Orbitofrontal and Insular Cortex: Neural
Responses to Cocaine-Associated Cues and
KARINE GUILLEM,1ALEXXAI V. KRAVITZ,2DAVID E. MOORMAN,3AND LAURA L. PEOPLES1,2*
1Department of Psychiatry, TRL, University of Pennsylvania, Philadelphia, Pennsylvania 19104
2Neuroscience Graduate Group, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19106
3Laboratory of Neuromodulation and Behavior, Department of Neurosciences, Medical University of
South Carolina, South Carolina 29425
prefrontal cortex; conditioned cue; instrumental behavior; addiction;
hypothesized that increases in neural activity within several regions of the prefrontal
cortex contribute to cue-induced cocaine seeking and cocaine-induced compulsive drug
self-administration. However, electrophysiological tests of these hypotheses are lack-
ing. In the present study, animals were trained to self-administer cocaine (0.75 mg/kg)
for 14 days. On the 14th day, we conducted electrophysiological recordings of lateral
orbitofrontal (LO) and ventral anterior insula (AIV) neurons. A subset of the combined
population of recorded neurons showed a change in firing rate in association with one
or more of the following discrete events: (1) presentation of a discriminative stimulus
that signaled the onset of the self-administration session, (2) occurrence of the first
cocaine-directed operant response, (3) occurrence of a cocaine-reinforced press, and
(4) presentation of cues normally paired with delivery of the cocaine reinforcer. The
majority of the stimulus- and response-related changes in firing involved a brief
increase in firing during the stimulus and response event, respectively. In addition to
these event-specific responses, approximately half of the recorded neurons exhibited a
sustained change in average firing (i.e., discharges per 30-s bin) during the cocaine
self-administration session, relative to average firing during a presession, drug-free
period (referred to as session changes). The prevalence of session-increases and
decreases were not significantly different. These and other findings are discussed in
relation to hypotheses about cue-evoked and cocaine-maintained cocaine-directed
behavior. Synapse 64:1–13, 2010.
Based on neuro-imaging studies in cocaine-addicted humans, it is
C2009 Wiley-Liss, Inc.
Neuro-imaging studies of cocaine-addicted individu-
als show that during early periods of drug abstinence,
several regions of the prefrontal cortex, including the
orbitofrontal cortex, are hypermetabolic. This hyper-
metabolism is correlated with the intensity of sponta-
neous craving (Volkow et al., 1991). Additionally, in
addicts with a history of either limited (e.g. 24 h) or
extended (e.g. 2 weeks) abstinence, the orbitofrontal
cortex, insula, and other prefrontal regions show an
increase in metabolic activity during cue-induced co-
caine craving (Childress et al., 2008; Garavan et al.,
2000; Goldstein et al., 2007; Grant et al., 1996; Kilts
increased orbitofrontal metabolic activity is associated
with provocation of compulsive behaviors in obses-
sive-compulsive patients (Breiter and Rauch, 1996;
McGuire et al., 1994); moreover, cocaine-addicted
individuals score higher than normal on obsessive-
compulsive scales and exhibit a higher than average
incidence of obsessive-compulsive disorder (Crum and
Anthony, 1993; Fals-Stewart and Angarano, 1994;
Yeager et al., 1992). Based on these observations, it
Contract grant sponsors: NIH Director’s Bench-to-Bedside (L.L.P. and Elliot
Stein), predoctoral NRSA; Contract grant number: DA 021449; Contract grant
sponsor: NIH/NIDA; Contract grant number: P50 DA 012756 (H.M. Pettinati);
Contract grant sponsor: Institute for Translational Medicine and Therapeutics,
University of Pennsylvania School of Medicine (L.L. Peoples, A.R. Childress);
Contract grant sponsor: NIDA; Contract grant number: P60 DA 05186 (C.P.
*Correspondence to: Laura L. Peoples, Department of Psychiatry, TRL, Uni-
versity of Pennsylvania, Philadelphia, Pennsylvania 19104.
Received 21 November 2008; Accepted 6 April 2009
Published online in Wiley InterScience (www.interscience.wiley.com).
C2009 WILEY-LISS, INC.
SYNAPSE 64:1–13 (2010)
is hypothesized that cue-induced activation of the
orbitofrontal cortex, and other prefrontal regions, con-
tribute to compulsive cue-evoked cocaine-seeking.
hypothesized to contribute to the cocaine effects
which activate and maintain compulsive cocaine-
directed behavior (Kalivas et al., 2005; Kalivas and
Hu, 2006; Volkow and Fowler, 2000; Volkow et al.,
1999, 2005). Previous studies have not conducted elec-
trophysiological tests of these hypotheses.
The primary goals of the present study were to use
chronic electrophysiological recording procedures to
test the following two hypotheses: (1) cocaine-associ-
ated cues and the onset of cocaine-seeking behavior
are associated with increases in orbitofrontal and
insula neural activity, and (2) self-administration of
cocaine is associated with increased activity of orbito-
frontal and insula neurons. Animals were trained to
self-administer cocaine (0.75 mg/kg/inf) for 14 days.
Chronic extracellular recording techniques were used
to record the activity of individual neurons within the
lateral orbitofrontal cortex (LO) and the anterior ven-
tral insula cortex (AIV), two regions of the orbitofron-
tal network (Ongur and Price, 2000; Price, 2007).
Neural recordings were made during three periods of
a cocaine self-administration session, including pre-
sentation of a discriminative stimulus, which signaled
the onset of the self-administration session, the ensu-
ing onset of cocaine-seeking, and the subsequent
maintenance of cocaine self-administration.
We report that LO and AIV neurons exhibited pre-
dominantly, but not exclusively excitatory responses
in association with cocaine-associated cues and the
onset of cocaine-seeking. The LO and AIV neurons
were equally likely to exhibit either an increase or a
decrease in average firing during exposure to self-
administered cocaine, relative to firing during a drug-
free, presession period. These findings are discussed
in relation to the hypotheses about cue-evoked and
cocaine-maintained cocaine-directed behavior.
MATERIALS AND METHODS
Male Long-Evans rats were obtained from Charles
started the study at ?12 weeks of age, weighing 350–
400-g. Protocols were in accordance with the Guide
for the Care and Use of Laboratory Animals pub-
approved by the Animal Care and Use Committee of
the University of Pennsylvania.
Surgery and postoperative maintenance
A detailed description of surgical and postoperative
procedures was described in an early report (Peoples,
2003). Briefly, animals were anesthetized with keta-
mine (30 mg/kg IP) and xylazine (5 mg/kg IP) and
administered penicillin (0.25 ml, IM) prior to surgery.
A catheter was implanted in the jugular vein and
exited through a J-shaped stainless steel cannula
cemented to the skull. Under isofluorane anesthesia,
an array of microwires was implanted unilaterally in
the LO cortex and AIV [AP: 12.2 to 13.7 mm, ML:
61.5 to 64.5 mm, and DV: 5 mm (Paxinos and Watson,
2004)], along with a stainless steel ground wire. The
array consisted of 16 quad-teflon-coated stainless steel
wires arranged in two rows of eight (wire diameter
without insulation 5 40 lm). Adjacent wires within a
row were separated by 250 lm (wire center to wire cen-
ter). The rows were separated by 500 lm (wire center
to wire center). Animals were allowed between 7 and
10 days to recover from surgery before training was
Behavioral procedures were carried out in operant
chambers placed inside sound-attenuating cubicles.
Chambers were equipped with two retractable levers,
a signal light above each lever, a drinking trough, a
house light, a white noise-generator, and a tone gen-
erator. Operant equipment and control software were
purchased from Med-Associates (St. Albans, VT).
Chronic extracellular recording
and discrimination of neural data
Voltage signals from each microwire were recorded,
amplified up to 32,0003, processed, and digitally cap-
(Plexon, Dallas, TX). Single units were discriminated
offline with principal component analysis (Offline
Sorter, Plexon). The quality of recorded units was
ensured with an interspike interval criterion (>1 ms)
and a signal:noise criterion (>33 noise band) (Fig.
1A). Waveforms of units isolated from the same elec-
trode were plotted against time to confirm stability of
waveforms during each recording.
All firing rate data were analyzed using Neuro-
Explorer (Plexon) and Matlab (Mathworks, Natick,
MA). Datasets were determined to be nonnormal (P <
0.05, Bera-Jarque test), therefore nonparametric Wil-
coxon signed-rank and Mann–Whitney tests were
used for comparison of paired and unpaired values
respectively (a 5 0.01). Z-tests were used to compare
proportions. Values are reported as mean 6 the
standard error of the mean (6SEM).
Waveform duration was used to differentiate putative
interneurons and pyramidal neurons (Fig. 1B). Wave-
form duration was defined as the interval that lapsed
between the peak depolarization of the action potential
and the peak after-hyperpolarization. The distribution
of these waveform durations was bi-modal with a small
group of short-duration waveforms and a larger group
K. GUILLEM ET AL.
of long-duration waveforms. The two distributions split
at 300 ls. We thus defined putative interneurons as
neurons, for which the waveform duration was 300 ls
or less. Based on the prevalence of pyramidal neurons
(estimated between 75 and 90% of neurons in the PFC)
(Kandel et al., 2000; Yuste, 2005), most of the remain-
ing neurons are expected to be pyramidal neurons. Our
procedures and observations are consistent with those
of previous reports (Constantinidis and Goldman-Rakic,
2002; Csicsvari et al., 1998; Rao et al., 1999).
Experiment 1: Fixed-ratio 1 cocaine
Cocaine self-administration training sessions.
The start of each cocaine self-administration session
was signaled by the illumination of a house light and
the insertion of a response lever. Each reinforced lever
press was followed by an intravenous cocaine infusion
(0.75 mg/kg in 0.2 ml delivered over 7.5 s), a 10-s tone,
a 10-s illumination of the light above the lever, and im-
mediate retraction of the lever. A 60-s timeout pre-
ceded the reinsertion of the lever and the start of the
next trial. At the end of the session, the house light
retracted from the chamber. Each self-administration
session was preceded and followed by a 60-min period
during which no session events occurred.
Training and recording history. After recovery
from surgery, animals were first trained to self-admin-
ister sucrose under a fixed ratio one schedule of rein-
forcement (FR1) for 3–4 days. Cocaine self-administra-
tion training was initiated thereafter and performed in
the same chambers as the sucrose training sessions,
though several changes were made to the chamber con-
text. During the cocaine sessions, the active lever for
cocaine was on the opposite wall as it was during the
sucrose sessions. A black and white striped wallpaper
was placed on one wall, and the white noise cue that
remained on throughout the sucrose sessions was
replaced with a house light during the cocaine sessions.
Animals (n 5 5) were exposed to cocaine (0.75 mg/kg)
self-administration training for 14 consecutive days.
The first cocaine self-administration session was lim-
ited to 60 min or 20 infusions. All other cocaine ses-
sions were 3 h in duration. All animals were tethered
to the combined fluid/electronic swivel at least three
times before the recording session.
Identification of specific firing patterns during
the cocaine self-administration session. To char-
acterize firing patterns in relation to drug-associated
cues and drug-directed behavior, neurons were tested
for changes in firing time-locked to the following
events: (1) presentation of the discriminative stimulus
(i.e. house light illumination) that signaled the onset
of the self-administration session, (2) occurrence of
the first operant response, (3) cocaine-reinforced oper-
ant responses during the maintenance phase of the
self-administration session, and (4) presentation of ei-
ther of two cues associated with delivery of the co-
neurons. A: On the left side of Panel A is shown a scatter plot of
the first two principal components of all large amplitude electrical
events recorded from one microwire. Events with similar shapes
cluster in different areas of this plot. To the right of the scatter plot
is shown the waveform of a single neuron (i.e., same neuron repre-
sented by the black cluster in the scatter plot) and the interspike
interval histogram for that neuron. B: Demonstration of criteria for
separating putative interneurons and putative pyramidal neurons.
Extracellularly recorded pyramidal neurons and inter-
The histogram shows the frequency distribution of the average
waveform durations of all recorded neurons. Waveforms with dura-
tions shorter than 300 ls were classified as putative interneurons
(gray bars), and waveforms with durations longer than 300 ls were
classified as putative pyramidal neurons (black bars). Waveform
plots below the histogram are examples of interneuron and pyrami-
dal neuron waveforms. C: Average firing rates of all interneurons
and pyramidal neurons in the presession baseline period (* denotes
P < 0.0005).
ORBITOFRONTAL NEURAL ACTIVITY
caine reinforcer (i.e. operation of the retractable
response lever and presentation of a tone 1 light
cue). To test for increased neural activity in associa-
tion with exposure to self-administered cocaine, we
tested for sustained changes in firing during the co-
caine self-administration session relative to a preses-
sion, drug-free period.
Discriminative stimulus (SD) and first-press
neural responses. A neural response time-locked to
the discriminative stimulus (i.e., SD) was defined as a
significant change in firing rate between the 1 s pre-
SDand the 1 s post-SD. To compare firing pre- and
post-SD, number of discharges was determined as a
function of 0.1 s bins. The number of discharges dur-
ing the 1 s pre-SDwas then compared to the number
of discharges during the 1 s post-SD, using a Mann–
Whitney test. A neural response to the first press of
the self-administration session (i.e., first-press neural
response) was similarly defined and analyzed. Specifi-
cally, a significant first-press response was defined as
a significant change in firing during either the 1 s
before or after the first press, relative to firing during
the 1 s pre-SD.
Press responses. All neurons were tested for a
change in firing time-locked to the cocaine-reinforced
lever press. These firing patterns were identified using
lever presses that occurred during the maintenance
phase of the self-administration session, when cocaine
levels and response rates were stable (last 15 presses).
Across these 15 trials, the average firing rates during
the 1 s pre- and postpress were compared to average fir-
ing rate during a baseline period 212 to 29 s before the
lever press using a Wilcoxon test.
Lever-cue responses. Neurons were tested for a
change in firing time-locked to lever insertion, which
occurred at the end of each timeout period during the
self-administration session (i.e., referred to as the le-
ver cue). Lever insertion shared auditory stimulus
characteristics with lever retraction, which was one
cue paired with delivery of the cocaine reinforcer. To
test for a neural response to the lever cue, the num-
ber of discharges during the 1 s after the onset of the
lever insertion was compared to the number of dis-
charges during the 1 s before the lever insertion,
using a Mann2Whitney test.
Session changes in average firing. Animals
maintain drug level within a stable range during the
maintenance phase of cocaine self-administration ses-
sions (Pettit and Justice, 1989). A stable change in
average firing during the same period potentially cor-
responds to an acute pharmacological effect of co-
caine. We thus tested for stable changes in firing dur-
ing the session relative to the presession, drug-free
period (referred to as a session change) (Kravitz
et al., 2006; Kravitz and Peoples, 2008; Peoples et al.,
1998b). To test for a significant session-change, firing
rate (i.e., Hertz per 30-s bin) was calculated for the
60-min presession baseline period and for the last
120 min of the self-administration session (i.e., the
maintenance phase of the self-administration ses-
sion). Firing rates during the self-administration ses-
sion and the presession baseline period were con-
trasted using a Mann2Whitney test. If a significant
difference in firing was observed, an additional analy-
sis was conducted to characterize the stability of the
change in firing. For the self-administration session,
we determined the direction of the difference in aver-
age firing between each 30-s bin and the average pre-
session firing rate. If the direction of the difference
was consistent with the outcome of the significance
test for more than 90% of the bins, the change was
defined as stable, and therefore to correspond to a
session change in firing.
To further characterize the stability of the session
change firing patterns, we characterized firing rates
during specific behaviors that occurred during the self-
administration session and compared those firing rates
to average firing during the drug-free period. Locomo-
tion and stereotypy were the predominant behaviors
during the cocaine self-administration session. Periods
of locomotion and stereotypy were identified using video
analysis (Peoples et al., 1998a). Average firing during
each of the behaviors was compared to firing during the
presession baseline period, using Wilcoxon tests.
Experiment 2: Cue-probe session
An additional experiment was conducted in a sepa-
rate group of animals (n 5 3) to test whether press-re-
sponsive neurons showed a change in firing when the
tone 1 light cue was presented in the absence of the
operant behavior. Animals were first trained to self-
administer cocaine. On the 14th day of self-administra-
tion, we conducted the cue-probe session. The session
was similar to a normal self-administration session,
except for the following: after the first 20 cocaine-rein-
forced lever presses (first phase), an additional 15 pre-
sentations of the light 1 tone cue were interspersed
responses (second phase). The additional cue presenta-
tions occurred 2 min after every other press. All other
aspects of the cue-probe session were consistent with
the daily self-administration training sessions.
Experiment 3: Effect of experimenter-delivered
cocaine in naı ¨ve rats
Session changes in firing potentially reflect a sus-
tained state associated with the operant session,
acute pharmacological effects of cocaine, or both. To
begin to differentiate between these possibilities, we
tested for dose-dependent changes in firing during
K. GUILLEM ET AL.
periods in which conditioning- and drug-naı ¨ve ani-
mals were exposed to experimenter-delivered intrave-
nous cocaine infusions.
In experiment 3, a cumulative dose response curve
was determined for cocaine in a group of three animals.
After 1 week of recovery from surgery, animals (n 5 3)
were exposed to three habituation sessions, each 1 h in
duration. In these sessions, animals were transferred
to the recording chamber and tethered to the recording
swivel, as would normally occur on a recording day.
Thereafter, a single recording session was conducted.
During the session, the activity of LO and AIV neurons
was recorded during exposure to response-noncontin-
gent infusions of different cocaine doses. In separate
phases, animals were exposed to a single intravenous
infusion of 0, 0.75, or 1.5 mg/kg cocaine. The order of
the dose phases was determined according to a within-
Latin square design. The infusions were not paired
with the tone 1 light cue. The response lever was
retracted during the entire session. Each infusion was
preceded by a 60-min baseline period.
To test for changes in the firing rate of individual
neurons during the phases of cocaine exposure, we com-
pared firing rate during the 2–6 min after each infu-
sion, to firing during the 2–6 min that preceded the
onset of the infusion, using a Mann–Whitney test. This
analysis time was based on available cocaine pharma-
cokinetic data (Pettit and Justice, 1991) and prelimi-
nary analyses, which indicated that the peak neural
response, occurred during the 2–6-min postinfusion.
The location of recorded neurons was determined
histologically (Fig. 2). Anodal current (50 lA for 5 s)
was passed through each microwire. Animals were
perfused with ?300 ml of 4% paraformaldehyde in
0.9% saline, and ?50 ml of 5% potassium ferricyanide
and 10% hydrochloric acid to stain the iron deposits
left by the recording tips. The brains were cut into
50-lm coronal sections, which were mounted on
slides. Each slide was visualized under a microscope,
and the location of each wire tip was plotted on the
coronal plate that most closely corresponded to its an-
terior–posterior position (Paxinos and Watson, 2004).
Neurons recorded from wires that were not within
the LO and AIV were excluded from this plot and
were additionally excluded from all data analyses.
Experiment 1: Fixed-ratio 1 cocaine
Behavior during the onset and maintenance of
In seven of nine sessions, the latency between the
onset of the discriminative stimulus (i.e. SD) and the
first operant response (i.e., first-press) was <3 min
(average 5 1.01 min 6 0.28). During the nine cocaine
self-administration recording sessions, rats earned an
average of 29.33 6 2.85 cocaine infusions. The aver-
age interinfusion interval during the nine sessions
equaled 6.54 6 0.56 min.
During the cocaine self-administration recording
session, 175 neurons were recorded from LO and AIV
(Fig. 2). Of these neurons, 101 were LO neurons and
74 were AIV neurons. Based on the action potential
duration of these neurons, 88% of the LO neurons
and 85% of the AIV neurons were identified as py-
ramidal neurons; the remaining neurons were identi-
fied as interneurons (Figs. 1B–1C). Given the small
sample of interneurons, formal analyses were limited
to pyramidal neurons. Direct comparisons of LO and
AIV neurons showed comparable firing patterns. The
data were thus combined.
Changes in firing associated with the onset of
the cocaine self-administration session
Thirty-four percent (51 of 152) of all pyramidal neu-
rons showed a significant change in firing in associa-
tion with the SD, the first-press, or both (Fig. 3).
Twenty-five percent (13 of 51) of these neurons
showed a response to only the SD, 49% (25 of 51)
showed a response to only the first-press, and 25%
(13 of 51) showed a response to both. For each of
the three firing-pattern
three-fourth of the responses were increases. For
all subtypes combined,
were increases and 25.5% were decreases (Z 5 4.95;
P < 0.001). There was a significant effect of period
LO and AIV neural recordings were made. Numbers indicate posi-
tion anterior to bregma.
Histology: locations of individual wire tips from which
ORBITOFRONTAL NEURAL ACTIVITY
(i.e., 1 s pre-SD, 1 s post-SD, 1 s pre-first-press, and 1 s
post-first-press) on average firing of the population of
all pyramidal neurons (F149, 35 3.37; P < 0.05). Post
hoc comparisons (paired t-tests) showed differences in
firing rate between the pre-SDand post-SDperiods
(4.7 6 0.47 Hz vs. 6.0 6 0.62 Hz; P < 0.01), the pre-SD
and pre-first press periods (4.7 6 0.47 Hz vs. 5.9 6
0.63 Hz; P < 0.05), and the pre-SDand post-first press
periods (4.7 6 0.47 Hz vs. 6.5 6 0.66 Hz; P < 0.005).
Changes in firing time-locked to the reinforced
Twenty-six percent (40 of 152) of all pyramidal neu-
rons showed a significant change in firing during the
seconds that bracketed the cocaine-reinforced lever
press (i.e., referred to as press responses) (Fig. 4). Of
these neurons, 15% (i.e. 6 of 40) responded exclusively
before the press, 33% (i.e. 13 of 40) responded both
pre- and postpress; and 53% (21 of 40) responded
exclusively after the press. Eighty-three percent of
the exclusively prepress responses were increases.
Sixty-nine percent of the combined pre- and postpress
responses were increases. Fifty-two percent of the
exclusively postpress responses were increases. For
all subtypes combined, 63% (25 of 40) of the responses
were increases and 37% (15 of 40) were decreases
(Z 5 2.24; P < 0.05).
Changes in firing associated with the lever cue
Thirty percent (12 of 40) of the press-responsive
neurons exhibited a significant change in firing dur-
ing the 1 s after the onset of the lever-cue (not
shown). All but one of the press-responsive neurons
that responded to the lever cue were of either the
exclusively postpress type (i.e. 50%, 6 of 12 neurons)
or the combined pre- and postpress type (i.e. 42%, 5
of 12 neurons). Seventy-five percent of the responses
were increases. The press and lever cue responses
were directionally consistent in all cases.
Session changes in average firing
Fifty-three percent (81 of 152) of all recorded neu-
rons showed a significant session-change in firing
during cocaine self-administration relative to the pre-
session period (see Methods section and Fig. 5). Of
these neurons, 55% (45 of 81) showed a session
increase in firing during the cocaine session relative
to the presession baseline; 44% (36 of 81) exhibited a
decrease. The prevalence of the session increases did
not differ significantly from that of session decreases
(Z 5 1.41; P 5 0.16). The average firing rate of
all neurons was increased during the self-administra-
tion session (4.49 6 0.37 Hz) compared to average fir-
ing during the presession baseline period (5.40 6 0.49
Hz) (F11515 15.8; P < 0.001).
Additional analyses showed that for 72% of the ses-
sion-increase neurons, firing rate was significantly
elevated during the self-administration session rela-
tive to the presession period regardless of whether
the self-administration firing rate was calculated dur-
ing either locomotion or stereotypy. Similarly, 100% of
the session-decrease neurons exhibited a significantly
decreased firing rate during the self-administration
session regardless of which behavioral period within
the self-administration session was compared to the
presession baseline period. These results demonstrate
that most session changes in firing were consistent
across the behaviors, which were the most common
Experiment 2: Cue-probe session
In the cue-probe session, we recorded the activity of
35 neurons from three rats. Ten of the 35 recorded
neurons (29%) exhibited a significant change in firing
time-locked to the press. Of these neurons, 20%
exclusively post-press, and 30% responded both pre-
and post-press. Comparison of the average press fir-
ing patterns between the two phases (Fig. 6) showed
that there was no significant effect of phase on base-
line and prepress signal periods (Wilcoxon; P 5 0.15
and P 5 0.18, for baseline and prepress signal,
the session. Each histogram shows the firing rate (Hz per 0.3 s bin)
of a single neuron plotted for either the 5 s before and after SD
onset (left panels) or the 5 s pre-first press (right panels). A: excita-
tory SDand pre-first press responses exhibited by a single neuron.
B: inhibitory SDand pre-first press responses exhibited by a single
neuron. In both A and B, the horizontal black lines at the top of the
histograms mark the 1 s pre- and post-SD, and the 1 s pre-first-
Changes in firing time-locked to events at the onset of
K. GUILLEM ET AL.
press exhibited by individual neurons during the maintenance
phase of the cocaine self-administration session (last 15 presses).
Each histogram shows the firing rate (Hz per 100 ms bin) of a single
neuron plotted during the 12 s before and after the cocaine-rein-
forced lever-press. A–B: Single-neuron examples of the exclusively
prepress firing pattern (A: prepress increase and B: prepress
Phasic firing patterns time-locked to the reinforced lever
decrease). C–D: Single-neuron examples of the exclusively postpress
firing pattern (C: postpress increase and D: postpress decrease). E–
F: Single-neuron examples of the combined pre- and postpress firing
pattern (E: increase and F: decrease). Above each histogram is a
raster display that shows firing of the neuron on a trial-by-trial ba-
sis. Lever-press trials are shown chronologically from the bottom
row to the top row of the raster.
ORBITOFRONTAL NEURAL ACTIVITY
respectively, NS). There was also no effect of phase on
baseline and postpress signal periods (P 5 0.15 and P
5 0.82, for baseline and postpress signal, respectively,
NS), indicating that the press firing patterns were
stable between the two phases. Only 3 of the 35 neu-
rons (9%) exhibited a significant change in firing dur-
ing the 1 s after the onset of the cue probe and none
of these neurons were press-responsive neurons.
These results show that press firing patterns did not
reflect responses to the tone 1 light cue.
Experiment 3: Effect of experimenter-delivered
cocaine in conditioning-naı ¨ve rats
In a third experiment, we characterized the effect
of experimenter-delivered (i.e., response-noncontin-
gent) cocaine on LO and AIV neural activity in condi-
tioning-naı ¨ve animals.In
recorded the activity of 38 pyramidal neurons in three
animals. Acute response-noncontingent infusion of co-
caine produced an increase in average firing rate of
LO and AIV neurons compared to vehicle injection
(Friedman ANOVA: X25 15.76, df 5 2, P < 0.001;
posthoc test: D0 vs. D0.75, P < 0.01; D0 vs. D1.5, P <
0.001) (Fig. 7A). There was a significant effect of dose
(i.e., 0, 0.75, 1.5) on the prevalence (X25 18.67, P <
0.001) and magnitude (X25 18.69, df 5 2, P < 0.001)
of session increases, but no significant effect of dose
on session decreases (Fig. 7).
As already described, the number of recorded inter-
neurons is too small to include in formal statistical
made of the 23 interneurons recorded in Experiment
1 (i.e., the FR1 cocaine self-administration recording
session). Interneurons exhibited the same categories
of firing patterns that were exhibited by pyramidal
neurons. Thirty-five percent of the 23 neurons showed
a response to the events associated with the onset of
the self-administration session (i.e., in response to SD
and the first press). The majority (75%) of these neu-
ral responses were increases. Seventeen percent of
the neurons exhibited a press response during the
self-administration session, with an equal percent of
those responses being increases and decreases (i.e.,
two of four increases and two of four decreases).
Finally, 74% of the 23 interneurons exhibited a ses-
sion change. Most of these session changes (82%, 14
of 17) were increases.
Under drug-free conditions, LO and AIV pyramidal
neurons exhibited changes in firing during presenta-
tion of a cocaine-predictive discriminative stimulus.
Neurons also responded during the ensuing onset of co-
caine-directed behavior. The majority (75%) of the neu-
ral responses to both the discriminative stimulus and
the onset of cocaine seeking were increases. During the
maintenance of cocaine self-administration, LO and
AIV pyramidal neurons showed responses during the
seconds that bracketed the cocaine-reinforced operant.
A majority of those responses were increases (63%).
Finally, during cocaine self-administration, about half
of the LO and AIV neurons exhibited session-long
changes in average firing, the prevalence of increases
and decreases did not differ significantly.
Firing patterns associated with cocaine cues
and onset of cocaine seeking
Based on human neuro-imaging studies, a cue-
induced increase in orbitofrontal neural activity is
hypothesized to contribute to cue-evoked cocaine-
directed behavior (i.e. relapse) (Kalivas et al., 2005;
London et al., 2000; Volkow and Fowler, 2000). A
number of neuropsychopharmacological rat studies
support the idea that the orbitofrontal cortex is
involved in cue-evoked cocaine seeking (although see
Fuchs et al., 2004). For example, local administration
of GABA antagonists to the LO block reinstatement
of cocaine seeking induced by presentation of cues
that have previously been paired with delivery of the
cocaine reinforcer (Fuchs et al., 2004). In the present
study, LO and AIV neurons showed predominantly
istration session. Each histogram shows the firing rate (Hz per 30 s
bin) of a single neuron plotted as a function of time (i.e. hours) dur-
ing the recording session. A: A single-neuron example of a session
increase in firing. B: A single-neuron example of a session decrease
in firing. In both histograms, the 0- and 3-h time points on the ab-
scissa mark the onset and the offset of the cocaine self-administra-
tion session, respectively.
Session changes in firing during the cocaine self-admin-
K. GUILLEM ET AL.
histogram shows average firing rate (Hz per 100-ms bin) plotted
during the 12 s before and after the following (from left to right): (1)
completion of the cocaine-reinforced lever-press during the first
phase of the cue-probe session, (2) completion of the cocaine-rein-
forced lever press during the second phase of the cue-probe session,
and (3) onset of the cue-probe (i.e., light 1 tone cue) presentation
during the second phase of the cue-probe session. A: Average popu-
Phasic firing patterns during the cue-probe session. Each
lation histograms for the group of neurons that exhibited excitatory
lever-press responses during both the first phase and the second
phase. B: Average population histograms for the group of neurons
that exhibited inhibitory lever-press responses during both the first
phase and the second phase. In each histogram, the vertical gray
line corresponds to either the time of the lever-press or the onset of
the cue-probe presentation.
response test in naı ¨ve rats. A: Overall average firing rate of the
entire combined LO and AIV neuron population after experimenter-
delivered infusion of different cocaine doses (0, 0.75, and 1.5 mg/kg).
B: Prevalence of neurons that showed either an increase (black
bars) or a decrease (white bars) in average firing is plotted for each
cocaine dose. C: Average magnitude of the increases (black bars)
Changes in firing rate during a within-session dose-
and decreases (white bars) in firing is plotted for each cocaine dose.
D–E: Each histogram shows the firing rate (Hz per 30-s bin) of a
single neuron after a single experimenter-delivered infusion of 1.5
mg/kg cocaine. In each histogram, the hatched and cross-hatched
sections mark the 2–6 min before and after infusion onset, respec-
tively. D: A single neuron example of an increase in firing. E: A sin-
gle-neuron example of a decrease in firing.
increases in firing in response to the discriminative
stimulus that signaled the onset of the cocaine self-
administration session. A similar neuronal response
was observed during the subsequent onset of cocaine-
seeking behavior. These findings are correlative evi-
dence that predominantly excitatory neural responses
mediate the orbitofrontal network contribution to cue-
evoked cocaine seeking (Ongur and Price, 2000; Price,
2007). It will be of interest to determine whether
medial orbitofrontal cortex and dorsal insula, parts of
the prefrontal network (Ongur and Price, 2000; Price,
2007), exhibit a comparable response during cue-
evoked cocaine-directed behavior.
Based on the connectivity of the orbitofrontal cortex
and insula, responses of neurons in those brain
regions to cocaine-predictive cues could reflect affer-
ent input from the amygdala and the medial prefron-
tal cortex. Furthermore, dorsolateral striatum and
nucleus accumbens shell are potential efferent targets
for the neuronal responses (Price, 2007; Schilman
et al., 2008). These proposals are consistent with sev-
eral lines of evidence. First, human neuro-imaging
data show that activations of amygdala, striatum
(i.e., caudate, ventral striatum, nucleus accumbens),
and medial prefrontal cortex occur in response to co-
caine-associated cues (Bonson et al., 2002; Childress
et al., 1999; Garavan et al., 2000; Grant et al., 1996;
Kilts et al., 2001, 2004; Volkow et al., 2006). Second,
electrophysiological rat data show that predominantly
increases in accumbal neural activity occur during
presentation of cocaine-predictive cues and cocaine-
directed behavior (Ghitza et al., 2003; Peoples and
Cavanaugh, 2003). Third, the basolateral amygdala,
dorso-lateral striatum are implicated in cue-induced
seeking, and second-order cocaine self-administration
in rats (Fuchs et al., 2006; See et al., 2007; Vander-
schuren et al., 2005).
cortex, accumbens, and
Firing patterns associated with the
During FR1 cocaine self-administration sessions,
26% of LO and AIV neurons exhibited changes in fir-
ing associated with the reinforced lever press (i.e.
press responses). A majority of the press responses
were excitatory. These findings are consistent with
the predominantly excitatory cue- and press-associ-
ated firing patterns observed at the onset of the self-
Press responses during cocaine self-administration
have been observed in other brain regions, including
the nucleus accumbens, basolateral amygdala, and
medial prefrontal cortex (Carelli et al., 1993, 2003;
Chang et al., 1998; Uzwiak et al., 1997). Comparison
of those firing patterns to the press patterns observed
in the present study highlights one notable difference.
In the present experiment, LO and AIV neurons did
not respond to the tone 1 light cue paired with drug
delivery; whereas amygdala and accumbal press-re-
sponsive neurons did respond to a comparable tone 1
light cue (Carelli, 2000; Carelli et al., 2003; Peoples
et al., 1997). Orbitofrontal neural responses to cues
can vary depending on the paradigm; moreover, orbi-
tofrontal neurons were weakly responsive to condi-
tioned reinforcers (i.e., cues normally paired with the
primary reinforcer) in a previous primate study of
Rolls, 1996; Rolls et al., 1989; Thorpe et al., 1983;
Tremblay and Schultz, 2000b). The absence of LO and
AIV responses to the tone 1 light cue might reflect
normal response to cues paired with reinforcers deliv-
ered on a simple FR1 schedule. Alternatively, it is
possible that the different responses to the tone 1
light cue reflect a between-experiment difference in
the cues that were paired with cocaine delivery, which
consisted of only the tone 1 light cue in the accumbal
and amygdala studies, but also included lever retrac-
tion in the LO and AIV study. Consistent with this
possibility, 30% of the press-responsive LO and AIV
neurons responded to the lever cue, which shared au-
ditory characteristics with lever retraction. This 30%
prevalence of neurons responsive to the lever cue
matches the prevalence of neurons responsive to the
tone 1 light cue in the accumbal study (prevalence
not determined in the amygdala study).
The findings of the present study extend other elec-
trophysiological rat studies of orbitofrontal cortex,
which demonstrate that orbitofrontal neurons show
responses associated with operant behavior (Feier-
stein et al., 2006; Furuyashiki et al., 2008; Kravitz
and Peoples, 2008; Tremblay and Schultz, 2000b).
Such responses have not been observed in primate re-
cording studies of the orbitofrontal cortex (Critchley
and Rolls, 1996; Roesch and Olson, 2004; Schoen-
baum et al., 1999; Tremblay and Schultz, 1999,
2000a). The different findings of the rodent and pri-
mate studies could reflect multiple factors (Feierstein
et al., 2006; Furuyashiki et al., 2008; Simmons and
Richmond, 2008); however, the evidence that orbito-
frontal neurons are responsive in relation to actions,
in addition to cocaine-predictive cues may be an im-
portant finding for understanding the role of the orbi-
tofrontal cortex in drug addiction.
Session changes in firing
Approximately half of the pyramidal neurons exhib-
ited a session change in firing during the self-admin-
istration session. Most of these changes in firing were
stable across the two behaviors that predominated
during the cocaine session. Such changes in firing
could reflect a stable state associated with the oper-
K. GUILLEM ET AL.
ant session, an acute pharmacological effect of co-
caine, or both. A previous study showed that LO and
both dorsal and ventral anterior insula neurons ex-
hibit session increases and decreases in average firing
duringFR1, sucrose self-administration
which were similar to those observed in the present
study (Kravitz and Peoples, 2008). This observation is
suggestive of a potential contribution of normal affer-
ent-input to the firing-rate increases and decreases
that occur during cocaine self-administration session.
However, the present study also showed that in condi-
tioning-naı ¨veanimals, response-noncontingent
caine incremented the prevalence and amplitude of
increases in average firing of LO and AIV neurons
relative to saline but had no significant effect on
decreases in average firing. This latter finding shows
that increases in average firing during cocaine expo-
sure can be observed in the absence of either operant
conditioning or operant behavior. In light of available
data, we hypothesize that the session changes associ-
ated with self-administered cocaine reflect a combined
bidirectional influence of nonpharmacological varia-
bles related to the operant session (c.f., Kravitz and
Peoples, 2008) and an excitatory acute pharmacologi-
cal effect of cocaine.
On the basis of the human neuro-imaging data,
Volkow et al. (1999) hypothesized that cocaine-
induced increases in activity of orbitofrontal cortex,
and other regions, might contribute to compulsive
drug taking (i.e., the inability of addicts to stop tak-
ing drug once drug-taking has been initiated). In the
present study, average LO and AIV neural firing
during the self-administration session increased sig-
nificantly relative to the presession drug-free period,
though the prevalence of increases and decreases in
average firing did not differ significantly. Moreover,
increases but not decreases in firing exhibited dose
dependence in conditioning-naı ¨ve animals. These
data provide some support for the hypothesis of Vol-
kow et al. (1999). However, the dose-dependent na-
ture of changes in firing associated with self-admin-
istered cocaine, and the relationship between the
changes in firing and cocaine-directed behavior need
to be examined further.
Findings of previous human and animal studies
are mixed in supporting the hypothesis of Volkow
et al. (1999). Human neuro-imaging studies of psy-
chomotor stimulant effects on orbitofrontal and
insula neural activity have yielded inconsistent find-
ings, with some studies showing increases in meta-
bolic activity during psychomotor stimulant expo-
sure and others showing decreases (Breiter et al.,
1997; Grant et al., 1996; Kufahl et al., 2005; Lyons
et al., 1996; Risinger et al., 2005; Volkow et al.,
1999). Neuropsychopharmacological tests conducted
in animals investigating the role of the orbitofrontal
cortex in cocaine-evoked and maintained behavior
have also yielded findings, which are ambiguous
with respect to the hypothesis. For example, prima-
tes will self-administer cocaine directly to the orbito-
frontal cortex (Phillips et al., 1981); however, lesions
of the ventro-lateral and LO cortex in the rat do not
block cocaine-induced reinstatement of previously
extinguished cocaine seeking or FR1, cocaine self-
administration (Capriles et al., 2003; Hutcheson and
appear inconsistent with the idea that cocaine-
induced increases in neural activity in the orbito-
frontal cortex (and insula) contribute importantly to
drug taking behavior. However, cocaine exposure in
human neuro-imaging studies is often limited to one
or two experimenter-delivered infusions. This co-
caine exposure may not have the same effect as
freely, self-administered cocaine. Additionally, rat
studies, including the present, have thus far focused
on animals, which have a short drug history (e.g., 2-
week history of daily 2-h self-administration ses-
sions), and for which drug-taking behavior may not
be compulsive. It will be of interest to extend tests
of the hypothesis to paradigms that establish and
index compulsive drug taking [e.g., (Belin et al.,
and animal data
Evidence for a role of prefrontal cortex
hypoactivity in drug addiction
As we have already described, orbitofrontal cortex
with a limited history of drug abstinence. However, in
regions, including the orbitofrontal cortex are hypoac-
tive (Goldstein and Volkow, 2002; Rogers et al., 1999).
This hypoactivity has been proposed to contribute to
drug addiction (Jentsch and Taylor, 1999; Volkow and
Fowler, 2000). On first glance, this proposal appears to
conflict with evidence linking increased prefrontal ac-
tivity to both drug craving in humans and evoked
drug seeking in animals (Kalivas et al., 2005; Kalivas
and McFarland, 2003). However, it is possible that the
neurophysiological mechanisms, which mediate a pre-
frontal cortex role in cocaine-directed behavior, vary
depending on abstinence history. Additionally, it is pos-
sible that both cue- or drug-evoked increases in neuro-
nal activity and basal hypoactivity make different but
nevertheless concomitant contributions to drug addic-
tion symptoms [cf. (Kalivas et al., 2005; Kalivas and
Hu, 2006; Volkow and Fowler, 2000); for relevant dis-
cussion, also see (Peoples et al., 2004, 2007a,b)].
SUMMARY AND CONCLUSIONS
It is hypothesized that cocaine-associated cues acti-
vate orbitofrontal and insula neurons and that these
activations contribute to the onset of cocaine-seeking
behavior and relapse in cocaine-addicted individuals.
ORBITOFRONTAL NEURAL ACTIVITY
Increased neuronal activity is also hypothesized to
contribute to compulsive drug taking. Neuro-imaging
studies in humans and studies of cue-induced rein-
statement in rats, as well as the present electrophysi-
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latter hypothesis, though there are outstanding issues
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