the reinforcer devalued
by pairings with lithium chloride responded less than animals
that had not received reinforcer devaluation. A novel finding of
this study is, therefore, the demonstration that vmPFC dopa-
mine is a specific substrate that determines the expression of an
instrumental response as an action or habit.
Numerous reports have shown that vmPFC function affects
behavioral disinhibition (Arnsten and Li 2005; Robbins 2005)
including, possibly, the disinhibition of instrumental actions
(Coutureau and Killcross 2003; Killcross and Coutureau 2003).
This latter study reported that temporary inactivation of the
vmPFC using the c-aminobutyric acid A agonist, muscimol,
increased responding for a ‘‘valued reinforcer’’ (i.e., nondeval-
ued) after habit training. Notably, muscimol failed to alter
responding for the ‘‘devalued reinforcer’’ when compared
with muscimol-infused valued animals. This finding appears
inconsistent with a reversal of habit because instrumental
responding that fails to track reinforcer devaluation does not
meet the objective criterion defining habits (Dickinson 1985). It
is possible in the study of Coutureau and Killcross (2003) that
muscimol infusions produce a general increase in responding
that masks any decrease in devalued animals. The increased
responding in muscimol-infused valued animals would be
consistent with this possibility. A major component of our
data is the unequivocal demonstration of a reversal of in-
strumental habit because dopamine reduces responding for
a devalued reinforcer and increases responding for a valued
reinforcer, thereby eliminating interpretational difficulties im-
posed by potential changes in general performance.
In addition to the reversal of an instrumental habit measured
by a reduction of instrumental responding following reinforcer
devaluation, vmPFC dopamine infusions enhanced responding
when the reinforcer was not devalued. This is a second major
finding of this study that vmPFC dopamine exerted a bidirec-
tional effect on instrumental performance depending on the
current reinforcer value. This observation is significant for 2
reasons. First, the fact that identical infusions both reduced and
enhanced responding diminishes an interpretation based upon
a nonspecific disruptive effect of vmPFC function by dopamine.
Second, a bidirectional modulation of responding, appropriate
to the current value of the reinforcer, suggests that dopamine
likely contributes to the generation of adaptive behavior by the
vmPFC (Price 2005). It is possible that the increased responding
in valued animals following vmPFC dopamine infusion may
reflect the normal level of responding expected of animals not
responding habitually. That is, the higher levels of responding
observed in dopamine-infused, relative to vehicle-infused,
valued animals may be attributable to differences among action
and habit responders, respectively. Dysregulation of vmPFC
dopamine function may contribute to maladaptive states, where
behavior is dissociated from its consequences.
Attentional Modulation within the vmPFC
The vmPFC has been proposed to generate cognitive--emotional
response‘‘sets’’(Price1999; Barbas2000; WallandMessier 2001;
Critchley 2005). Specifically, it has been demonstrated that
vmPFC integrity is necessary for the generation of autonomic
responses that guide effective decision making (Bechara et al.
shown to gate input of biologically significant information,
requiring the redirection of attention, into working memory
(Botvinick et al. 2001; Wall and Messier 2001; Corbetta and
Shulman 2002; Ullsperger and von Cramon 2004) while filtering
out information extraneous to the ongoing task (Fuster 1997).
Notably, the labeling of information as biologically significant
predominantly occurs ‘‘upstream’’ of the vmPFC in regions such
as the amygdala, hippocampus and the lateral subregion of
orbitofrontal cortex (OFC) (Schoenbaum et al. 1998; Wall and
Messier 2001). Thus, the vmPFC itself does not appear to
modulate the biological significance/value of events but rather
is consistent with the effects in humans of vmPFC lesions, and in
experience the detrimental consequences of their behavior yet
are unable to modify it (Bechara 2005; Ersche et al. 2005).
Our data accord with the view that vmPFC function deter-
mines the sensitivity of behavior to its consequences, while
extending it by implicating dopamine. Dopamine infusions were
without effect on consumption of the reinforcer itself, in-
dicating that dopamine did not alter sensitivity to the reinforcer
per se. We believe that vmPFC dopamine enhanced the
processing of task-relevant information and suppressed pro-
cessing of task-irrelevant information. That such a view impli-
cates dopamine in the modulation of a known function of the
vmPFC (Fuster 1997; Wall and Messier 2001; Corbetta and
Shulman 2002) lends additional credence to this hypothesis that
will be evaluated in future studies.
Attentional Modulation by Dopamine: Potential
Mechanism of Action
The region of the vmPFC targeted in the present study has been
implicated in ‘‘supervisory attentional functions,’’ such as extra-
dimensional set shifting (Birrell and Brown 2000; Dalley et al.
2004). Recent evidence demonstrates that performance in such
tasks is facilitated by vmPFC dopamine (Fletcher et al. 2005;
Floresco et al. 2006). This dopaminergic facilitation of cognitive
flexibility has been argued to promote behavioral adaptation in
both appetitive and aversive situations (Hollerman et al. 2000;
Sullivan 2004). Our findings add to this role of vmPFC dopamine
in 2 new ways. First, we have extended the role of vmPFC
dopamine to include the redirection of attention necessary for
the shift in instrumental control from habit to action that occurs
when a prepotent response produces a detrimental outcome.
Second, vmPFC control of behavioral flexibility is anatomically
dissociable (Dalley et al. 2004). Notably, only dopamine infu-
sions into the vmPFC were effective in producing bidirectional
modulation of instrumental performance.
Summary and Implications
The insensitivity of instrumental behavior to its consequences is
not necessarily maladaptive, whereas a failure to restore this
sensitivity can be. An organism without such flexibility is left
vulnerable to detrimental consequences of its behavior. The
associative basis for this deficit is a failure to shift responding
from habit to action, the anatomical locus of which has been
hypothesized to be the vmPFC (Balleine and Dickinson 1998).
Our data confirm this view and, furthermore, provide evidence
that optimal dopamine function is necessary for adaptive,
prospective (i.e., goal directed) control of behavior. In this
respect, it is notable that cortical dysfunction is common to
Cerebral Cortex December 2007, V 17 N 12 2825
by guest on June 12, 2013
several psychiatric disorders characterized by stimulus-elicited,
compulsive behaviors lacking sensitivity to their detrimental
consequences (Toates 1998; Volkow et al. 2004). Perhaps the
most obvious example is the inability of addicts to modify
the instrumental act of drug taking despite knowledge of the
negative consequences of this behavior (Bechara 2005; Everitt
and Robbins 2005). Whereas previous models have emphasized
the role of PFC dopamine in the inhibition of subcortical
substrates of reward-related learning (Jentsch and Taylor
1999; Jentsch et al. 2000), our data suggest that dysfunction of
cortical dopamine transmission would result in an attentional
deficit whereby biologically significant information fails to
functionally interrupt striatal-dependent, prepotent stimulus--
response habits (Yin and Knowlton 2006).
The authors thank Peter Holland for his helpful comments on an earlier
draft of the manuscript. This research was supported by grant DA11717
from the National Institutes of Health (NIH) and by the Tourette’s
Syndrome Association. JJQ was supported by NIH 5T32MH014276 to
Ronald Duman. Conflict of Interest: None declared.
Address correspondence to Dr Jane R. Taylor, Department of
Psychiatry, Division of Molecular Psychiatry, Yale University School
of Medicine, 34 Park Street, New Haven, CT 06508, USA. Email: jane.
Arnsten AF, Li BM. 2005. Neurobiology of executive functions: cate-
cholamine influenceson prefrontal
Balleine BW. 2005. Neural bases of food-seeking: affect, arousal
and reward in corticostriatolimbic circuits. Physiol Behav. 86:
Balleine BW, Dickinson A. 1998. Goal-directed instrumental action:
contingency and incentive learning and their cortical substrates.
Barbas H. 2000. Connections underlying the synthesis of cognition,
memory, and emotion in primate prefrontal cortices. Brain Res Bull.
BecharaA. 2005.Decisionmaking,impulsecontroland lossof willpower
to resist drugs: a neurocognitive perspective. Nat Neurosci.
Bechara A, Damasio AR, Damasio H, Anderson SW. 1994. Insensitivity to
future consequences following damage to human prefrontal cortex.
Bechara A, Tranel D, Damasio H, Damasio AR. 1996. Failure to respond
autonomically to anticipated future outcomes following damage to
prefrontal cortex. Cereb Cortex. 6:215--225.
Birrell JM, Brown VJ. 2000. Medial frontal cortex mediates perceptual
attentional set shifting in the rat. J Neurosci. 20:4320--4324.
Botvinick MM, Braver TS, Barch DM, Carter CS, Cohen JD. 2001. Conflict
monitoring and cognitive control. Psychol Rev. 108:624--652.
Clark L, Cools R, Robbins TW. 2004. The neuropsychology of ventral
prefrontal cortex: decision-making and reversal learning. Brain Cogn.
Colwill RM. 1994. Associative representations of instrumental contin-
gencies. In: Medin D, editor. The psychology of learning and moti-
vation: advances in research and theory, Vol. 31. Academic Press: San
Diego, CA. pp. 1--72.
Corbetta M, Shulman GL. 2002. Control of goal-directed and stimulus-
driven attention in the brain. Nat Rev Neurosci. 3:201--215.
Coutureau E, Killcross S. 2003. Inactivation of the infralimbic prefrontal
cortex reinstates goal-directed responding in overtrained rats. Behav
Brain Res. 146:167--174.
Critchley HD. 2005. Neural mechanisms of autonomic, affective, and
cognitive integration. J Comp Neurol. 493:154--166.
Dalley JW, Cardinal RN, Robbins TW. 2004. Prefrontal executive and
cognitive functions in rodents: neural and neurochemical substrates.
Neurosci Biobehav Rev. 28:771--784.
Dickinson A. 1985. Actions and habits: the development of behavioural
autonomy. Philos Trans R Soc Lond Ser B Biol Sci. 308:67--78.
Dickinson A, Wood N, Smith JW. 2002. Alcohol seeking by rats: action or
habit? Q J Exp Psychol. 55B:331--348.
Ersche KD, Fletcher PC, Lewis SJ, Clark L, Stocks-Gee G, London M,
Deakin JB, Robbins TW, Sahakian BJ. 2005. Abnormal frontal
activations related to decision-making in current and former
amphetamine and opiate dependent individuals. Psychopharmacol-
ogy (Berl). 180:612--623.
Everitt BJ, Robbins TW. 2005. Neural systems of reinforcement for drug
addiction: from actions to habits to compulsion. Nat Neurosci.
Faure A, Haberland U, Conde F, Massioui NE. 2005. Lesion to the
nigrostriatal dopamine system disrupts stimulus-response habit
formation. J Neurosci. 25:2771--2780.
Fletcher PJ, Tenn CC, Rizos Z, Lovic V, Kapur S. 2005. Sensitization to
amphetamine, but not PCP, impairs attentional set shifting: reversal
by a D1 receptor agonist injected into the medial prefrontal cortex.
Psychopharmacology (Berl). 183:190--200.
Floresco SB, Magyar O, Ghods-Sharifi S, Vexelman C, Tse MT. 2006.
Multiple dopamine receptor subtypes in the medial prefrontal
cortex of the rat regulate set-shifting. Neuropsychopharmacology.
Fuster JM. 1997. Network memory. Trends Neurosci. 20:451--459.
Gehring WJ, Knight RT. 2000. Prefrontal-cingulate interactions in action
monitoring. Nat Neurosci. 3:516--520.
Hitchcott P, Anderson G, Lombroso P, Taylor JR. 2005. Prefrontal
cortical modulation of striatal instrumental habit learning. Soc
Neurosci Abstr No. 997.918. 31.
Hollerman JR, Tremblay L, Schultz W. 2000. Involvement of basal ganglia
and orbitofrontal cortex in goal-directed behavior. Prog Brain Res.
Jentsch JD, Roth RH, Taylor JR. 2000. Role for dopamine in the
behavioral functions of the prefrontal corticostriatal system: impli-
cations for mental disorders and psychotropic drug action. Prog
Brain Res. 126:433--453.
Jentsch JD, Taylor JR. 1999. Impulsivity resulting from frontostriatal
dysfunction in drug abuse: implications for the control of be-
havior by reward-related stimuli. Psychopharmacology (Berl). 146:
Killcross S, Coutureau E. 2003. Coordination of actions and habits in the
medial prefrontal cortex of rats. Cereb Cortex. 13:400--408.
Lhermitte F. 1986. Human autonomy and the frontal lobes. Part II:
patient behavior in complex and social situations: the ‘‘environmen-
tal dependency syndrome’’. Ann Neurol. 19:335--343.
Ljungberg T, Apicella P, Schultz W. 1992. Responses of monkey
dopamine neurons during learning of behavioral reactions. J Neuro-
Miles FJ, Everitt BJ, Dickinson A. 2003. Oral cocaine seeking by rats:
action or habit? Behav Neurosci. 117:927--938.
Miller EK, Cohen JD. 2001. An integrative theory of prefrontal cortex
function. Annu Rev Neurosci. 24:167--202.
Montague PR, Berns GS. 2002. Neural economics and the biological
substrates of valuation. Neuron. 36:265--284.
Ostlund SB, Balleine BW. 2005. Lesions of medial prefrontal cortex
disrupt the acquisition but not the expression of goal-directed
learning. J Neurosci. 25:7763--7770.
Paxinos G, Watson C. 2005. The rat brain in stereotaxic coordinates. 5th
ed. San Diego (CA): Academic Press.
Price JL. 1999. Prefrontal cortical networks related to visceral function
and mood. Ann N Y Acad Sci. 877:383--396.
Price JL. 2005. Free will versus survival: brain systems that underlie
intrinsic constraints on behavior. J Comp Neurol. 493:132--139.
Quinn J, Hitchcott PK, Arnold AP, Taylor JR. 2006. Chromosomal sex
determines habit formation: relevance to addiction. Soc Neurosci
Abstr No. 483.4. 32.
Robbins TW. 2005. Chemistry of the mind: neurochemical modulation
of prefrontal cortical function. J Comp Neurol. 493:140--146.
Prefrontal Dopamine and Instrumental Habit
Hitchcott et al.
by guest on June 12, 2013
Schoenbaum G, Chiba AA, Gallagher M. 1998. Orbitofrontal cortex and Download full-text
basolateral amygdala encode expected outcomes during learning.
Nat Neurosci. 1:155--159.
Smiley JF, Williams SM, Szigeti K, Goldman-Rakic PS. 1992. Light
and electron microscopic characterization of dopamine-immunore-
active axons in human cerebral cortex. J Comp Neurol. 321:325--335.
Sullivan RM. 2004. Hemispheric asymmetry in stress processing in rat
prefrontal cortex and the role of mesocortical dopamine. Stress.
Toates F. 1998. The interaction of cognitive and stimulus-response pro-
cesses in the control of behaviour. Neurosci Biobehav Rev. 22:59--83.
Ullsperger M, von Cramon DY. 2004. Neuroimaging of performance
monitoring: error detection and beyond. Cortex. 40:593--604.
Van Eden CG, Hoorneman EM, Buijs RM, Matthijssen MA, Geffard M,
Uylings HB. 1987. Immunocytochemical localization of dopamine in
the prefrontal cortex of the rat at the light and electron microscop-
ical level. Neuroscience. 22:849--862.
Volkow ND, Fowler JS, Wang GJ. 2004. The addicted human brain
viewed in the light of imaging studies: brain circuits and treatment
strategies. Neuropharmacology. 47(Suppl) 1:3--13.
Wall PM, Messier C. 2001. The hippocampal formation—orbitomedial
prefrontal cortex circuit in the attentional control of active memory.
Behav Brain Res. 127:99--117.
Yin HH, Knowlton BJ. 2006. The role of the basal ganglia in habit
formation. Nat Rev Neurosci. 7:464--476.
Cerebral Cortex December 2007, V 17 N 12 2827
by guest on June 12, 2013