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Single Neuronal Responses in Medial
Prefrontal Cortex During Cocaine
Self-Administration in Freely Moving Rats
JING-YU CHANG,*STEVEN F. SAWYER, JOSEPH M. PARIS, ALEXANDER KIRILLOV,
AND DONALD J. WOODWARD
Department of Physiology and Pharmacology, Bowman Gray School of Medicine,
Wake Forest University, Winston-Salem, North Carolina 27157
KEY WORDS drug of abuse; electrophysiology; behavior; mesolimbic system; reward
ABSTRACT Chronic single neuronal recording techniques were applied to investi-
gate the involvement of the medial prefrontal cortex (mPFC) during cocaine self-
administration in the rat. Rats were trained to press a lever for cocaine under continuous
reinforcement and fixed ratio schedules. Different patterns of phasic neuronal activity
changes were found to be associated with lever-pressing for cocaine. The neuronal
responsescouldbeclassifiedintofivecategories:1)increasesinneuronalfiringbeforethe
lever press (15 out of 121 neurons, 12.4%); 2) decreases in neuronal firing before the lever
press (13 neurons, 10.7%); 3) increases in neuronal firing after cocaine infusion (4
neurons,3.3%);4)decreasesinneuronalfiringaftercocaineinfusion(32neurons,26.4%);
and 5) no alteration of neuronal activity throughout the self-administration session (67
neurons, 55.4%). The anticipatory responses, i.e., neuronal activity appearing before the
lever press, were observed for both the continuous reinforcement and fixed ratio
schedules. In a few cases, alteration of firing rate was not observed for the first lever
press but appeared before subsequent lever presses in fixed ratio schedules. Eliminating
cocaine abolished the inhibitory neuronal responses observed after lever press, suggest-
ing that these inhibitory responses after cocaine self-administration were attributable to
the pharmacologic effect of cocaine. The data provide initial electrophysiological evidence
that the mPFC may play a role in mediating the task sequencing which leads to cocaine
self-administration.Synapse 26:22–35, 1997. r1997 Wiley-Liss, Inc.
INTRODUCTION
In previous studies using chronic electrophysiologic
recording techniques to examine nucleus accumbens
(NAc) neuronal activity during cocaine self-administra-
tion, we discovered a variety of neuronal activity
changes before and after lever-pressing for cocaine
(Chang et al., 1990, 1991, 1994a). The neuronal activity
changes before a lever-press are termed ‘‘anticipatory
responses’’ and may represent a segment of a trigger
mechanism within NAc to initiate task sequencing
needed for cocaine self-administration. In contrast, the
inhibitory responses observed after cocaine self-admin-
istration may establish conditions needed for the rein-
forcing properties of cocaine. Importantly, the anticipa-
tory responses were not affected by dopamine
antagonist,suggestingthattheNAcmayemploynondo-
paminergic signals in its control of cocaine-reinforced
behavior (Chang et al., 1994a). Hence, inputs in addition
to dopaminergic afferent are likely to affect neuronal
activity within the NAc.
Although these results strongly suggest an impor-
tant role that the NAc might play in the cocaine
self-administration process, the issue of how other
mesolimbicstructuresmay contribute is only beginning
to be clarified. Many regions contribute afferent input
to NAc regions, including the prelimbic, infralimbic,
and agranular insular cortices, the basolateral amyg-
dala region, and the dorsal and ventral subiculum
(Berendse et al., 1992; Christie et al., 1987; Groenewe-
gen et al., 1982, 1987; McDonald, 1991). Characteriza-
tion of the activity generated by each region and the
nature of the information coded are major goals for
understanding the neuronal basis for cocaine self-
administration.
Contract grant sponsor: NIDA; Contract grant number: DA-2338 (to D.J.W.).
*Correspondence to: J.-Y. Chang, Dept. of Physiology and Pharmacology,
Bowman Gray School of Medicine, Wake Forest University, Medical Center Blvd.,
Winston-Salem, NC 27157. E-mail: jchang@biogfx.bgsm.wfu.edu
Received 13 June 1996; Accepted 30 August 1996
SYNAPSE 26:22–35 (1997)
r1997 WILEY-LISS, INC.
The concept of the involvement of the medial prefron-
tal cortex (mPFC) in reward-related behavior is derived
from evidence that rats will readily electrically self-
stimulate the mPFC (Mora and Cobo, 1990; Robertson,
1989; Routtenberg and Sloan, 1972). A large body of
studies also indicates that the self-stimulation (SS) of
another mesolimbic pathway, the medial forebrain
bundle (MFB), involves different neuronal mechanisms
(Robertson, 1989). Lesions of MFB fail to alter mPFC
SS (Corbett et al., 1982). Furthermore, neuroleptic
treatment causes an upward shift in the rate-frequency
curve for MFB SS at a low dose and abolishes SS at a
high dose; on the other hand, mPFC SS is not affected
by either low or high doses of neuroleptics (Corbett,
1990). These results suggest that a dopamine-indepen-
dentneuronal circuit is responsible for SS in the mPFC.
However, the finding that cocaine facilitates mPFC SS
appearstoimplicatedopamineinthemPFCSS(McGre-
gor et al., 1992; Moody and Frank, 1990). In addition,
neurochemical studies have shown that mPFC-regu-
lated dopamine release in the NAc is possibly mediated
by glutamate action on the ventral tegmental area
(VTA) dopamine neurons (Karreman and Moghaddam,
1996; Taber and Fibiger, 1995). Direct self-administra-
tion of cocaine into the mPFC has been reported, and
6-hydroxydopamine lesions of mPFC effectively attenu-
ate cocaine self-administration into that area (Goeders
and Smith, 1983, 1986). In accordance with this find-
ing, a recent study has shown that microinjection of the
D1antagonist SCH23390 into the mPFC increases the
response rate for intravenous cocaine self-administra-
tion (McGregor and Roberts, 1995). However, other
studies have shown that lesions of mPFC dopamine
terminals fail to alter (Martin-Inverson et al., 1986) or
even increase (Schenk et al., 1991) intravenous cocaine
self-administration. The different experimental proto-
cols (intracranial vs. intravenous injection) utilized in
these studies make it difficult to directly compare
experimental results. The inconsistencies nevertheless
reflect the complexity of the issue regarding involve-
ment of the mPFC in cocaine self-administration.
In light of the close anatomic connections between
NAcandtheregionofthemPFCandfunctionalsimilar-
ity between these two structures involved in reward
processes, we explored the neuronal activity changes in
the mPFC during cocaine self-administration as a next
step in the analysis of mesolimbic system function.
Preliminary results from this report have been pre-
sented in abstract form (Chang et al., 1993).
MATERIALS AND METHODS
Animals and surgery
Twenty-eight young adult male Sprague-Dawley rats
weighing 250–300 g were used in these experiments.
Animals were housed in a reverse dark-light cycle
(lights off from 7.00–19.00 h). In preparation for sur-
gery, rats were anesthetized with pentobarbital (50
mg/kg, i.p.). Two splayed bundles of eight stainless-
steel teflon-insulated microwires (45–62 µm diameter,
NB Labs, Denison, TX), soldered onto connecting pins
onaheadstage, were stereotaxically lowered bilaterally
into the mPFC (eight wires per side) (Chang et al.,
1994a). Coordinates for the mPFC were obtained from
the atlas of Paxinos and Watson (1986): 0.5 mm lateral
to midline, 3.5–3.8 mm anterior to bregma, and 3.5–4.0
mm ventral to the dorsal surface of the brain. In
addition, ground wires were positioned about 2 mm
ventral to the cortical surface. The headstage was
secured onto the cranium with dental cement, using
skull screws as anchors. The headstage and dental
cement weighed about 7 g. Under sterile conditions,
silastic tubing (26 mm long, 0.3 mm i.d. diameter
cannula tubing, connected to a 90-mm-long, 0.6-mm i.d.
diameter outlet tubing) was inserted in the right jugu-
lar vein for subsequent intravenous drug infusion. The
infusion tubing was glued to silastic implant sheeting,
which was sutured to the subdermal connective tissue.
The exposed plugged end of the tubing emanated from
the dorsal aspect of the neck. The animal received
ampicillin (60,000 units, i.m.) after surgery. Animals
were housed individually after surgery, and treated in
accordance with the U.S. Public Health Service’s Guide
for the Care and Use of Laboratory Animals.
Apparatus and behavioral training
Five to seven days after surgery, rats were placed in
separate rectangular operant conditioning cages, each
of which was enclosed in a sound-attenuating chamber.
The base of the cage was 20 323 cm, and was 20 cm in
height. Alever was mounted on one wall 8 cm above the
cage floor. Rats were initially trained to press the lever
for a water reward, using a continuous reinforcement
schedule; cocaine was later substituted for water. Daily
experimental sessions typically began about 2 h into
the animal’s dark cycle and lasted about 2 h. Training
started with a continuous reinforcement schedule in
which a single lever-press was followed by infusion of
1.0 mg/kg cocaine. Once stable rates of responding were
achieved, fixed ratio schedules (FR5 and FR10) were
imposed. Well-trained rats pressed the lever for cocaine
self-administration about every 4–5 min.
Once trained, extracellular recording of mPFC spike
activity was accomplished by connecting a headset onto
the implanted headstage. Lightweight cabling con-
nected the headset to a commutator and electronics
(described below). The commutator was free to turn as
necessary. In this manner, the animal was permitted
unrestricted movement in the operant chamber. The
indwelling jugular cannula was connected to an infu-
sion pump via a plastic tube. A cocaine-contingent
lever-press activated the pump for 4 sec (with a 0.5-sec
delay), thereby infusing approximately 1 mg/kg of
cocaine (0.33 mg in 0.1 ml lactated Ringer’s solution)
into the jugular vein. Twenty-second ‘‘time-out’’ periods
23FRONTAL ACTIVITY IN COCAINE SELF-ADMINISTRATION
were then imposed during which the lever-press was
inactivated to prevent an overdose of cocaine.
Electrophysiological recording
Neuronal activity was recorded during experimental
sessions by securing detachable headsets (containing
16 field-effect transistors, one for each microwire) to the
headstage cemented on the animal’s head. Neuroelec-
tric signals were passed into a programmable amplifier,
filter (0.5 and 5 KHz 3-db cutoffs), and multichannel
spike-sorting device. The in vitro impedance of micro-
wires at 1 KHz was 100–200 KVwith similar in vivo
values. As many as 16 mPFC neurons per rat were
monitored concurrently in later sessions as the method
improved. When spike activity was recorded from the
same microwire across different self-administration
sessions, it appeared that the same neuron was re-
corded in view of: 1) constancy of shape and polarity of
the extracellular spike waveform, and 2) similarities in
firing rate and pattern (e.g., interspike interval and
autocorrelation histograms). The conclusion that the
same unit was monitored across consecutive sessions
was particularly unambiguous in cases of large ampli-
tude neurons (signal-to-background ratio .5).
Spike activity, lever pressing, pump activation, and
the houselights were monitored or controlled with data
acquisition software operating on a computer with a
time resolution of 1 msec. Neuronal spike activity was
collected from the same rat on a daily basis for 1–4
weeks, beginning about 2 weeks after surgery, at which
timelever-pressingbehavior had stabilized. Spike train
activity was analyzed with a commercially available
PC-basedprogram (STRANGER, Biographics Inc., Win-
ston-Salem, NC).
Histology
At the conclusion of the final experimental session,
10–20 sec of 10–20 nA positive current were passed
through two selected microwires to deposit iron ions.
The marking current was passed through no more than
two microwires in a bundle of eight microwires, since it
was not possible to distinguish more than two sites
using different current parameters. Since it was often
the case that more than two microwires in a bundle of
eight yielded isolated single units, not every recording
site was identified. Microwires from which ‘‘anticipa-
tory responses’’ (see Results) had been recorded were
preferentially selected for marking. The animals were
then sacrificed and perfused with a formalin solution.
Coronal sections were cut through the mPFC and
mounted on slides. Incubation of the mounted sections
in a solution of 5% potassium ferricyanide/10% HCl
revealed iron deposits (recording sites) in the form of
blue dots. If marked recording sites were localized to
the mPFC, it was assumed that unmarked microwires
had also been positioned in the mPFC, since the
dispersiondiameter of the implanted microwire bundles
was no more than 0.5 mm (as verified in situ with
X-rays). Boundaries of the mPFC were assessed with
reference to the rat-brain atlas of Paxinos and Watson
(1986).
Data analysis and statistics
The mean firing rate was measured in perievent
histograms in which a behavioral node (lever-press,
raising head, etc.) was selected as a reference point
(time zero in the perievent histogram plot), and the
spike activity of each trial was plotted for the duration
of 100 sec before and 100 sec after the behavioral node.
The average firing rate of all the trials measured was
calculated as control (40–80 sec before lever-press),
anticipatory (1–3 sec before lever-press), and postco-
caine (40–80 sec after lever-press) phases. Pairwise
comparisons of means were evaluated with a two-tailed
Student’s t-test. Analysis of variance (ANOVA) was
used when evaluating more than two groups, with the
Tukey highest significant difference (HSD) test used for
specific comparisons when indicated by ANOVA. Statis-
tical analyses were performed with a commercially
available software program (SYSTAT, Inc.). Data are
presented as mean 6SEM.
RESULTS
General profile of single neuronal activity
in mPFC
A total of 121 single neurons was recorded from the
mPFC during different experimental procedures from
24 rats. In a given session, 1–16 neurons were recorded.
Each neuron recorded during a session was defined as a
‘‘neuron-session.’’ A total of 236 neuron-sessions were
recorded in all animals during different behavioral
protocols. The firing rate was evaluated during a ‘‘con-
trol period,’’ 40–80 sec prior to the lever-press. Activity
appearing 1–3 sec before the lever-press was defined as
an anticipatory response, and activity from 40–80 sec
after the lever-press as ‘‘postcocaine response.’’ The
mean firing rate during the control period was 5.19 6
0.65 Hz (n 5121). According to changes in neuronal
activities during the cocaine self-administration ses-
sion, the response of these 121 neurons could be classi-
fied into five categories: 1) neurons that increased their
firing rate immediately before the lever-press (15 neu-
rons, 12.4% of total neurons recorded); 2) neurons that
decreased their spike discharge shortly before cocaine
self-administration (13 neurons, 10.7% of total); 3)
neurons that showed postcocaine excitation responses
in which an increase in firing rate occurred after
cocaine infusion; four (3.3% of total) neurons possessed
this response; 4) neurons that decreased their firing
rate after cocaine self-administration; among the latter
group, 22 had postcocaine inhibitory responses and 10
exhibited both anticipatory responses and postcocaine
inhibitory responses, altogether a total of 32 (26.4% of
24 J.-Y. CHANG ET AL.
total) neurons in this group; and 5) neurons that had no
responseseitherbeforeoraftercocaineself-administra-
tion(67 neurons, 55.4% of total). TableI summarizes all
the neuronal responses observed in mPFC.
Anticipatory responses
Anticipatory responses were characterized as an
increase or decrease in firing rate shortly before a
lever-press. As shown in Figure 1, a robust change in
firing rate was observed before the lever-press. These
two mPFC neurons were simultaneously recorded from
different wires in the same session. One exhibited
excitatory anticipatory response (Fig. 1A), while the
other displayed an inhibitory anticipatory response
(Fig. 1B).
A correlation between behavioral context and neuro-
nal activity change was obtained by detailed video
analysis, as described previously (Chang et al., 1994a).
The lever-pressing behavior usually consisted of sev-
eral phases. During a cocaine self-administration ses-
sion, the rats spent most of the time engaged in
stereotypic behavior, i.e., sniffing, and head shaking
during the period between each trial. The self-adminis-
tration procedure usually started with the rat turning
to the lever, and then raising its head towards the lever,
followed by a front paw leaving the floor, and pressing
the lever. The front paw then went back to floor and the
rat turned away from the lever. In some cases, the
turning phase was absent because the rat remained
facing the lever. Neuronal activity changes were found
associatedwith different phases ofthe sequential behav-
ioral episode before the lever-press. Figure 2 shows an
increase in neuronal activity associated with a ‘‘raising
head’’ behavior. This enhanced activity persisted until
the lever-press was finished. Figure 3 depicts anticipa-
tory responses which occurred coincident with ‘‘turning
behavior’’ when the rat turned towards the lever. Other
neurons,as displayed in Figure 4, showed no significant
correlations between anticipatory neuronal responses
and any detectable behavioral episode. For example,
neuronal activity increased during the stereotypical
phase before any other measurable behavioral episode
(in this case, ‘‘raising head’’).
Results from this behavioral data analysis suggest
that the anticipatory responses observed before a lever-
press are unlikely to be the result of locomotion per se.
We believe this to be true for two reasons: first, as
mentioned above, in some cases, the firing rate already
changed before any detectable locomotor episode. Sec-
ond, in the case described in Figure 3, the alteration of
firing rate was only associated with turning behavior
when the rat turned towards the lever for cocaine
self-administration. Activity did not appear when the
rat turned back to the opposite corner after a lever-
press was completed, even though the rat turned in the
same direction with a similar speed, as assessed by
video-frame analysis.
In order to further determine the nature of the
anticipatory responses, anticipatory neuronal activity
was compared in the cases of continuous reinforced
schedule and fixed ratio reinforced schedules (FR) in
which a rat was trained to press a lever 5 or 10 times to
obtain one cocaine infusion. Most of the anticipatory
responsesweresustained during each of the lever-press
events during the fixed ratio schedule. Figure 5 dis-
plays neuronal responses in an FR10 schedule using
lever-presses 1, 5, and 10 as separate event nodes to
create a raster and perievent histogram plots. Anticipa-
tory responses, both excitatory and inhibitory, were
observed before the first lever-press and persisted
during all the lever-presses which followed. The re-
sponses ceased immediately after the lever-press which
resulted in cocaine infusion. Figure 6 shows the results
of a statistical analysis of anticipatory responses in an
FR10schedule.Forboth excitatory (Fig. 6A) and inhibi-
tory (Fig. 6B) anticipatory responses, no significant
differencescould be detected between lever-presses1,5,
and 10. In another three neurons, the alteration of
spike activities occurred only after the first lever-press
and was sustained during the following lever-presses
(here the term anticipatory response may not be appro-
priate, since no changes occurred before the first lever-
press). In two other neurons, the excitatory anticipa-
tory responses appeared only prior to the first lever-
press and vanished during the following lever-press in
the FR-10 schedule.
TABLE I. Summary of different neuronal activities observed in mPFC during cocaine self-administration session1
Type of
response Control,
firing rate
Prelever press Postlever press
n%of
totalFiring rate % change Firing rate % change
No response 6.40 61.04 6.93 61.16 5.46 63.17 6.24 61.04 23.58 62.0 67 55.37
Excitatory 5.16 61.12 10.04 61.75 122.4 614.7 4.49 61.01 219.1 65.8 15 12.39
Inhibitory 3.37 60.73 2.01 60.61 248.8 66.2 3.06 60.77 29.6 64.94 13 10.74
Postcocaine excitation 1.20 60.40 1.26 60.43 1.75 611.3 2.49 60.93 86.8 626.2 4 3.31
Postcocaine inhibition 3.43 60.19 3.03 60.66 21.52 66.9 2.23 60.65 233.56 63.11 22 18.18
Postcocaine inhibition
(including AI andAE) 3.25 60.64 3.53 60.59 22.81 612.56 2.21 60.46 234.82 62.64 32 26.45
1Different types of neuronal activities observed in mPFC during cocaine self-administration session. Firing rate and percentage change of firing rate are expresed as
mean 6EM. Postcocaine inhibition is shown in two columns. One is postcocaine inhibition only (n 522), and the other includes the postcocaine inhibitory response of
anticipatory neurons (n 532). Note that the sum of the percentage of the total exceeds 100% due to the inclusion of the postcocaine inhibitory responses of anticipatory
neurons.
25FRONTAL ACTIVITY IN COCAINE SELF-ADMINISTRATION
mPFC neuronal responses following
cocaine infusion
Two different types of responses were observed in
mPFC neurons following cocaine infusion. Most neuro-
nal responses were inhibitory (32 out of 121 neurons,
26.4%). These neurons could be further classified into
two groups, one with only postcocaine inhibitory re-
sponses (22 out of 121 neurons, 18.2%), and another
that exhibited both postcocaine inhibitory responses
and excitatory/inhibitory anticipatory responses (10
out of 121 neurons, 8.3%). Asmaller portion of neurons
(4 out of 121, 3.3%) increased their firing rate following
cocaine infusion (Fig. 7).
In order to determine whether the postcocaine re-
sponse was due to the pharmacologic effects of cocaine
or was caused by a conditional cue (noise from syringe
pump during the 4-sec cocaine delivery period) associ-
ated with cocaine self-administration, we eliminated
Fig. 1. Raster and perievent histogram plots for two frontal cortex
neurons before and after cocaine self-administration. Each tick in
raster plot represents a spike activity, and the vertical line at 0 sec
indicates a lever-press for cocaine self-administration. Two neurons
were simultaneously recorded in the same session. A: A neuron
exhibitedboth excitatory anticipatory response and postcocaine inhibi-
tory response. Note increase in spike activity around 10 sec before
lever-press, and long-lasting inhibition after cocaine self-administra-
tion. B: A neuron with inhibitory anticipatory response.A decrease in
firing rate was observed around 10 sec before lever-press.
Fig. 2. Relationship between anticipatory neuronal activity and
series of lever-pressing behaviors. A: Schematic images of rat during
the four sequential behaviors termed (a) stereotypy, (b) turning, (c)
raising head, and (d) lever-press. B: Raster and perievent histogram
plots were created using different behavioral episodes as nodes. a: Plot
using ‘‘raising head’’ as a behavioral node. Onset of enhanced spike
activitywas coincident with raising head behavior,which occurred at 0
sec. b, c: Plots using ‘‘leave floor’’ (when front paw left floor) and ‘‘lever
press’’ as behavioral nodes. Increased neuronal firing rate persisted
during these two behavioral episodes. d: ‘‘Resuming stereotypical
behavior’’ was used as a node to create this plot. Note that spike
activity markedly declined at the onset of stereotypical behavior at the
0-sec point.
26 J.-Y. CHANG ET AL.
Fig. 2 (Legend on facing page.)
Fig. 3 (Legend on facing page.)
the cocaine syringe during a self-administration ses-
sion so that a lever-press did not engender cocaine
delivery. Eliminating cocaine produced marked in-
creases in rates of responding. This high rate gradually
decreased until the rat finally ceased lever pressing.
Comparing the postlever-press response with and with-
out cocaine revealed that the inhibitory responses only
existed in trials when cocaine was available but not in
trails when cocaine was removed. Figure 8 shows the
statistical results of comparing groups of trials with
and without cocaine. Asignificant difference was found
inthe postlever-press responses between the group that
received cocaine and the group that did not (242.0 6
6.95 vs. 5.23 65.57, P,0.01).
Neuron localization
All the neurons recorded in this experiment were
histologically located in the mPFC area. Figure 9 is a
chart of the histologic location of microwires in the
mPFC area revealed by the staining of deposited iron
with potassium ferricyanide. Since the current histo-
logic method could not distinguish more than two
positions in the splayed microwire bundles employed,
priority was given to the wires that recorded anticipa-
tory neurons, as designated by a solid circle in the plots.
The distribution of these anticipatory neurons was
found to be confined to the anterior part of the mPFC in
the prelimbic area, while the nonanticipatory neurons
wereinboth the anterior and caudal parts of the mPFC.
DISCUSSION
Theresults of this study provide an initial experimen-
tal determination of neural activity in the medial
prefrontal cortex of the rat during an operant lever-
press task to obtain cocaine reinforcement. The find-
ingssuggest that this cortical area, in combination with
its striatal targets, may be involved in the initiation
and control of task-sequencing toward the goal of
obtaining cocaine infusion.
Consequences of anticipatory responses
Video analysis of the detailed movement sequence
prior to the lever-press revealed that some neurons in
the mPFC became active prior to the initial movements
at the break from stereotypy. Others became active at
the moment of turning, and yet others became active at
the moment of raising the head. The termination of
neural activity was often marked by finishing the
lever-press or resuming the stereotypical behavior.
Similar task segment-related neurons were found in
our previous study of the NAc (Chang et al., 1994a). We
Fig. 3. Raster and perievent histogram for an anticipatory neuro-
nal activity related to turning behavior. A: Onset of turning (when rat
started turning from opposite side of chamber toward lever) was used
as the behavioral node. Increase in firing rate was observed at onset of
turning behavior at 0 sec. B: ‘‘Raising head’’ behavior was selected as
the behavioral node to create this plot. Enhanced firing rate was found
both before and after the raising head behavior. C: ‘‘Back to floor’’was
the behavioral node in this plot. Firing rate returned to baseline when
the front paw returned to the floor after lever-press. The rat then
turned back to the opposite corner, where stereotypical behavior
resumed. D: ‘‘Back to corner’’ served as the behavior node in this plot.
At the 0-sec point, the rat finished turning from the lever and resumed
stereotypical behavior. No increase in neuronal activity was observed
during turning, which occurred before the 0-sec point. The same
situation could also be seen in C, where the firing rate did not increase
after the 0-sec point (back to floor) when the rat started turning to the
opposite corner.
Fig. 4. In contrast to the cases described in Figures 2 and 3, the
anticipatory response in this neuron was not associated with any
detectable behavioral episode. A: Raster and perievent histogram
plots using lever-press as node. The clear excitatory anticipatory
response could be seen before lever-press. B: Raising head was the
behavioral node to create the raster and perievent histogram plots.
Note that increase in firing rate occurred before raising head, when
the rat was still engaged in stereotypical behavior and no characteris-
tic behavioral event could be detected.
29FRONTAL ACTIVITY IN COCAINE SELF-ADMINISTRATION
interpreted these different temporal signals as due to
the action of distinct cortical-striatal loops that became
active in different time points in the behavioral se-
quence.
An open question is precisely what these signals
represent in this portion of the cortico-neostriatal sys-
tem. These phasic signals in both the mPFC and NAc
are not obligatorily linked to movement, since similar
movements unrelated to obtaining rewards may not be
associated with alteration of neuronal activity, such as
is demonstrated in Figure 3. In this case, the increased
neuronal firing was coincident with a turning motion
from the opposite side of the chamber towards the lever
to seek cocaine self-administration. After the lever-
press, the rat turned back to the opposite corner in the
same direction, but increased neuronal activity was not
seen during this same direction of turning (the turning
occurred between Fig. 3C and 3D). In another case,
demonstrated in Figure 4, neuronal activity was in-
creased during stereotypy with no correlation to any
detectable locomotor event, in this case, a raising head.
Similartypes of neural correlates were also found in the
NAcduring a cocaine self-administration session(Chang
et al., 1994a).
To further explore the nature of the anticipatory
responses observed in mPFC, we applied fixed ratio
schedules to see if there was any change in the pattern
of anticipatory neuronal responses during repeated
lever-pressingbehavior.In these experiments, anticipa-
tory responses persisted as sustained activity during
the entire lever-pressing period, and yet terminated
immediately after cocaine was delivered (Fig. 5). The
persistence of anticipatory responses in the fixed ratio
schedules suggests that these responses were motiva-
tional or intentional in nature, since they were ob-
served during the entire predrug period. Three neurons
(10% of total anticipatory neurons) did not alter their
firing rate until after the first lever-press. This quality
of establishing sustained activity in the middle of a
response sequence seems related to the postulated
short-term memory function of the mPFC (Funahashi
et al., 1993; Fuster, 1991). The neuronal response
observed in this case may be analogous to the steady
responsein delayed response task studies (Chang et al.,
1994b), which is thought to encode the delay period.
Two other neurons exhibited anticipatory responses
only before the first lever-press in the FR 10. Overall,
these patterns may represent a neural activation of
circuit involved in the initiation of drug-seeking behav-
ior, and are clearly dissociated from actual movement.
Our current conjecture is that these varied anticipatory
signals prior to lever-press are not specific motor com-
mands, but constitute enabling commands which inte-
grate representations of different goals or reinforcers
with an ongoing interpretation of the status of the
behavioral sequence being executed.
Structural basis of anticipatory responses
The prefrontal cortex in the rat is most generally
defined as a group of areas reciprocally connected with
the mediodorsal nucleus of the thalamus (Groenewe-
gen, 1988; Groenewegen et al., 1990; Pirot et al., 1994;
Ray and Price, 1992; Rose and Woolsey, 1948). The
mPFC also receives projections from dopamine neurons
in the VTA, serotonergic neurons in the raphe nuclei,
and noradrenergic neurons from the locus ceruleus
(Bjorklund and Lindvall, 1984; Divac et al., 1978;
Oades and Halliday, 1987; Van Bockstaele et al., 1993).
Other limbic structures, including the amygdala and
lateral hypothalamus also contribute afferents to the
mPFC (Divac et al., 1978; McDonald, 1991). Subregions
of the mPFC have been shown to receive input from
callosal connections as well as visual, and post- and
parasubicular cortices, in addition to motor areas and
other cingulate regions (Vogt and Miller, 1983). All of
these extensive interconnections support the concept
that this area extracts features from the sensory envi-
ronment, participates in sensorimotor and limbic inte-
gration, and is integral in decoding movements from
this information. An open question concerns the contri-
bution each afferent makes to activity within each
differentbehavioral contest. In this context, the current
study is the first of a series which must clarify the
linkages between the mPFC and its sources of afferents
and targets of efferents.
The mPFC in turn projects to the anterior caudate,
nucleus accumbens, and dopamine neurons in the
substantial nigra and VTA(Berendse et al., 1992; Brog
et al., 1991; Groenewegen et al., 1990; Naito and Kita,
1994; Sesack and Pickel, 1992). The ventral striatum
then projects to the ventral pallidum and through the
medial dorsal thalamic nucleus back to prefrontal
corticalregions; the substantial nigra and entopeduncu-
lar areas project to the ventral lateral thalamic nuclei
and onto the medial and lateral agranular motor corti-
ces. The mPFC has reciprocal connections with limbic
and visual cortical areas (Miller and Vogt, 1984), and
also projects to the central gray of the brain stem
(Hardy and Leichnetz, 1981). These parallel, open loops
control a variety of neuronal functions (Alexander et
al., 1990; Jurgens, 1983; Russchen et al., 1987; Vogt et
al., 1979). The prefrontal cortex, a component of a
system of cortical-striatal loops, is also a focal structure
within the limbic circuitry and therefore is in a position
to play a critical role in regulating the physiology of
emotional, mnemonic, and cognitive functions.
Fig. 5. Anticipatory neuronal responses during FR10 schedule in
mPFC. Solid diamond at top of raster represents each lever-press
during FR 10 schedule. A: Excitatory anticipatory neuron. Persistent
increased neuronal activity was observed in first (left), fifth (middle),
and tenth (right) lever-presses. B: Inhibitory anticipatory neuron,
showing decreased neuronal activity before first, fifth, and tenth
lever-presses.
30 J.-Y. CHANG ET AL.
Fig. 5 (Legend on facing page.)
31FRONTAL ACTIVITY IN COCAINE SELF-ADMINISTRATION
ThedistributionofanticipatoryneuronsinthemPFC
in this study may reflect some anatomic specificity of
neuronal circuits involved in cocaine self-administra-
tion.As demonstrated in Figure 9, anticipatory neurons
were largely located in the anterior part of the mPFC
(the prelimbic area), the area known to project to the
NAc (Berendse et al., 1992). This finding suggests that
the anticipatory responses observed in the mPFC and
NAc represent a mesolimbic neuronal process which
triggers drug-seeking behavior.
Direct actions of cocaine
Electrophysiological studies of the direct effects of
cocaine in the mPFC in anesthetized animals and in
slice preparations have been carried out in a number of
different laboratories. Cocaine reduces both the ampli-
tude of the EPSP and after-hyperpolarization in the
slice preparations (Jahromi et al., 1993). Iontophoretic
applicationofcocaineinanesthetizedratsresultsinthe
inhibition of spontaneous firing of prefrontal cortex
neurons, and this inhibition is blocked by the dopamine
antagonist, sulpiride, but not by the serotonin antago-
nist methysergide or the opiate antagonist naloxone
(Qiao et al., 1990). The dopaminergic involvement in
these cocaine-induced inhibitory responses is also sug-
gested by a study indicating that cocaine enhances the
inhibitory effect of ventral tegmental area stimulation
on mPFC neurons in the anesthetized rat (Peterson et
al., 1990).
The fact that the mPFC receives not only dopaminer-
gic but also seretonergic and adrenergic inputs should
be taken into account to interpret cocaine actions
(Mantz et al., 1991; Thierry et al., 1990); multiple
modulatory actions may play a significant role. About
26% of mPFC neurons exhibited inhibitory responses
after cocaine infusion in this study. These responses
appear to be pharmacologic in nature rather than a
conditional response to the lever-pressing and its asso-
ciated cues, because the response was abolished when
cocaine was removed from the syringe pump. This
finding is congruent with the data obtained from anes-
thetized animals showing that the majority of re-
sponses to iontophoritically-applied cocaine are inhibi-
tory (Qiao et al., 1990). Whether these inhibitory
responses following cocaine infusion are due entirely to
the accumulation of dopamine in the synaptic cleft or to
combined effects of dopamine and other transmitter(s),
as suggested by many other studies (Mantz et al., 1991;
Sesack and Bunney, 1989; Yang and Mogenson, 1990),
needs to be explored further using different pharmaco-
logical tools such as dopamine antagonists. Some neu-
rons in the present study displayed an increase in spike
activity after cocaine self-administration, in parallel
with in vitro studies demonstrating that cocaine and
dopamine also may exert excitatory effects on mPFC
neurons (Jahromi et al., 1993; Penti-Soria et al., 1987).
Role in reinforcement
Substantialevidence has accumulated that the mPFC
is a component of the mesolimbic system involved
specifically in reinforcement mechanisms (Kolb, 1984;
Robertson, 1989), and that dopamine plays an impor-
tant role. Intracranial electrical self-stimulation (SS), a
model for the study of reward mechanisms, can be
demonstrated in the mPFC (Mora and Cobo, 1990;
Robertson,1989; Routtenberg and Sloan, 1972), yet it is
unclearpreciselyhow the dopamine system mediates or
modulates mPFC reward processes. A dopamine-
independent theory was suggested by the finding that
neuroleptics selective affect medial forebrain bundle
(MFB) but not mPFC electrical self-stimulation (Cor-
bett, 1990), and that 6-OHDA lesions of dopamine
terminals in mPFC fail to alter intravenous cocaine
self-administration (Martin-Inverson et al., 1986). On
the other hand, the finding that cocaine has been
demonstrated to facilitate electrical self-stimulation in
Fig. 6. Bar chart showing alteration of mPFC neuronal activity
duringFR10 schedule.A: Inhibitory anticipatoryresponse. Firingrate
during control (measured during 40–80 sec before each lever-press,
solid bar), and anticipatory (measured 1–3 sec before corresponding
lever-press, open bar) during lever-presses 1, 5, and 10. B: Same plot
for excitatory anticipatory responses. No significant difference in
firing rate could be detected between lever-presses 1, 5, and 10 in both
inhibitory anticipatory (n 54) and excitatory (n 58) responses
(ANOVA, Tukey’s test, P.0.05).
32 J.-Y. CHANG ET AL.
the mPFC does implicate a dopaminergic mechanism
(McGregor et al., 1992). Likewise, rats have been
reported to self-administer cocaine into the frontal
cortex, an effect postulated to be mediated by the
release of dopamine in nerve terminals of the mPFC
and NAc originating from the VTA(Goeders and Smith,
1983, 1986, 1993). Furthermore, recent studies have
revealed that electrical stimulation of the frontal cortex
increases dopamine release in the NAc, via a glutama-
tergic synaptic action on VTA dopamine neurons
(Karreman and Moghaddam, 1996; Taber and Fibiger,
1995). If both the mPFC and NAc participate in cocaine
self-administration as parallel and serial stages within
the mesolimbic reward loop, then the neuronal activity
observed in the mPFC and the NAc might reflect the
coordination communication between these two areas.
Thepercentageof neurons exhibiting anticipatory,exci-
tatory, and inhibitory responses is similar between the
mPFC and the NAc (12.4% and 10.7% in the mPFC,
9.9% and 9.3% in the NAc for excitatory and inhibitory
anticipatory responses, respectively; Chang et al.,
1994a). The postcocaine responses, however, were
slightly more often observed in the NAc than in the
mPFC (35% vs. 26%). This could reflect a difference in
the action of dopamine on local circuitry as demon-
Fig. 7. Postcocaine infusion responses of mPFC neurons. A: Strip
chart of neuronal activity during cocaine self-administration session.
Solid diamond at top indicates time of lever-press. Note decrease in
firing rate after each lever-press. B: Neuron exhibiting excitatory
response after cocaine self-administration. Enhanced firing was ob-
served after each lever-press for cocaine self-administration.
Fig. 8. Bar chart for data obtained from postlever-press neuronal
responses, with and without cocaine, from the same neurons. Solid bar
represents firing rate in control period (measured 10–20 sec before
lever-press, left ordinate). Hatched bar represents firing rate mea-
sured 10–20 sec after lever-press (left ordinate). Open bar represents
percentage change (right ordinate). Postlever-press inhibition only
occurred in presence of cocaine (cocaine 1). A significant difference of
percentage change was detected between groups with and without
cocaine (Student’s t-test, **P,0.01, n 59).
33FRONTAL ACTIVITY IN COCAINE SELF-ADMINISTRATION
strated by microdialysis study, indicating that increase
of dopamine concentration is more in the NAc than in
the mPFC upon cocaine injection (Moghaddam and
Bunney, 1989).
The mechanisms of anticipatory and postcocaine
responses pose a major unresolved question. The re-
sults of this study mainly demonstrate the presence of
neuronal activity patterns within the mPFC at critical
times in the behavioral sequence during the execution
of drug-seeking behavior, and during the responses
following cocaine infusion. The hypothesis is that if the
frontal cortex is the structure that integrates the
sensoryinput (rewarding effects of cocaineself-adminis-
tration), as well as prospective, future-related planning
(lever-pressing for cocaine self-administration), then
the postcocaine response may represent the former
mechanism and the anticipatory responses observed in
this study may well represent the latter mechanism.
ACKNOWLEDGMENTS
We thank Dr. P.H. Janak for critical comment on the
manuscript.
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