 |
 Previous Article
The Journal of Neuroscience, April 15, 1998, 18(8):3098-3115
Comparison of Mesocorticolimbic Neuronal Responses During Cocaine
and Heroin Self-Administration in Freely Moving Rats
Jing-Yu
Chang,
Patricia H.
Janak, and
Donald J.
Woodward
Department of Physiology and Pharmacology, Wake Forest University,
School of Medicine, Winston-Salem, North Carolina 27157
 |
ABSTRACT |
To compare neuronal activity within the mesocorticolimbic circuit
during the self-administration of cocaine and heroin, multiple-channel single-unit recordings of spike activity within the rat medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) were obtained during the consecutive self-administration of cocaine and heroin within
the same session. The variety of neuronal responses observed before the
lever press are termed anticipatory responses, and those observed after
the lever press are called post-drug infusion responses. For the total
of the 110 mPFC and 111 NAc neurons recorded, 30-50% of neurons,
depending on the individual sessions, had no alteration in spike
activity in relation to either cocaine or heroin self-administration.
Among the neurons exhibiting significant neuronal responses during a
self-administration session, only a small portion (16-25%) of neurons
responded similarly under both reinforcement conditions; the majority
of neurons (75-84%) responded differently to cocaine and heroin
self-administration as revealed by variations in both anticipatory
and/or post-drug infusion responses. A detailed video analysis of
specific movements to obtain the self-administration of both drugs
provided evidence against the possibility that locomotive differences
contributed to the observed differences in anticipatory responses. The
overall mean activity of neurons recorded in mPFC and NAc measured
across the duration of the session segment for either cocaine or heroin self-administration also was different for some neurons under the two
reinforcement conditions. This study provides direct evidence that, in
mPFC and NAc, heterogeneous neuronal circuits mediate cocaine and
heroin self-administration and that distinct, but overlapping,
subpopulations of neurons in these areas become active during operant
responding for different reinforcers.
Key words:
electrophysiology; cocaine; heroin; mesocorticolimbic
system; medial prefrontal cortex; nucleus accumbens; reinforcement; reward; drug abuse; behavior
| |
INTRODUCTION |
A consensus exists that the
mesocorticolimbic circuit is involved in both cocaine and heroin
self-administration (Zito et al., 1985 ; Wise and Rompre, 1989; Koob,
1992; Wise, 1996). However, the degree to which common versus
independent neuronal circuits are used to mediate a similar behavior
driven by a different reinforcer is not yet clear. Reciprocal
interconnections are found among the mesocorticolimbic structures. The
medial prefrontal cortex (mPFC) projects to the nucleus accumbens
(NAc), amygdala, and ventral tegmental area (VTA) (Berendse et al.,
1992, Naito and Kita, 1994). The NAc, in turn, sends a projection back
to the frontal cortex via substantia nigra reticulata, ventral
pallidum, and the medial dorsal thalamic nucleus (Zahm et al., 1987;
Groenewegen, 1988; Groenewegen et al., 1990; Deniau et al.,
1994). Dense dopamine and opioid receptors located within these areas
provide for the anatomic basis that contributes to the multiple actions
of cocaine and heroin on the mesocorticolimbic reward system (Mansour
et al., 1987, 1994; Tempel and Zukin, 1987).
An emerging hypothesis is that cocaine and heroin to some extent
share a common pathway within the mesocorticolimbic system, perhaps via
subgroups of medium spiny neurons in the NAc, for the mediation of
their rewarding actions (Wise and Bozarth, 1985). In this view, the NAc
medium spiny neuron is necessary for drug-reinforced operant
responding, independent of whether the primary receptor-mediated drug
action is directly on these neurons, on neurons of other afferent
regions (for example, the VTA), or both. Supporting this idea is the
finding that the integrity of the NAc is required for both cocaine and
heroin self-administration, as demonstrated by reductions in operant
responding for either drug after cell body lesions of this region (Zito
et al., 1985). In addition, microinjection of opioid and dopamine
receptor antagonists into the NAc selectively impairs heroin and
cocaine self-administration, respectively (Vaccarino et al., 1985;
Corrigall and Vaccarino 1988; Caine et al., 1995).
A specific role of the mPFC in drug self-administration is less well
defined, even though the direct self-administration of cocaine into the
mPFC has been reported (Goeders and Smith, 1983, 1986), and lesions of
mPFC have resulted in an increase in the rate of responding for
intravenous morphine self-administration (Glick and Cox, 1978).
Although 6-OHDA lesions of the dopaminergic input to the mPFC
suggest that dopamine input to the mPFC is not required for intravenous
cocaine self-administration (Martin-Inverson et al., 1986), the
presence of substantial direct and indirect projections from the mPFC
to the NAc indicates that these regions may function together to
control drug self-administration. Indeed, recent electrophysiological
studies found that neurons of the mPFC and NAc show phasic alterations
in activity during operant responding for intravenous cocaine (Chang et
al., 1990; 1994; 1997a) and heroin (Chang et al., 1997b), suggesting
that the mPFC, along with interconnected regions, may contribute to
behaviors related to drug selfadministration.
Evidence that dopamine levels within the NAc are altered during
both opiate (Wise et al., 1995a) and stimulant (Petit and Justice,
1989, 1991; Wise et al., 1995b; Kiyatkin and Stein, 1996) self-administration suggests a common mechanism at the level of the NAc
for the mediation of opiate and stimulant reward (Hemby et al., 1995).
In contrast, studies of dopamine depletion (Petit et al., 1984; Gerrits
and VanRee, 1996) or antagonism (Ettenberg et al., 1982) suggest that
opiate self-administration is not largely dependent on dopamine input
to the NAc.
The working hypothesis for the present study was that, if a
common pathway within the mesocorticolimbic system is involved in
cocaine and heroin self-administration, one would expect to see similar
responses for both cocaine and heroin self-administration in the same
neuron. An alternative hypothesis supported by the results of the
current study is that different functional neuronal networks are wired
up by cocaine and heroin self-administration and, therefore, different
neuronal responses should emerge in the same neuron during cocaine and
heroin self-administration, respectively. Preliminary results of this
study were presented in abstract form (Chang and Woodward, 1996).
| |
MATERIALS AND METHODS |
Animals and surgery. Ten young adult male Sprague
Dawley rats weighing 250-300 gm were used in these experiments.
Animals were housed under a reverse light/dark cycle (lights off from 7:00 A.M. to 7:00 P.M.). Except during initial lever press response shaping, food and water was available ad libitum. Surgical
procedures are described here briefly and in detail in Chang et al.
(1994). In preparation for catheterization surgery, rats were
anesthetized with ketamine (100 mg/kg) and xylazine (10 mg/kg, i.m.).
Under sterile conditions, SILASTIC tubing [Dow Corning; 26 mm long, 0.3 mm inner diameter (i.d.) cannula tubing, connected to a 90-mm-long, 0.6 mm i.d. outlet tubing] was inserted in the right jugular vein for
subsequent intravenous drug infusion. The infusion tubing was glued to
a SILASTIC implant sheeting that was sutured to subdermal connective
tissue. The exposed plugged end of the tubing emanated from the dorsal
aspect of the neck.
Recording microwires were implanted after training for cocaine and
heroin self-administration. Anesthesia was the same as in the
catheterization surgery. Four splayed bundles of eight stainless steel
Teflon-insulated microwires (45-62 µm diameter; NB Labs, Denison,
TX), soldered to connecting pins on a head stage, were stereotaxically
lowered bilaterally into the mPFC and NAc (eight wires per side) (Chang
et al., 1994). Coordinates for the mPFC and NAc were obtained from the
atlas of Paxinos and Watson (1986): for mPFC, 0.5 mm lateral to
midline, 3.5-3.8 mm anterior to bregma, 3.5-4.0 mm ventral to the
dorsal surface of the brain; for NAc, 1.4-1.5 mm lateral, 1.8-2.0 mm
anterior and 6.5-7 mm ventral. In addition, ground wires were
positioned ~2 mm ventral to the cortical surface. The head stage was
secured onto the cranium with dental cement using skull screws as
anchors. The head stage and dental cement weighed ~10 gm. The animal
received ampicillin (60,000 U, i.m.) after surgery. Animals were housed
individually after surgery and treated in accordance with the United
States Public Health Service Guide for the Care and Use of Laboratory Animals.
Apparatus and behavioral training. Two to 3 d after
intravenous catheterization, 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 cm × 23 cm
and was 20 cm in height. A lever was mounted on one wall 8 cm above the
cage floor. Daily experimental sessions began ~2 hr into the
animal's dark cycle and lasted ~3 to 4 hr. Rats were trained
initially to press the lever for a water reinforcer using a continuous
reinforcement schedule; cocaine or heroin was substituted later for
water. Drug self-administration training started with a continuous
reinforcement schedule in which each lever press activated the pump for
4 sec thereby infusing ~1.0 mg/kg cocaine or 30 µg/kg heroin in 0.1 ml of lactated Ringer's solution into the jugular vein. The indwelling jugular cannula was connected to an infusion pump via a plastic tube.
Twenty second time-out periods were imposed immediately after drug
delivery, during which the lever was inactivated to prevent an overdose
of drugs. Once stable rates of responding were achieved for cocaine or
heroin, a different drug was introduced in the following sessions until
responding stabilized. Rats were then self-administering cocaine and
heroin on alternative days. Well trained rats pressed the lever for
cocaine self-administration approximately every 3-4 min and heroin
approximately every 10-15 min. To compare the effects of
self-administered and passively administered cocaine and heroin on the
neuronal activity, cocaine (1 mg/kg per infusion) and heroin (30 µg/kg per infusion) were passively infused into the jugular vein by a
computer-controlled timer. Random intervals were used that were within
the range of mean ± SE of the intertrial intervals obtained
during self-administration sessions in the same animal.
Once the rats were trained, surgery was performed to implant
microwires in the recording regions. After 5 d of recovery,
extracellular recording of mPFC and NAc spike activities during
self-administration sessions was accomplished by connecting a field
effect transistor head stage plug and lightweight cabling onto the
implanted microwire assembly. The cabling was in turn connected to a
commutator located in the center of the ceiling of the chamber. The
commutator was free to turn as necessary. In this manner, the animal
was permitted unrestricted movement in the operant chamber.
Electrophysiological recording. Electrophysiological
recording during self-administration sessions was started with a 200 sec control period during which the lever was not available. The neuronal firing rate during this period served as baseline predrug activity for comparison with activity during the period of cocaine and
heroin self-administration. After the control period, the lever became
available, and a lever press by subjects led to an intravenous infusion
of either cocaine or heroin, depending on which drug was used as the
first reinforcer. In the middle of the session (generally after more
than eight lever presses were made), a change of drug was accomplished
by switching the syringe and thoroughly flushing the connecting tubing.
The assignment of the drug that served as the first reinforcer each day
was counterbalanced among sessions. The recording sessions lasted
~3-4 hr and consisted of a total of 20-30 lever presses for both
cocaine and heroin reinforcement.
Neuroelectric signals were passed from the headset assemblies to
programmable amplifiers, filters (0.5 and 5 kHz, 3 dB cutoffs), and a
multichannel spike sorting device. As many as 31 mPFC and NAc neurons
per rat were monitored concurrently. When spike activity was recorded
from the same microwire across different self-administration sessions,
the determination that the same neuron was recorded was made in view of
(1) constancy of the shape and polarity of the extracellular spike
waveform and (2) similarities in firing rate and pattern (e.g.,
interspike interval and autocorrelation histograms). Spike activity,
lever pressing, and pump activation 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 2 weeks. Spike train activity was
analyzed with a commercially available PC-based program (STRANGER;
Biographics Inc., Winston-Salem, NC).
Video analysis of behavior. The animal's behavior during
self-administration was recorded on videotape with the experimental time superimposed on the display for off-line analysis. Frame-by-frame analysis of behavior, at 30 frames/sec, provided 33 msec temporal resolution. In practice, interframe times could be extrapolated into
thirds, permitting ~11 msec resolution. Evaluation of behavioral time
epochs with respect to concurrent spike activity was performed off-line
with special purpose computer software package included in
STRANGER.
Drugs. Cocaine hydrochloride (3.33 mg/ml; Sigma, St.
Louis, MO) and heroin (100 µg/ml; National Institute on Drug Abuse,
Rockville, MD) was dissolved in Ringer's solution with heparin (10 U/ml) and sterilized by passing the solution through a 0.22 µm Star filter (Corning Costar Inc.).
Histology. At the conclusion of the final experimental
session, 10-20 sec of 10-20 µA of positive current was passed
through selected microwires to deposit iron ions. The marking
current was passed through no more than two microwires in a bundle of eight microwires, because it was not possible to distinguish more than
two sites using different current parameters. It was often the case
that more than two microwires in a bundle of eight yielded isolated
single units; therefore, not every recording site was identified,
although the relative position could be ascertained. Microwires, from
which anticipatory responses (see Results) were recorded, were
preferentially selected for marking. The animals were then killed and
perfused with a 4% paraformaldehyde solution. Coronal sections were
cut through the NAc and the mPFC and mounted on slides. Incubation of
the mounted sections in a solution of 5% potassium ferricyanide and
10% HCl revealed iron deposits (recording sites) in the form of blue
dots. If marked recording sites were localized to the NAc or the mPFC,
it was assumed that unmarked microwires had also been positioned in the
regions of interest, because the dispersion diameter of the implanted
microwire bundles was no more than 0.5 mm (as verified in
situ with x rays). Boundaries of the mPFC and NAc were assessed
with reference to the rat brain atlas of Paxinos and Watson (1986).
Statistics. Two arbitrary criteria were used
concurrently to indicate a change in firing rate of neurons before and
after a lever press during a session. First, the mean rate changes
(excitatory or inhibitory) by 20% during the time epochs measured.
Baseline activity was measured 40-50 sec before the lever press as a
control period. Anticipatory activity and postdrug activity were
calculated 1-3 secs before and 40-50 sec after lever press,
respectively. Second, t values were computed based on
variation in counts per bin during the time epochs and
p < 0.01 were required to indicate a difference. These
measures accounted for slow- and fast-firing neurons to show both
substantial (100%) and significant changes. Nonparametric
 2 goodness of fit and 2 × 2 contingency
table tests were used to determine whether the distribution of
numbers of neurons across response categories was the same for cocaine
versus heroin. Regression analysis was performed with a commercial
software program (STATISTICA; StatSoft, Tulsa, OK). A power
analysis ( = 0.05) was used to verify the significance of the
correlation coefficients from the regression analyses. Data are
presented as mean ± SEM.
| |
RESULTS |
General neuronal responses in mPFC and NAc during cocaine and
heroin self-administration
Neurons from mPFC and NAc were recorded from 10 rats during
cocaine and heroin self-administration sessions. Because the same neuron was recorded in different sessions, each neuron recorded in one
session was defined as a neuron session. According to this definition,
a total of 422 neuron sessions, each lasting 3-4 hr, were included in
this study, with at least 211 different neurons within the sessions
(110 mPFC and 111 NAc). The mean firing rate was 3.99 ± 0.52 Hz
for the mPFC and 4.73 ± 0.65 Hz for the NAc.
The neuronal responses in relation to the lever press behavior during
cocaine and heroin self-administration can be classified into two gross
categories, i.e., the responses before the lever press (anticipatory
responses) and the responses after the lever press (post-drug infusion
responses). Both categories could be further divided into excitatory
and inhibitory responses. Some neurons exhibited both anticipatory and
post-drug infusion responses. This was more frequently observed in the
case of the coexistence of excitatory anticipatory and inhibitory
post-cocaine responses. Figure 1
demonstrates the typical neuronal responses for these different
categories, which include excitatory anticipatory responses (Fig.
1A,B), inhibitory anticipatory
responses (Fig. 1C), inhibitory postdrug responses (Fig.
1A), and excitatory postdrug responses (Fig.
1D).
View larger version (52K):
[in this window]
[in a new window]
|
Figure 1.
Different categories of neuronal responses in mPFC
and NAc during cocaine and heroin self-administration.
A, Raster and perievent histogram plots show excitatory
anticipatory and post-cocaine inhibitory responses by a mPFC neuron.
Each dot in the raster plot (top)
represents a neuronal spike, and each row represents an
individual trial. The perievent histogram (bottom)
depicts the average neuronal activity of the individual trials within
the raster around the lever press event (50 sec before and 100 sec
after lever press in this case). The zero point corresponds to the
behavioral event of the lever press for cocaine self-administration. An
increase in spike activity was found a few seconds before the lever
press (excitatory anticipatory response), and a decrease in neuronal
activity was observed after cocaine self-infusion (post-cocaine
inhibitory response). B, Example of an excitatory
anticipatory response during a heroin self-administration session by a
NAc neuron. C, Inhibitory anticipatory neuronal response
recorded from the mPFC during cocaine self-administration. Note a
decrease in firing rate before the lever press. D,
Excitatory post-heroin response recorded from a mPFC neuron during a
heroin self-administration session. An increase in spike activity after
heroin infusion is evident.
|
|
Table 1 summarizes neuronal
responses recorded from the mPFC and the NAc during cocaine and heroin
dual-drug self-administration sessions. The data in this table are
reported from sessions in which each drug was the first reinforcer
tested to present the responses of neurons associated with the
individual reinforcer under conditions in which an interaction with the
earlier self-administered drug is avoided (see Materials and Methods).
More than half of the neurons recorded in both the mPFC and the NAc had
no response during cocaine or heroin self-administration either before
or after the lever press. In comparison with the mPFC, the majority of
anticipatory responses in the NAc were excitatory. Another noticeable
difference is that more neurons exhibited post-drug infusion responses
in the NAc than in the mPFC during both cocaine and heroin
self-administration.
Comparison between the neuronal responses in mPFC and NAc during
cocaine and heroin self-administration
Responses of the same neuron during cocaine and heroin
self-administration were compared under three different conditions. We
compared the neuronal responses within dual-drug self-administration sessions that either started with cocaine, followed by heroin, or
started with heroin, followed by cocaine. The first reinforcers for
each of these two sessions, 24 hr apart, were also compared. In all
three comparison conditions, different responses were frequently observed in the same neuron during cocaine and heroin
self-administration; in some cases, the opposite responses were found
(excitatory vs inhibitory).
Figure 2 shows an NAc neuron during a
heroin-cocaine self-administration session. An increase in firing rate
was detected a few seconds before the lever press, resulting in heroin
infusion; when the reinforcer was changed to cocaine, no significant
alteration of spike activity was observed before the lever press,
although an altered spike activity developed after cocaine infusion.
Figure 3 illustrates another example for
a different response in a mPFC neuron, recorded during a
cocaine-heroin session. In this case, an inhibitory anticipatory
response appeared during the cocaine self-administration trials (Fig.
3B, arrow) but did not exist during the trials in which
heroin was self-administered (Fig. 3C).
View larger version (48K):
[in this window]
[in a new window]
|
Figure 2.
Comparison of NAc neuronal activity during a
single heroin and cocaine self-administration session.
A, This rate meter record shows the spike activity of a
NAc neuron during a heroin-first, cocaine-second
self-administration session.  , Lever press events. The initial eight
lever presses were for heroin self-administration and were followed by
11 presses for cocaine self-administration. Cocaine self-administration
resulted in an increase in neuronal activity. B, Raster
and perievent histogram for the heroin self-administration trials. Note
the increase in firing rate before the lever press (excitatory
anticipatory response). C, Same neuron as in
B during the cocaine self-administration period. In
contrast to B, no significant alteration of neuronal
activity was observed before the lever press for cocaine
self-administration.
|
|
View larger version (41K):
[in this window]
[in a new window]
|
Figure 3.
Comparison of mPFC neuronal activity during
a cocaine-first, heroin-second self-administration session using the
same plot as in Figure 2. A, This rate meter plot
demonstrates the firing rate of a mPFC neuron during the entire
cocaine-heroin self-administration session. In this case, heroin
self-administration caused general inhibition. B, Raster
and perievent histogram for cocaine self-administration trials. A
decrease in firing rate occurred ~2 sec before the lever press
(inhibitory anticipatory response). C, Raster and
perievent histogram for heroin self-administration trials.
The inhibitory anticipatory response observed during cocaine
self-administration trials (B) was absent during
heroin selfadministration.
|
|
To examine the reliability of these reinforcer-specific responses, data
obtained during single-drug self-administration sessions, in which
heroin and cocaine alternated as the reinforcer of that day, were
examined. Different neuronal anticipatory responses were observed also
in these cases when cocaine and heroin self-administration was
performed in different sessions. Figure 4
depicts the spike activity of the same NAc neuron during four
consecutive, alternating cocaine and heroin self-administration
sessions. Inhibitory anticipatory responses were observed during
cocaine self-administration sessions for days 1 and 3 (Fig.
4A,C), whereas during the heroin self-administration sessions for days 2 and 4, no such responses could be detected (Fig.
4B,D). This result showed that the same neuron could
be recorded reliably across different sessions.
View larger version (74K):
[in this window]
[in a new window]
|
Figure 4.
Different anticipatory neuronal responses across
alternating daily cocaine and heroin sessions recorded from the same
NAc neuron. A, NAc neuron exhibited inhibitory
anticipatory responses before the lever press for cocaine
self-administration in session 1. B, Same neuron
depicted in A showed no response during the heroin
self-administration session of the following day. C, An
identical inhibitory anticipatory response was observed by the same
neuron on the third day when cocaine self-administration was repeated.
D, No alteration of neuronal activity of this same
neuron was found when the subject was switched back to heroin
self-administration for the session of the fourth day.
|
|
Cocaine and heroin also induced different neuronal responses after the
lever press for drug self-injection (post-drug infusion response).
Figure 5 shows activities of
simultaneously recorded mPFC and NAc neurons during a cocaine-heroin
self-administration session. Whereas an increase in firing rate was
observed after heroin self-administration in the mPFC neuron (Fig.
5A), no significant change was found during cocaine
self-administration (Fig. 5B). In the NAc, a decrease in
neuronal activity was observed after cocaine self-administration (Fig.
5D), whereas heroin self-administration did not induce any
changes in the same neuron (Fig. 5C).
View larger version (54K):
[in this window]
[in a new window]
|
Figure 5.
Comparison of post-drug infusion responses in
simultaneously recorded mPFC and NAc neurons. A, Raster
and perievent histogram plots for a mPFC neuron during the heroin
self-administration trials of a heroin-cocaine self-administration
session. An increase in firing rate was observed after heroin
self-administration that occurred at 0 sec. B, Same
neuron depicted in A during the cocaine
self-administration period of the same session. No significant change
in firing rate was found during cocaine self-administration.
C, This NAc neuron did not change its firing rate after
the lever press during the heroin self-administration trials.
D, Same NAc neuron as in C
displayed an inhibitory response after cocaine self-administration
during the same session. This neuron also exhibited an excitatory
anticipatory response immediately before the lever press at 0 sec.
|
|
To compare the neuronal responses between cocaine and heroin
self-administration, we divided the neuronal response into anticipatory excitatory (AE), anticipatory inhibitory (AI), postdrug excitatory (PE), postdrug inhibitory (PI), and no response (NR) categories. Some
neurons with both anticipatory and postdrug responses were classified
into both categories, therefore the sum total percentage of neurons
with different responses exceeds 100%. Each neuron that exhibited one
response was defined as a neuron response case; one neuron, when having
both anticipatory and postdrug responses, can be classified into more
than one neuron response case. Data for three different conditions are
summarized in
Tables 2-4. Table
2A summarizes data from the mPFC in cocaine-first, heroin-second
sessions. The most evident finding was that the responding neurons were
clearly not the same between cocaine and heroin. For example, in Table
2A, 47% of neurons did not change during any behavioral epoch during
cocaine or heroin session. For the anticipatory excitatory response
group, 15 of 110 (13.5%) were present during cocaine, and 11 of 110 (10%) were present during heroin self-administration. Only six (5.5%)
neurons responded similarly with both cocaine and heroin. This is
clearly above the number of co-responding neurons expected by chance
(1.3%), but the two groups showed considerable difference, 14 of 20 of
the anticipatory excitatory neurons were different in responding to
cocaine and heroin. Also in other categories, most of the neurons with
responses to cocaine or heroin self-administration responded
differently to these two drugs. Overall, only 18.7% of these neuron
response cases exhibited similar responses for both cocaine and heroin
self-administration across all four response categories (Table 2A, dark
shaded blocks in a diagonal line), whereas 81.3% of the neuron
response cases responded differently during cocaine and heroin
self-administration (light shaded blocks). As summarized by Table
2B, the response profile for the NAc was very similar
to that observed in mPFC, with most neurons responding differently to
cocaine and heroin self-administration.
Table 3 summarizes the data from heroin-first, cocaine-second sessions,
in which the majority of neuronal responses recorded from both the mPFC
and the NAc also differed during cocaine and heroin self-administration
intervals.
Caution must be exercised when comparing neuronal activity within the
dual-drug self-administration session because of a potential pharmacological interaction between the two self-administered drugs.
Therefore, data from the first part of different sessions 24 hr apart
were compared to eliminate the within-session interactions between
cocaine and heroin. Table 4 shows the results of this comparison of
neuronal responses during cocaine and heroin self-administration in
different sessions. The results are similar to those obtained from the
comparison of cocaine and heroin within the same session. In the mPFC,
only 19.5% of neuron response cases exhibited similar responses for
cocaine and heroin and 80.5% of neurons exhibited different responses.
In the NAc, there were 19.2 and 79.6% for the same and different
neuron response cases, respectively.
The independence of the neuronal responses observed during cocaine and
heroin self-administration was revealed by a regression analysis
performed with respect to two different conditions (cocaine first,
heroin second and heroin first, cocaine second). Neurons with
anticipatory and post-drug infusion responses in either the cocaine or
heroin self-administration condition were selected and classified
according to the type of response. Figure
6A depicts the
correlation between the cocaine and heroin self-administration conditions for anticipatory responses in the mPFC. The correlation coefficients for the responses to cocaine and heroin were 0.37 and 0.46 for cocaine-first and heroin-first sessions, respectively; both reached
a significant level (p < 0.05). These weak
correlations are what one expects when a few co-responding neurons are
found within a predominantly independent population. Figure
6B shows the regression analysis for anticipatory
responses in the NAc for both drugs, with correlation coefficients of
0.27 and 0.14 for cocaine-first and heroin-first session, respectively;
both failed to reach significance (p > 0.05).
Correlations between cocaine and heroin post-drug infusion responses in
the mPFC are plotted in Figure 6C. In this case, the slopes
for the cocaine-first and heroin-first sessions were almost flat and
parallel (r = 0.06 and 0.03 for cocaine-first and
heroin-first sessions, respectively; p > 0.05). Figure
6D plots data for the NAc, again revealing no significant correlations between cocaine and heroin responses (r = 0.05 and 0.12 for cocaine-first and heroin-first
sessions, respectively; p > 0.05). Power analysis for
type II error ( = 0.05) in which there would be a 5% chance of
falsely identifying nonsignificant correlations revealed that the
correlation coefficient would be at least >0.47.
View larger version (22K):
[in this window]
[in a new window]
|
Figure 6.
Multiple regression analysis of the neuronal
responses to cocaine and heroin self-administration from
cocaine-heroin and heroin-cocaine sessions. A,
Anticipatory responses recorded from the mPFC during the
self-administration of cocaine and heroin in the same session. The
responses were measured as a percentage change of neuronal activity.
Two sessions were plotted in this figure: the cocaine-first,
heroin-second session (n = 39,  ) and the
heroin-first, cocaine-second session (n = 53,  ).
The correlation coefficient values (r) for
cocaine-first and heroin-first sessions were 0.37 and 0.46, respectively. Both correlations were significant
(p < 0.05). B, Same plot as
in A for the NAc. The correlations between cocaine and
heroin responses are not significant (p > 0.05) for either cocaine-first (r = 0.27;
n = 43) or heroin-first sessions
(r = 0.14; n = 40).
C, Regression analysis for post-drug infusion responses
recorded from the mPFC. The regression lines were nearly flat and
parallel for cocaine and heroin self-administration in both
cocaine-first (r = 0.06; n = 38) and heroin-first (r = 0.03;
n = 29) conditions, and there were no significant
correlations between cocaine and heroin responses. D,
Same plot as in C for NAc. No significant correlations
were observed between cocaine (r = 0.05;
n = 48) and heroin (r = 0.12;
n = 43) post-drug infusion responses.
|
|
Behavioral correlations of mPFC and NAc anticipatory neuronal
responses during cocaine and heroin self-administration
A critical issue concerning the different anticipatory responses
exhibited by the same neurons during cocaine and heroin
self-administration is whether movement could have contributed to the
different neuronal responses. It might be argued that the way in which
a rat reaches for and then presses the lever differs when the subject
is responding for cocaine or heroin. If this were the case, differences
in neuronal activity generated before the lever press for cocaine or
heroin reinforcement could be attributed to differences in locomotor behavior, rather than differences in motivational processes associated with cocaine and heroin reinforcement.
Off-line video analysis was conducted to determine whether
locomotor activity before the lever press is a factor responsible for
the different anticipatory neuronal activities before lever press.
Although cocaine and heroin elicited different stereotypic behaviors
after self-administration (cocaine self-administration most often
caused head shaking and increased general locomotor activity, whereas
heroin self-administration induced typical floor-licking behavior), of
10 rats analyzed for cocaine and heroin self-administration, only one
showed a detectable difference in locomotor behavior, leading to the
lever press for cocaine or heroin reinforcement. In this case, during
heroin self-administration trials, the rat stayed away from the lever
during heroin-stereotypical behavior and reached and pressed the lever
for drug self-administration. In contrast, during cocaine
self-administration trials, the rat stayed close beside the lever
during the cocaine-stereotypical behavior and simply reared toward and
pressed the lever for drug self-administration. Although each subject
displayed a unique and characteristic behavioral sequence preceding and
including the lever press, each of the remaining nine rats analyzed had no noticeable within-subject differences in locomotor behaviors leading
to lever presses for cocaine or heroin.
Figure 7 illustrates the anticipatory
neuronal activity in an NAc neuron in association with specific
behavior episodes during cocaine and heroin self-administration. The
same behavioral nodes of raising head and lever press are completed by
the rat in a predictable sequence to accomplish cocaine and heroin
self-administration. However, opposite neuronal responses were
exhibited by this neuron during cocaine and heroin self-administration.
Note that during cocaine self-administration trials, increased spike
activity occurred during the raising head behavioral epoch, whereas
during heroin self-administration trials, a decrease in spike activity
was associated with the raising head behavior. Figure
8 illustrates an example for an mPFC
neuron during cocaine and heroin self-administration within the same
session. The sequence leading to the lever press in this case is
raising head  lever press back to floor. During cocaine
self-administration trials, a decrease in neuronal activity started
with the raising head behavior and ended at the point when the paw of
the rat returned back to the floor after completion of the lever press
(Fig. 8A). No significant activity changes associated
with the same behavior in the same neuron could be detected during
heroin self-administration trials (Fig. 8B).
View larger version (67K):
[in this window]
[in a new window]
|
Figure 7.
Behavioral correlations of an anticipatory
neuronal response recorded from a NAc neuron. Behavioral nodes
(raising head, lever press) were created by video
analysis and used as reference points for the creation of the raster
and perievent histogram plots. A, C, Plot of data during
cocaine self-administration period. Note the increase in firing rate at
the onset of the raising head behavioral episode as
indicated by the arrow in A. The
increased firing rate continued until the lever press.
B, D, Same neuron during heroin
self-administration within the same session. In contrast to cocaine
self-administration, the identical raising head behavior
during heroin self-administration was associated with a decrease in
firing rate as indicated by the arrow in
B. The decreased neuronal activity persisted until the
lever press episode as depicted in
D.
|
|
View larger version (71K):
[in this window]
[in a new window]
|
Figure 8.
Behavioral correlations of the anticipatory
neuronal activity recorded from a mPFC neuron. A, From
top to bottom, the panels demonstrate the
behavioral sequence of raising head, lever press, and
back to floor during cocaine self-administration trials.
Note the onset of a decrease in spike activity at the raising head
behavior episode (top panel). The decreased
activity continued through the lever press episode (middle
panel) and until the subject returned its paws back to
the floor (bottom panel). B, The
same neuron during heroin self-administration trials during the same
session. No significant change in firing rate was detected during
raising head, lever press, and return back to floor behavioral
episodes.
|
|
Overall, the behavioral analysis indicates that different anticipatory
responses observed before the lever presses for cocaine and heroin
reinforcement are not primarily associated with different patterns of
movement or locomotion.
Comparing overall neuronal firing rate during the period of cocaine
and heroin self-administration
Self-administration of cocaine and heroin also
produced long-lasting alterations of overall spike activity during the
entire self-administration period. The mean firing rates of recorded neurons were compared during cocaine and heroin self-administration periods and also to the 200 sec control period at the beginning of the
session (see Materials and Methods). Figure
9 shows the result of this type of
analysis for one heroin-cocaine session by depicting the firing rate
of 19 neurons simultaneously recorded in mPFC and NAc from an
individual subject. A long-lasting change in overall firing rate is
apparent after the switch from heroin to cocaine. The asterisks denote
the points where statistically significant firing rate changes
occurred. A pattern of mean activity changes is also observed during a
session of passive drug administration, as demonstrated in Figure
10. Figure 10A shows
the overall neuronal activity changes during a heroin-cocaine
self-administration session. Asterisks on the right of individual strip
charts indicate the neurons with significant alterations in firing
rates when switched from heroin to cocaine self-administration. Figure
10B depicts the same neurons recorded in the
following session during which same dose of heroin (30 µg/kg per
infusion) and cocaine (1 mg/kg per infusion) were administered by
computer on a random interval schedule based on the average
interinfusion interval during the previous self-administration session.
Similar neuronal activity changes were observed as during the
self-administration session when the two drugs were switched.
View larger version (71K):
[in this window]
[in a new window]
|
Figure 9.
Baseline neuronal activity changes during a
heroin-cocaine self-administration session. This rate meter record
shows 19 neurons simultaneously recorded from the mPFC and from the NAc
(mPFC neurons are indicated by 1-16 in the
parentheses along the right y-axis; NAc
neurons are indicated by 17-32). Neurons with changes
in baseline neuronal activity are marked by an asterisk.
Note that many of the changes after the switch to the cocaine
reinforcer (vertical line) are inhibitory.
|
|
View larger version (57K):
[in this window]
[in a new window]
|
Figure 10.
Comparison of baseline neuronal activities
between self and passive administering heroin-cocaine.
A, Twenty neurons recorded simultaneously in the mPFC
and the NAc during heroin-cocaine self-administration session (see
Fig. 9 for neuron identification). Alteration of neuronal activity
induced by switching from heroin to cocaine, indicated by a
vertical line, was observed in several neurons (*).
B, The next day, a computer-controlled, passive
administration of heroin-cocaine was performed in the same animal with
the same dose of cocaine (1 mg/kg per infusion) and heroin (30 µg/kg
per infusion) used in self-administration sessions. The interinfusion
interval was randomly selected by computer using the range of mean ± SE calculated from self-administration session in A.
Note that the same pattern of neuronal activity changes occurred in
comparison to the neurons marked in A. , Bar press in
A and passive drug infusion in B.
|
|
Table 5 compares the overall
neuronal activity (firing rates) of mPFC and NAc neurons in different
conditions, with the results expressed as percent change from the
initial 200 sec baseline recordings taken just before the first trial
of the self-administration session. In general, more neurons showed
overall decreases in firing rates during cocaine self-administration
phase than in the heroin self-administration phase. In both the mPFC
and the NAc, 2 × 2 contingency table test revealed a significant
difference between the number of neurons responding by increasing or
decreasing their mean activity in response to cocaine and heroin in
heroin-first, cocaine-second sessions (p < 0.05). When comparing the overall neuronal activity during cocaine
self-administration with heroin self-administration (rather than with
the baseline control period) more neurons were found to decrease than
increase their firing rate in the cocaine phase. The
2 goodness of fit test revealed a significant
difference between the number of excitatory response neurons and
inhibitory response neurons in heroin-first, cocaine-second sessions
(p < 0.05 in mPFC; p < 0.01 in
NAc; Table 5). Figure 11 is a scatter
plot that illustrates the distribution of firing rate changes of
individual neurons for the heroin-first, cocaine-second sessions in the
mPFC and the NAc using the same data as in Table 5.
View this table:
[in this window]
[in a new window]
|
Table 5.
Comparing the average neuronal activity during cocaine and
heroin self-administration in the same session
|
|
View larger version (34K):
[in this window]
[in a new window]
|
Figure 11.
Scatter plots of the overall firing rates of mPFC
and NAc neurons during cocaine and heroin self-administration and the
control period. All the plots are constructed from heroin-first,
cocaine-second sessions. A, Comparison of the firing
rates recorded from the mPFC during cocaine and heroin
self-administration conditions with the control period of that session.
The ordinate depicts the firing rate (spikes per second)
during cocaine and heroin self-administration trials, and the
abscissa depicts the firing rate (spikes per second) for
the control condition. Inhibitory responses elicited by cocaine ()
and heroin () are under the line that represents the
control responses ( ), whereas excitatory responses induced by
cocaine ( ) and heroin ( ) are above the control
line. B, Same plot as A
for NAc. C, Comparison of the firing rates recorded from
the mPFC during cocaine and heroin self-administration periods. Firing
rates (spikes per second) during the cocaine self-administration period
are represented along the ordinate, and the firing rates
during the heroin self-administration trials are represented along the
abscissa. Inhibitory responses () are defined as a
decrease in firing rate under the cocaine self-administration condition
in comparison with the heroin self-administration condition. Excitatory
responses () are defined as an increase in firing rate under cocaine
self-administration in comparison with the heroin self-administration
condition. Note that more neurons exhibited inhibitory responses under
the cocaine self-administration condition. D, Same plot
as in C for the NAc.
|
|
Histological localization of recording sites
Recording sites were localized by a potassium ferrincyanide
staining method to reveal the iron deposited at the tips of selected microwires. Figure 12 depicts the
location of microwires in mPFC (Fig. 12A) and NAc
(Fig. 12B). Because it is difficult to distinguish more than two locations with respect to distinct iron deposit sizes,
priority was given to wires from which neurons with anticipatory responses were recorded. The remaining six wires from the same bundle
are located in close proximity to the marked wires.
View larger version (29K):
[in this window]
[in a new window]
|
Figure 12.
Histological location of recording sites in mPFC
(A) and NAc (B) revealed by
potassium ferricyanide staining of iron deposited by current applied to
recording microwires. Cg1, Cingulate cortex area 1;
Cg2, cingulate cortex area 2; Cg3,
cingulate cortex area 3; IL, infralimbic cortex;
mo, medial orbital cortex; vlo,
ventrolateral orbital cortex; Fr1, frontal cortex area
1; Fr2, frontal cortex area 2; AcbC,
nucleus accumbens core; AcbSh, nucleus accumbens
shell.
|
|
| |
DISCUSSION |
The present experiment was designed to compare the neuronal
responses during cocaine and heroin self-administration under three
different conditions: (1) sessions started with cocaine and followed by
heroin, (2) sessions started with heroin and followed by cocaine, and
(3) a comparison of the first drugs tested from the sessions in 1 and 2 that were 24 hr apart. The experiment was designed in this manner so
that data obtained from the same session control for nonstationarity in
neural activity; that is, results formed in conditions 1 and 2 are
independent of drug effects across different sessions. Furthermore,
condition 3, which compares the data from different sessions in which
cocaine or heroin was self-administered first, respectively, controls
for potential pharmacological interactions between cocaine and heroin
within the same session. The results indicated that most neurons
responded differently in all three conditions during operant tasks to
self-administer cocaine versus heroin, indicating that neither
day-to-day neuronal variability nor within-session drug interactions
can readily account for the distinctly different neuronal activity
patterns observed during self-administration of the two drugs.
In our previous studies, we postulated that two separate neuronal
mechanisms within the NAc and the mPFC underlie drug
self-administration (Chang et al., 1990, 1994; Chang and Woodward,
1996). First, the anticipatory responses that are evident before the
lever press for drug reinforcement are postulated to represent the
neuronal basis of a motivational process, leading to movements to
complete the task. This type of neuronal response was demonstrated to
be dopamine-independent in the studies of cocaine self-administration (Chang et al., 1994). Second, the time of occurrence of the post-drug infusion responses suggests that they might reflect the direct reinforcing effects of the infused drug. These post-drug infusion responses, in the case of cocaine self-administration, are partially mediated by dopamine transmission (Chang et al., 1994), because they
could be blocked by dopamine antagonists in some cases. In the present
study, predominately different neuronal responses were recorded from
the same neurons during cocaine and heroin self-administration, both
before and after the lever press (both anticipatory and post-drug
infusion responses) within both the mPFC and the NAc. Thus the neuronal
responses provided little evidence for a common action of released
endogenous dopamine. This conclusion was true for all three comparison
conditions described above; in all three conditions, most of the
neurons that did respond to cocaine and heroin self-administration did
so differently. These results suggest that cocaine and heroin not only
act on different receptors to exert reinforcing effects as determined by their different pharmacological properties but also may activate different neuronal circuits leading to drug self-administration.
The now routine but novel experimental observation of mean firing rates
of neurons in ensembles during long behavior sessions will yield new
insights into the information within neuron populations across states.
Background firing rates appear to specify unique patterns corresponding
to each new behavioral context. This introduces an apparent confound in
that the presence of a phasic response to a lever press during cocaine
or heroin self-administration either may be attributed to the different
context in which a similar behavior occurs or may be a simple
consequence of a background rate change. However, clear instances are
readily found in which changes are different during cocaine versus
heroin sessions when background rates are similar (Figs. 2-4). The
assertion clearly can be made that a subset of neurons responds
differently in the context of cocaine versus heroin
self-administration. We have elected to use within-session firing rate
criteria to control for background rate by searching for the presence
of effects (a 20% absolute rate change and a significant
p < 0.01) that are independent of rate. Our hypothesis
is that the patterns of background activity in the mPFC and the NAc
represent the expression of response contingencies specific to a
context. This concept will require extended future study.
Anticipatory responses
Previous work suggested that anticipatory responses observed
before lever presses for cocaine reinforcement are unlikely to be
associated with locomotion per se, because a detailed video analysis
revealed that locomotion not associated with the lever press for
cocaine failed to alter spike activity (Chang et al., 1994). In this
study, an important issue concerning the different anticipatory
responses during cocaine and heroin self-administration is whether the
anticipatory responses that are linked in time to a specific locomotor
action existed only in one drug self-administration condition. If major
differences in locomotor activity did occur just before the lever press
for cocaine or heroin, it is possible that the different anticipatory
neuronal responses simply represent activity time-locked to different
locomotor behaviors and not to different motivational processes.
Therefore, the video analysis of lever press behaviors for cocaine and
heroin self-administration is crucial to resolving this issue. We found
that in 9 of 10 rats, the behavioral context leading to the lever press
was similar for both cocaine and heroin self-administration. Thus,
different neuronal responses were present before the lever press during cocaine and heroin self-administration, even when associated with a
specific, identical behavioral episode (Figs. 7, 8). This finding supports the idea that distinct anticipatory responses observed in the
majority of neurons during cocaine and heroin self-administration reflect unique and specific neuronal circuits selectively involved in
cocaine- or heroin-seeking behaviors.
Although a minority (less than one-third in any given condition), there
are cases in which similar anticipatory responses are found for both
cocaine and heroin self-administration in the same neurons within the
mPFC and the NAc. Our interpretation is that the neurons exhibiting
similar anticipatory response may represent an embedded
mesocorticolimbic neuronal circuit that encodes a signal common to the
task to obtain reinforcement. Most anticipatory neurons, on the other
hand, may be specialized through learning to encode unique information
only associated with either cocaine or heroin self-administration.
Postdrug responses
Post-drug infusion responses are likely to be associated with the
reinforcing mechanism of drug self-administration. These responses span
much of the intertrial interval and are found to be partially blocked
by dopamine receptor antagonists in the case of cocaine
self-administration (Chang et al., 1994). If cocaine and heroin exerted
a common reinforcing effect, we would expect to see similar neuronal
responses in the same mPFC and NAc neurons after cocaine and heroin
self-administration. However, as observed for anticipatory responses, a
majority of neurons in mPFC and NAc responded differently during the
post-drug infusion period for the two drugs.
Mean firing rates
Similar differences were observed when the overall neuronal
activity across the entire cocaine and heroin self-administration segments of the sessions was compared. More neurons were found to be
inhibited (i.e., an overall decrease in firing rate) by cocaine than by
heroin self-administration. These changes in neuronal activity may be
attributable to the unique pharmacological effects of the drugs and/or
the conditioned responses associated with operant behavior during
self-administration. Importantly, the passive administration of
intravenous cocaine and heroin to well trained subjects elicits very
similar overall changes in mean spike activity, as observed during the
dual-drug self-administration sessions. This suggests that a
substantial part of neuronal activity changes during cocaine and heroin
self-administration may be attributed to the pharmacological effects of
the respective drugs on receptor targets, which then propagate widely
to influence steady-state activity throughout the mesocorticolimbic
system.
Cocaine and heroin reinforcement and the
mesocorticolimbic system
Cell body lesions of the NAc after kainic acid injection attenuate
both cocaine and heroin self-administration (Zito et al., 1985).
Furthermore, microinjection of dopamine and opiate receptor antagonists
into the NAc interrupts cocaine and heroin self-administration, respectively (Vaccarino et al., 1985; Corrigall and Vaccarino 1988;
Caine et al., 1995). Thus the notion of a common neural circuit for
obtaining reinforcement at the level of the NAc is well supported.
The specific role of VTA dopaminergic projections to the NAc in opiate
self-administration has been debated. It has been reported that
destruction of dopamine terminals in the NAc and systemic application
of dopamine antagonist more strongly disrupted cocaine than heroin
self-administration in the rat (Ettenberg et al., 1982; Pettit et
al., 1984). However, extracellular dopamine levels are reported to
fluctuate in relation to both cocaine-reinforced (Petit and Justice,
1989, 1991) and heroin-reinforced (Wise et al., 1995a) (but see Hemby
et al., 1995) operant responding. Moreover, a number of neurochemical
studies indicate that opiates stimulate dopamine release in mPFC and
NAc, a net effect similar to that produced by cocaine but by different
mechanisms (Di Chiara and Imperato, 1988; Spanagel et al., 1990, 1992;
Leone et al., 1991; Yokoo et al., 1994; Wise et al., 1995b). Heroin has
been proposed to increase dopamine release via opioid receptor-mediated
suppression of GABA release from GABA interneurons that tonically
suppress dopamine neuron firing (Johnson and North, 1992), whereas
cocaine blocks reuptake from DA terminals. On the other hand, the
effect of cocaine and heroin on the firing rate of VTA dopamine neurons appears to be opposite in in vitro and anesthetized
preparations (Gysling and Wang, 1983; Matthews and German, 1984;
Einhorn et al., 1988; Brodie and Dunwiddie, 1990; Lacey et al., 1990)
as well as during self-administration and pharmacological passive administration (preliminary observation from this laboratory). Other
studies report that naloxone alters the self-administration of low (0.1 mg/kg per infusion) doses of cocaine (Carroll et al., 1986; Corrigall
and Coen, 1991; Ramsey and van Ree, 1991). In this study, we used 1 mg/kg per infusion for cocaine self-administration, which is 10 times
higher than the dose influenced by naloxone. The doses of cocaine and
heroin in this study were chosen to balance the maximum reinforcing
effect with reasonable response rates. In addition, similar doses are
widely used by other laboratories in the study of cocaine and heroin
self-administration (Corrigall and Vaccarino 1988).
Functional concepts
Based on current and previous results, we hold to the concept that
representation of memories and processing of sensory cues and other
signals may be very different within the mesocorticolimbic system
during the performance of operant tasks resulting in cocaine and heroin
self-administration. As a result, two different, yet overlapping,
neuronal networks may be used during the acquisition of cocaine and
heroin self-administration behaviors. Neuronal activity in these
coextensive networks may correspond to two different reinforcement
contexts. The different neuronal responses observed in the
mesocorticolimbic system during cocaine and heroin self-administration may represent a switch from one context of drug reinforcement to
another, with the same neuron behaving differently depending on which
neuronal circuit has become switched on. These may be similar to the
different activity patterns reported in primate prefrontal cortex
specific to the anticipation of different rewards (Watanabe, 1996).
Because both cocaine and heroin actions may evoke dopamine release,
although by different mechanisms, the question arises of how different
functional neuronal circuits of the NAc and mPFC may emerge. Within a
session the self-infusion of the second reinforced drug may evoke
interoceptive stimuli that trigger the activation of different
appropriate circuits for initiating behavior. Midbrain dopamine systems
may play a role in facilitating the learning required to make these
rapid adjustments, because blocking DA receptor causes
self-administration to cease. Other studies (Schultz et al., 1997)
suggest that dopamine release yields reinforcement by acting as a
learning or teaching signal that alters associated responses to cues
that are predictive of future reward. In this way stable and different
activity patterns may by created by different reinforcers.
In summary, predominantly different neuronal responses were detected
when neural activity during cocaine and heroin self-administration was
compared. Differences were observed in both anticipatory responses and
postdrug responses. In light of the evidence that a majority of neurons
exhibited different responses to cocaine and heroin self-administration, the results support the notion that specific, separate, but anatomically overlapping, central mechanisms are in part
responsible for cocaine and heroin self-administration.
| |
FOOTNOTES |
Received Aug. 22, 1997; revised Feb. 5, 1998; accepted Feb. 6, 1998.
This study was supported by National Institute on Drug Abuse Grant DA
2338 to D.J.W. We thank Dr. David Reboussin for help with statistics
and Lu Chen for technical assistance.
Correspondence should be addressed to Dr. Jing-Yu Chang, Department of
Physiology and Pharmacology, Wake Forest University, School of
Medicine, Winston-Salem, NC 27157.
| |
REFERENCES |
-
Berendse HW,
Galis-de Graaf Y,
Groenewegen HJ
(1992)
Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat.
J Comp Neurol
316:314-347[Web of Science][Medline].
-
Brodie MS,
Dunwiddie TV
(1990)
Cocaine effects in the ventral tegmental area: evidence for an indirect dopaminergic mechanism of action.
Naunyn Schmiedebergs Arch Pharmacol
342:660-665[Web of Science][Medline].
-
Caine SB,
Heinriches SC,
Coffin VL,
Koob GF
(1995)
Effects of the dopamine D-1 antagonist SCH23390 microinjected into the accumbens, amygdala or striatum on cocaine self-administration in the rat.
Brain Res
692:47-56[Web of Science][Medline].
-
Carroll MA,
Lac ST,
Walker MJ,
Kragh R,
Newman T
(1986)
Effects of naltrexone on intravenous cocaine self-administration in rats during food satiation and deprivation.
J Pharmacol Exp Ther
238:1-7[Abstract/Free Full Text].
-
Chang J-Y,
Woodward DJ
(1996)
Single neuronal activity in mesolimbic system during cocaine and heroin self-administrations in freely moving rats.
Soc Neurosci Abstr
22:927.
-
Chang J-Y,
Sawyer SF,
Lee R-S,
Maddux BN,
Woodward DJ
(1990)
Activity of neurons in nucleus accumbens during cocaine self-administration in freely moving rats.
Soc Neurosci Abstr
16:252.
-
Chang J-Y,
Sawyer SF,
Lee R-S,
Woodward DJ
(1994)
Electrophysiological and pharmacological evidence for the role of the nucleus accumbens in cocaine self-administration in freely moving rats.
J Neurosci
14:1224-1244[Abstract].
-
Chang J-Y,
Sawyer SF,
Paris JM,
Kirillov AB,
Woodward DJ
(1997a)
Single neuronal responses in medial prefrontal cortex during cocaine self-administration in freely moving rats.
Synapse
26:22-35[Web of Science][Medline].
-
Chang J-Y,
Zhang LL,
Janak P,
Woodward DJ
(1997b)
Neuronal responses in media frontal cortex and nucleus accumbens during heroin self-administration in freely moving rats.
Brain Res
754:12-20[Web of Science][Medline].
-
Corrigall WA,
Coen KM
(1991)
Opiate antagonists reduce cocaine but not nicotine self administration.
Psychopharmacology
104:167-170[Medline].
-
Corrigall WA,
Vaccarino FJ
(1988)
Antagonist treatment in nucleus accumbens or periaqueductal gray affects heroin self-administration.
Pharmacol Biochem Behav
30:443-450[Web of Science][Medline].
-
Deniau JM,
Menetrey A,
Thierry AM
(1994)
Indirect nucleus accumbens input to the prefrontal cortex via the substantia nigra pars reticulata: a combined anatomical and electrophysiological study in the rat.
Neuroscience
61:533-545[Web of Science][Medline].
-
Di Chiara G,
Imperato A
(1988)
Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.
Proc Natl Acad Sci USA
85:5274-5278[Abstract/Free Full Text].
-
Einhorn LC,
Johansen PA,
White FJ
(1988)
Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area.
J Neurosci
8:100-112[Abstract].
-
Ettenberg A,
Pettit HO,
Bloom FE,
Koob GF
(1982)
Heroin and cocaine intravenous self-administration in rats: mediated by separate neural systems.
Psychopharmacology
78:204-209[Medline].
-
Gerrits MA,
Van Ree JM
(1996)
Effect of nucleus accumbens dopamine on motivational aspects involved in initiation of cocaine and heroin self-administration in rats.
Brain Res
713:114-124[Web of Science][Medline].
-
Glick S,
Cox R
(1978)
Changes in morphine self-administration after Tel-Diencephalic lesions in rats.
Psychopharmacology
57:283-288[Medline].
-
Goeders NE,
Smith JE
(1983)
Cortical dopaminergic involvement in cocaine reinforcement.
Science
221:773-775[Abstract/Free Full Text].
-
Goeders NE,
Smith JE
(1986)
Reinforcing properties of cocaine in the medial prefrontal cortex: primary action on presynaptic dopaminergic terminals.
Pharmacol Biochem Behav
25:191-199[Web of Science][Medline].
-
Groenewegen HJ
(1988)
Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography.
Neuroscience
24:379-431[Web of Science][Medline].
-
Groenewegen HJ,
Berendse HW,
Wolters JG,
Lohman HM
(1990)
The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization.
Prog Brain Res
85:95-118[Medline].
-
Gysling K,
Wang RY
(1983)
Morphine-induced activation of A10 dopamine neurons in the rat.
Brain Res
277:119-127[Web of Science][Medline].
-
Hemby SE,
Martin TJ,
Co C,
Dworkin SI,
Smith JE
(1995)
The effects of intravenous heroin administration on extracellular nucleus accumbens dopamine concentrations as determined by in vivo microdialysis.
J Pharmacol Exp Ther
273:591-598[Abstract/Free Full Text].
-
Johnson SW,
North RA
(1992)
Opioids excite dopamine neurons by hyperpolarization of local interneurons.
J Neurosci
12:483-488[Abstract].
-
Kiyatkin EA,
Stein EA
(1996)
Conditioned changes in nucleus accumbens dopamine signal established by intravenous cocaine in rats.
Neurosci Lett
211:73-76[Web of Science][Medline].
-
Koob G
(1992)
Drugs of abuse: anatomy, pharmacology and function of reward pathways.
Trends Pharmacol Sci
13:177-184[Medline].
-
Lacey MG,
Mercuri NB,
North RA
(1990)
Actions of cocaine on rat dopaminergic neurons in vitro.
Br J Pharmacol
99:731-735[Web of Science][Medline].
-
Leone P,
Pocock D,
Wise RA
(1991)
Morphine-dopamine interaction: ventral tegmental morphine increases nucleus accumbens dopamine release.
Pharmacol Biochem Behav
39:469-472[Web of Science][Medline].
-
Mansour A,
Khachaturian H,
Lewis ME,
Akil H,
Watson SJ
(1987)
Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain.
J Neurosci
7:2445-2464[Abstract].
-
Mansour A,
Fox CA,
Burke S,
Meng F,
Thompson RC,
Akil H,
Watson SJ
(1994)
Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study.
J Comp Neurol
350:412-438[Web of Science][Medline].
-
Martin-Inverson MT,
Szostak C,
Fibiger HC
(1986)
6-hydroxydopamine lesions of the medial frontal cortex fail to influence intravenous self-administration of cocaine.
Psychopharmacology
88:310-314[Medline].
-
Matthews R,
German D
(1984)
Electrophysiological evidence for excitation of rat ventral tegmental area dopamine neurons by morphine.
Neuroscience
11:617-625[Web of Science][Medline].
-
Naito A,
Kita H
(1994)
The cortico-nigral projection in the rat: an anterograde tracing study with biotinylated dextran amine.
Brain Res
637:317-322[Web of Science][Medline].
-
Paxinos G,
Watson C
(1986)
In: The rat brain in stereotaxic coordinates. San Diego: Academic.
-
Pettit HO,
Justice Jr JB
(1989)
Dopamine in the nucleus accumbens during cocaine self-administration as studied by in vivo microdialysis.
Pharmacol Biochem Behav
34:899-904[Web of Science][Medline].
-
Pettit HO,
Justice Jr JB
(1991)
Effect of dose on cocaine self-administration behavior and dopamine levels in the nucleus accumbens.
Brain Res
539:94-102[Web of Science][Medline].
-
Pettit HO,
Ettenberg A,
Bloom FE,
Koob GF
(1984)
Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats.
Psychopharmacology
84:167-173[Medline].
-
Ramsey NF,
van Ree JM
(1991)
Intracerebroventricular naltrexone treatment attenuates acquisition of intravenous cocaine self-administration in rats.
Pharmacol Biochem Behav
40:807-810[Web of Science][Medline].
-
Schultz W,
Dayan P,
Montague PR
(1997)
A neural substrate of prediction and reward.
Science
275:1593-1599[Abstract/Free Full Text].
-
Spanagel R,
Herz A,
Shippenberg TS
(1990)
The effects of opioid peptides on dopamine release in the nucleus accumbens: an in vivo microdialysis study.
J Neurochem
55:1734-1740[Web of Science][Medline].
-
Spanagel R,
Herz A,
Shippenberg TS
(1992)
Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway.
Proc Natl Acad Sci USA
89:2046-2050[Abstract/Free Full Text].
-
Tempel A,
Zukin RS
(1987)
Neuroanatomical patterns of the µ,
 and  opioid receptors of rat brain as determined by quantitative in vitro autoradiography.
Neurobiol
84:4038-4312. -
Vaccarino FJ,
Bloom FE,
Koob GF
(1985)
Blockade of nucleus accumbens opiate receptors attenuates intravenous heroin reward in the rat.
Psychopharmacology
86:37-42[Medline].
-
Watanabe M
(1996)
Reward expectancy in primate prefrontal neurons.
Nature
382:629-632[Medline].
-
Wise RA
(1996)
Addictive drugs and brain stimulation reward.
Ann Rev Neurosci
19:319-340[Web of Science][Medline].
-
Wise RA,
Bozarth MA
(1985)
Brain mechanisms of drug reward and euphoria.
Psychiatr Med
3:445-460[Medline].
-
Wise RA,
Rompre PP
(1989)
Brain dopamine and reward.
Ann Rev Psychol
40:191-225[Web of Science][Medline].
-
Wise RA,
Leone P,
Rivest R,
Leeb K
(1995a)
Elevations of nucleus accumbens dopamine and DOPAC lever during intravenous heroin self-administration.
Synapse
21:140-148[Web of Science][Medline].
-
Wise RA,
Newton P,
Leeb K,
Burnette B,
Pocock D,
Justice JB
(1995b)
Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats.
Psychopharmacology
120:10-20[Medline].
-
Yokoo H,
Yamada S,
Yoshida M,
Takaka T,
Mizoguchi K,
Emoto H,
Koga C,
Ishii H,
Ishidawa M,
Kurasaki N,
Matsui M,
Tanaka M
(1994)
Effect of opioid peptides on dopamine release from nucleus accumbens after repeated treatment with methamphetamine.
Eur J Pharmacol
256:335-338[Web of Science][Medline].
-
Zahm DS,
Zaborszky L,
Alheid GH,
Heimer L
(1987)
The ventral striatopallidothalamic projection: II. The ventral pallidothalamic link.
J Comp Neurol
255:592-605[Web of Science][Medline].
-
Zito KA,
Vickers G,
Roberts DCS
(1985)
Disruption of cocaine and heroin self-administration following kainic acid lesions of the nucleus accumbens.
Pharmacol Biochem Behav
23:1029-1036[Web of Science][Medline].
Copyright © 1998 Society for Neuroscience 0270-6474/98/1883098-18$05.00/0
This article has been cited by other articles:
|
|
|
|
 
E. H. Baeg, M. E. Jackson, H. P. Jedema, and C. W. Bradberry
Orbitofrontal and Anterior Cingulate Cortex Neurons Selectively Process Cocaine-Associated Environmental Cues in the Rhesus Monkey
J. Neurosci.,
September 16, 2009;
29(37):
11619 - 11627.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Caille, L. Alvarez-Jaimes, I. Polis, D. G. Stouffer, and L. H. Parsons
Specific Alterations of Extracellular Endocannabinoid Levels in the Nucleus Accumbens by Ethanol, Heroin, and Cocaine Self-Administration
J. Neurosci.,
April 4, 2007;
27(14):
3695 - 3702.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J. Kargo, B. Szatmary, and D. A. Nitz
Adaptation of Prefrontal Cortical Firing Patterns and Their Fidelity to Changes in Action-Reward Contingencies
J. Neurosci.,
March 28, 2007;
27(13):
3548 - 3559.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. German and H. L. Fields
Rat Nucleus Accumbens Neurons Persistently Encode Locations Associated With Morphine Reward
J Neurophysiol,
March 1, 2007;
97(3):
2094 - 2106.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. R. Euston and B. L. McNaughton
Apparent Encoding of Sequential Context in Rat Medial Prefrontal Cortex Is Accounted for by Behavioral Variability
J. Neurosci.,
December 20, 2006;
26(51):
13143 - 13155.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. I. G. Wilson and E. M. Bowman
Rat Nucleus Accumbens Neurons Predominantly Respond to the Outcome-Related Properties of Conditioned Stimuli Rather Than Their Behavioral-Switching Properties
J Neurophysiol,
July 1, 2005;
94(1):
49 - 61.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Nicola, I. A. Yun, K. T. Wakabayashi, and H. L. Fields
Cue-Evoked Firing of Nucleus Accumbens Neurons Encodes Motivational Significance During a Discriminative Stimulus Task
J Neurophysiol,
April 1, 2004;
91(4):
1840 - 1865.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Nicola, I. A. Yun, K. T. Wakabayashi, and H. L. Fields
Firing of Nucleus Accumbens Neurons During the Consummatory Phase of a Discriminative Stimulus Task Depends on Previous Reward Predictive Cues
J Neurophysiol,
April 1, 2004;
91(4):
1866 - 1882.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Carelli and J. Wondolowski
Selective Encoding of Cocaine versus Natural Rewards by Nucleus Accumbens Neurons Is Not Related to Chronic Drug Exposure
J. Neurosci.,
December 3, 2003;
23(35):
11214 - 11223.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Peoples and D. Cavanaugh
Differential Changes in Signal and Background Firing of Accumbal Neurons During Cocaine Self-Administration
J Neurophysiol,
August 1, 2003;
90(2):
993 - 1010.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Carelli
The nucleus accumbens and reward: neurophysiological investigations in behaving animals.
Behav Cogn Neurosci Rev,
December 1, 2002;
1(4):
281 - 296.
[Abstract]
[PDF]
|
|
|
|
|
|
|
T. J. De Vries and T. S. Shippenberg
Neural Systems Underlying Opiate Addiction
J. Neurosci.,
May 1, 2002;
22(9):
3321 - 3325.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. Williams, M. J. Christie, and O. Manzoni
Cellular and Synaptic Adaptations Mediating Opioid Dependence
Physiol Rev,
January 1, 2001;
81(1):
299 - 343.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Carelli, S. G. Ijames, and A. J. Crumling
Evidence That Separate Neural Circuits in the Nucleus Accumbens Encode Cocaine Versus "Natural" (Water and Food) Reward
J. Neurosci.,
June 1, 2000;
20(11):
4255 - 4266.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Peoples, F. Gee, R. Bibi, and M. O. West
Phasic Firing Time Locked to Cocaine Self-Infusion and Locomotion: Dissociable Firing Patterns of Single Nucleus Accumbens Neurons in the Rat
J. Neurosci.,
September 15, 1998;
18(18):
7588 - 7598.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction
