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The Journal of Neuroscience, May 15, 2000, 20(10):3874-3883
Impact of Self-Administered Cocaine and Cocaine Cues on
Extracellular Dopamine in Mesolimbic and Sensorimotor Striatum in
Rhesus Monkeys
Charles W.
Bradberry1, 2,
Rita L.
Barrett-Larimore1,
Peter
Jatlow1, 2, and
Susan
R.
Rubino1
Departments of 1 Psychiatry and
2 Laboratory Medicine, Yale University School of Medicine
and the West Haven Veteran's Administration Hospital, West Haven,
Connecticut 06516
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ABSTRACT |
Studies were conducted to determine the impact of self-administered
cocaine on extracellular striatal dopamine in four rhesus monkeys. The
extent to which external cue conditioning contributed to the effects of
cocaine and whether there is activation of striatal dopaminergic
neurotransmission during drug-seeking behavior was also examined.
Microdialysis measurements were made at 2 min intervals in sensorimotor
(dorsolateral) and mesolimbic (central and ventromedial) striatum. A
fixed-ratio schedule of reinforcement was used, with cocaine
availability signaled by a visual cue. Studies examined the effects of
cocaine or cocaine cues against a drug-free baseline. Large (fivefold
to eightfold) increases in extracellular dopamine after a
self-administered infusion of 0.5 mg/kg cocaine were quite rapid and
matched the time course of reported subjective effects in human
laboratory studies. To determine if conditioning to external cues
contributed to the cocaine-induced increases, saline was substituted
for cocaine in the infusion, leaving all other visual and auditory
stimuli unchanged. No increase in extracellular dopamine in either
sensorimotor or mesolimbic striatal subdivisions was observed.
Extracellular dopamine during extended periods of drug-seeking behavior
triggered by a visual cue was determined in both central and
ventromedial striatum. This procedure also did not result in any
measurable changes in extracellular dopamine. These studies demonstrate
rapid and pronounced pharmacological actions of self-administered cocaine. No apparent conditioned component of those actions was associated with external environmental cues, suggesting that cues that
trigger drug-seeking behavior in nonhuman primates do not cause
conditioned increases in mesolimbic striatal dopamine.
Key words:
cocaine self-administration; rhesus monkey; microdialysis; ventral striatum; cue conditioning; drug-seeking
behavior; plasma cocaine
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INTRODUCTION |
Microdialysis studies in rodents
have examined neurochemical effects of intravenous cocaine in
investigator (Bradberry and Roth, 1989 )-, and self-administered (Pettit
and Justice, 1989; Meil et al., 1995; Wise et al., 1995) paradigms.
However, few neurochemical studies of the actions of self-administered
cocaine in primates have been undertaken and outside of our previous
microdialysis studies in anesthetized vervets (Iyer et al., 1995), only
postmortem indices have been examined, an approach unsuited for
studying dynamic neurochemical changes underlying the rapid and
transient subjective effects of cocaine.
Increased dopamine (DA) neurotransmission appears to be a primary
mediator of cocaine reward (Roberts et al., 1977; Ritz et al., 1987;
Wise and Bozarth, 1987; Volkow et al., 1997). In human laboratory
studies, subjective reports of cocaine euphoria and brain-imaging
measures of uptake site binding (Volkow et al., 1997) or altered
metabolism (Breiter et al., 1997) can be correlated with the time
course of plasma cocaine levels. However, a similar correlation of
plasma levels with a direct measure of the time course of
neurotransmitter alterations is not possible. Questions also remain as
to whether there are DAergic responses to specific environmental cues
associated with cocaine availability. These questions will need to be
addressed in primates because they display differences from rodents in
the organization and anatomical distribution of DAergic projections
(Berger et al., 1991) and in the presence of colocalized neuropeptides
(Gaspar et al., 1989, 1990; Febvret et al., 1991; Oeth and Lewis,
1992). Also, the effects of cocaine on metabolic activity in the rat
and nonhuman primate are strikingly different (Lyons et al., 1996),
with results in nonhuman primates being similar to those seen in humans
in that there are decreases in metabolism in both cortical and
subcortical regions (London et al., 1990; Pearlson et al., 1993). Thus,
it is necessary that neurochemical bases for interpreting such imaging
studies include primate data.
This report demonstrates the impact of self-administered cocaine and
cocaine-related cues on extracellular DA in two subdivisions of the
striatum in rhesus monkeys. In comparison to the rodent, in which the
nucleus accumbens is differentiated from the surrounding striatum by
cortical and subcortical limbic afferents, the pattern of limbic input
to the primate striatum includes areas of the ventral caudate and
medial ventral putamen outside what has historically been defined as
the nucleus accumbens (Russchen et al., 1985; Selemon and
Goldman-Rakic, 1985; Lynd-Balta and Haber, 1994b; Haber and McFarland,
1999). Consistent with the anatomy, electrophysiological studies in
monkeys have shown equivalent proportions of neurons with increased
activity linked to reception of reward throughout the ventral striatum
and nucleus accumbens (Schultz et al., 1992). Thus, instead of nucleus
accumbens, we will use a functionally more relevant descriptor of
mesolimbic striatum when making a distinction between it and
sensorimotor striatum.
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MATERIALS AND METHODS |
Behavior. Four male rhesus monkeys were used for the
present studies. Animals were restrained in a chair (Primate Products, Redwood City, CA) by a collar, and placed in a behavioral chamber fitted with an operant panel constructed from 1/4 inch aluminum to which the chair was attached. Med-Associates (Georgia, VT) software
and hardware were used for all inputs and outputs and data collection.
Animals were initially trained to self-administer food pellets under a
fixed ratio (FR) 10 (animals M103 and M32) or FR30 (animals M47
and M49) lever response schedule of reinforcement. Subsequent to food
training, a catheter was placed in the internal jugular that led to a
vascular access port (Access Technologies, Skokie, IL) placed
midscapula (Wojnicki et al., 1994), and animals were shifted to
cocaine. The vascular access port allows percutaneous nonstressful
access to vasculature without the need for a protective jacket, and
with reduced risk of infection because nothing is external to the skin.
The device can be used daily for periods of time well over a year
(Wojnicki et al., 1994; Glowa et al., 1995). In our laboratory, with
less frequent (biweekly) use, ports have been usable for up to 2 years.
Maintenance of the ports consists of a twice weekly flushing and
locking with a solution that has a final concentration of 25% dextrose
and 500 U/ml heparin. Animals quickly learned to lever press for
cocaine under the same FR contingency used for obtaining food pellets.
Figure 1 demonstrates typical cumulative
response records obtained during the microdialysis studies. Studies
began at 10:00 A.M., although there was some variability between
when an animal was first chaired and when the behavioral chamber was
closed depending on how much difficulty was associated with attaching
lines, etc. Animals were chaired in the behavioral chamber with a house
light on for a 60-90 min baseline period before presentation of the visual cue. During that time, no cue was presented, and lever pressing
was recorded but had no consequence. The visual cue indicating cocaine
availability was presented at the same time of day to each animal
(11:30 A.M. for animals 103 and 32; 11:00 A.M. for animals 49 and 47).
The visual cue was a horizontally placed pair of red and green lights,
and indicated that the FR response would result in an infusion of a
bolus of 0.5 mg/kg cocaine HCl in 0.5 ml. The visual cue was turned off
as the infusion began at a flow rate of 16.3 ml/min, continuing for 18 sec. The 0.5 ml cocaine solution was loaded into the line between the
syringe and the vascular access port, and an excess volume (5 ml) was
used to completely flush the cocaine dose into the animal, preventing the need to try and fill just the volume between the port and the
catheter tip. This avoided any "priming" that would result from
slightly overfilling that volume. Visual inspection of a dye solution
in a mock set up indicated that the loaded solution was infused into
the animal beginning 5 sec into the infusion and was essentially
completely infused by 10 sec into the infusion. After the infusion a
100 min timeout began, during which no cues were presented, and lever
pressing was recorded but had no consequences. After the timeout, the
cue was presented again, with the second cue presentation and infusion
the same as the first. In the present study, only results from the
initial cocaine infusion are presented.
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Figure 1.
Cocaine self-administration. Representative
cumulative response diagrams for each animal showing the pattern of
lever-pressing behavior during the microdialysis/self-administration
session. The visual cue indicating that cocaine was available was
illuminated at the arrow. Animals 103 and 32 were under
an FR10 schedule, whereas animals 49 and 47 were under an FR30
schedule. The short diagonal line indicates cocaine
delivery.
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Each animal was permitted at most one session per week during which two
infusions would be available, separated by the 100 min timeout
interval. Animals underwent studies for at least 3 months, during which
both infusions were 0.5 mg/kg cocaine, after which occasional saline
substitutions or sessions with no cue (or cocaine) presentation were
conducted. This was the extent of cocaine exposure in each animal
outside of the initial training with more traditional
self-administration parameters (lower unit doses and more frequent
infusions permitted). The amount of initial training each animal
received was as follows: animal 103, 3 months; animal 32, 1 month;
animals 49 and 47, 1 week each.
As can be seen in Table 1, animals were
under stimulus control, as indicated by the significantly higher
response rates after cue presentation. Precue rates were assessed over
the entire precue period for all monkeys except 32, which because of a
higher responding before cue sometimes exceeded the data storage
capacity of the behavioral data recording program as written.
Contingent response rate recording was unaffected. For that animal,
non-cue responding reflects at least 30 min of continuous behavior in
the chamber without cue presentation. Monkeys 103 and 32 always
performed under an FR10, whereas moneys 49 and 47 always performed
under an FR30.
In the "no cue presentation" studies done to monitor basal DA in
the absence of any cue or drug presentation, behavioral responses over
the entire session were essentially the same as during the usual
"pre-cue" period, a reflection of the extensive conditioning of the
animals to the extended periods in the box without any stimuli. Studies
in which saline was substituted for cocaine were conducted in exactly
the same manner as those when cocaine was administered, with the same
visual cue presentation and FR response triggering cue offset and
operation of the infusion pump with its associated sound. In the saline
substitution studies, the substitution came at the time the first dose
of cocaine would have been administered, and there was not a difference
in behavior from that with cocaine. This is as would be expected
because the saline infusions were not part of an extinction procedure,
but rather were occasional "surprise" substitutions designed to
examine conditioned neurochemical responses to cocaine-associated
behaviors and stimuli. There was very low responding after saline
infusion, thus, the duration of drug-seeking behavior in this paradigm
was only as long as it took to reach contingency (<20 sec). To perform neurochemical measurements during more prolonged drug-seeking behavior,
a similar visual cue to the one indicating cocaine availability was
used. This was a vertically placed set of red and green lights equidistantly centered on the same point in the panel as the horizontal set of lights signaling cocaine. They were illuminated at the time the
visual cue was normally presented, and left on for 10 min, with
responding having no consequence. Responses generalized to this cue as
indicated by rapid and prolonged lever pressing.
Microdialysis guide cannulae and probes. Guide cannulae for
microdialysis studies were constructed from Delrin plastic, in a
modification of a published design (Kolachana et al., 1994). Figure
2 is a scale drawing of the separate
components of the guide assembly. The guides have an open-well
baseplate machined from 1/2 inch Delrin with three threaded
holes that is permanently fixed to the skull. To the base, either a
solid cap ( inch Plexiglas) or grid array block (4 mm Delrin)
for directing microdialysis probes is attached. The grid has 16 × 6 holes at 1 mm spacing. Two cannulae were placed side by side (Fig. 2,
bottom), centered along the midline, and anchored using
plastic sheep's head bolts and standard dental acrylic. When placing
the baseplates, the bottom surfaces were ground in the surgical suite
using a sterile hand grinder to adjust for skull curvature to reduce
any cavities that would be difficult to clean and could attract
infection. A titanium head bolt (Christ Instrument Company, Damascus,
MD) for controlling head movements was situated posterior to the guide cannula assembly. Care of the assembly in place consists of a weekly
thorough flushing with disinfectant (1% dilute household bleach). A
sterile solid cap is attached after flushing.
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Figure 2.
Diagram of guide cannula assembly used.
Top, Open-well baseplate and grid array.
Middle, Plastic spacer (0.15 mm) placed under grid array
to serve as barrier in nonpenetrated holes. Bottom,
Bilateral arrangement of complete assembly.
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Microdialysis probes were constructed similar to the design of Robinson
and Whishaw (1988). The main body of the probe was extra thin wall 25 gauge tubing (Small Parts, Miami Lakes, FL), and the fused silica
tubing at the tip was bevelled and buried in the epoxy plug to maintain
a straight tip, despite the membrane stretching after wetting, the idea
being to minimize damage and/or deflection while penetrating to deep
brain structures. Probes were held in place by snug fit and were
prevented from rotating by a tab that fits into a hole in the array
adjacent to the hole in which the probe is placed. Tygon tubing [0.51
mm inner diameter (ID) × 1.5 mm outer diameter (OD)], press-fit
onto sections of 23 gauge tubing made all inlet and outlet connections.
The solution used to perfuse the probe was (in mM: KCl 2.4, NaCl 137, CaCl2 1.2, MgCl2
1.2, and NaH2PO4 0.9, pH
7.4). DA in the perfusates was determined using liquid chromatography
with electrochemical detection. A Bioanalytical Systems (West
Lafayette, IN) LC4 or Antec-Leyden (Zoeterwoude, The Netherlands) Intro
potentiostat and detector cell assembly were used in conjunction with
laboratory-packed 10 cm × 2.1 mm ID columns. Packing material
used was 3 µm ODS2 (Phase Separations), a C18 material. An ESA
(Chelmsford, MA) model 465 autosampler or LC Packings (Amsterdam, The
Netherlands) FAMOS autosampler was used for injection of samples.
Samples were stabilized by addition of acetic acid to prevent DA
degradation while in the autosampler, which was maintained at
4°C.
MRI-directed placement of dialysis probes. For accurate
estimation of probe placement, postsurgical MR imaging was conducted. The animals, with heads held in an MR-compatible stereotax, were placed
in the magnet with careful adjustment with a level and the positioning
light beams to ensure that the cannula assembly was orthogonal with the
axes of the magnet. The imager used was a 1.5 Tesla, Sigma III
(General Electric). Imaging was performed using a standard circular (3 or 5 inch diameter) receive-only surface coil. Animals were kept
anesthetized (isoflurane) for the duration of the procedure. After an
initial sagittal localizing series, axial and coronal sets of
contiguous images (slice thickness, 1 mm) were acquired using a spoiled
gradient recall at steady-state imaging sequence with 25 msec
repetition time, 6 msec echo time, 30° flip angle, two excitations,
and 192 phase encode steps. Either an 11 or 14 cm field of view was
used, with images displayed as a 256 × 256 pixel matrix. Because
the rows of holes in the array blocks were placed at 1 mm intervals,
acquiring scans at 1 mm intervals allowed a coronal image corresponding
to each row. Dummy probes constructed from (0.43 mm OD × 0.32 mm
ID) fused silica tubes (Polymicro Technologies, Phoenix, AZ) containing
a high-contrast agent (1% gadolinium diluted in saline) were placed
into selected locations in the array block to assign the location of
the holes (Fig. 3).
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Figure 3.
Postsurgical imaging. Magnetic resonance image in
a coronal plane containing the striatum obtained after surgical
placement of the guide cannula. High-contrast dummy probes (2 mm
separation) used to mark reference holes in the grid can be seen. Field
of view is 14 cm.
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Probes were placed the day before the experiment under either light
ketamine anesthesia (15 mg/kg) for animals M103 and M32, or without any
ketamine by immobilizing animals M47 and M49 with a head bolt. A
sterile array block was put in place, with a sterile thin (0.15 mm)
plastic sheet placed between the array and base blocks. For probe
insertion, this sheet is punctured with a 25 gauge needle through the
hole into which a probe will be placed leaving a protective barrier in
place under all the other holes in the array block to keep foreign
material out. The dura is also punctured using the same needle (after
topical application of 2% lidocaine to head-bolted animals). After
slowly lowering the probe, a protective molded plastic cap is put in
place. On the study day, animals were chaired, the cap was removed, and
inlet and outlet lines were attached to the probe. Probe placements were in sites in which a probe had not previously been placed. There
was usually just one probe in place, although occasionally two were
placed. No apparent difference was ever apparent between studies in
which two probes were in place as opposed to one. Placement order
varied between medial and lateral positions as well as between dorsal
ventral placements.
Data analysis. Changes in extracellular DA within a session
were determined by repeated measures ANOVA of extracellular
levels expressed as a percentage of a precue baseline defined as the mean of the three points preceding the cue (Robertson et al., 1991;
Klitenick et al., 1992). Each probe insertion was treated as an
individual statistical event, as individual neuronal recordings are
treated in electrophysiological studies (Schultz et al., 1993). Within
each animal, responses were collapsed across all striatal regions to
determine the mean responses presented in the figures showing results
from individual animals. For evaluation of striatal regional
differences, responses were collapsed across animals. Multifactorial
ANOVA was used to evaluate differences in basal levels (absolute
values) and responsiveness to cocaine (defined as the mean percentage
of increase over the first 10 min after cocaine).
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RESULTS |
Behavioral responding during microdialysis studies
Table 1 presents the lever press response rates during the
microdialysis studies. "Precue" responding is the mean rate for the
entire session before presentation of the visual cue (except animal 32, see Materials and Methods). "Cue" responding indicates the mean
rate while the visual cue is on. As can be seen, on average the rate of
responding during cue presentation (regardless of whether cocaine or
saline results from meeting the contingency) is ~100 times higher
than before cue presentation. Animal 32 showed more responding before
the cue (as the representative panel in Fig. 1 demonstrates), but even
that animal showed a 10 times greater response rate during cue
presentation, significantly greater than before the cue. This
demonstrates that motivation was undiminished during the saline trials.
Because of the strong stimulus control over the animal's behavior, the
actual duration of responding during the time the visual cue was on was
quite brief, with very little responding after the saline substitution.
This is further indication that the visual cue is controlling behavior,
namely, the tight temporal association of lever-pressing behavior with the presence of the cue. Lever pressing is minimal before the cue, is
high during the brief time of cue presentation, and then diminishes as
soon as the cue is extinguished. Extraneous stimuli from the laboratory
environment (the behavioral chambers were not soundproof and are not in
a room separate from the laboratory) were not associated with
lever-pressing, consistent with a high degree of saliency of the visual
stimuli used to signal cocaine availability. Precue responding before
the second infusion resembled that before the first.
Effect of anatomical placement on basal DA and
cocaine-induced changes
Placement of probes in the present studies was in the striatum,
with a distribution incorporating mesolimbic and sensorimotor subdivisions (Yeterian and Van Hoesen, 1978; Russchen et al., 1985;
Selemon and Goldman-Rakic, 1985; Lynd-Balta and Haber, 1994a; Haber et
al., 1995). One question addressed in the studies was whether there
were regional differences in basal levels (which did not show
systematic changes over time) or in the dopaminergic response to
self-administered cocaine. In looking for regional differences, two
approaches to distinguishing regions were used. The first was to use a
ventromedial to dorsolateral gradient as defined by Haber et al. (1995)
and Haber and McFarland (1999). Using that pattern, Figure
4 shows how the striatum was subdivided a
priori into three regions with associated corticostriatal inputs: ventromedial, innervated primarily by orbitofrontal cortex; central, innervated primarily by dorsolateral prefrontal cortex; and
dorsolateral, innervated primarily by motor, premotor, and
supplementary motor cortex. The second was to subdivide purely along
the medial to lateral gradient by dividing the six placement
possibilities into three groups of two. This method was also used
because of the medial to lateral gradient of cortical inputs.
Collapsing the data for all animals and using the first method of
subdivision (Fig. 4), there was a significant difference in basal
extracellular DA (F(2,60) = 10.21;
p < 0.001), with post hoc analysis by
Scheffe's F test indicating that ventromedial striatum had
lower basal levels (at the 95% confidence level) than the other two
regions that did not differ from each other (Fig.
5). There was also a significant difference in responsiveness to cocaine
(F(2,64) = 7.19; p < 0.002), with post hoc analysis by Scheffe's F
test indicating that DA in the ventromedial striatum increased more
than the other two regions that did not differ from each other.
Examining the data purely on a medial to lateral basis (Fig.
6), there was no difference in basal DA
levels (F(2,60) = 0.54;
p > 0.5). However, there was a difference between
these groups with respect to cocaine-induced increases in DA
(F(2,64) = 4.54; p < 0.015), with post hoc examination indicating that the most
medial group showed larger increases than each of the other two that
did not differ from each other.
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Figure 4.
Probe placement. This representative diagram shows
the pattern of probe placements and how they were assigned to
ventromedial (black), central (white), or
dorsolateral (black) striatal subdivisions.
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Figure 5.
Striatal regional differences using the
classification pattern indicated in Figure 4. Basal DA
(a, absolute values ± SEM) and cocaine-activated
DA levels (b, percentage of mean of three points before
cocaine ± SEM). *Significantly different from the other two
groups at p < 0.05, numbers in
parentheses indicate number of observations.
VM, Ventromedial; C, central;
DL, dorsolateral.
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Figure 6.
Striatal regional differences along medial to
lateral gradient. Basal DA (a, absolute values ± SEM) and cocaine-activated DA levels (b, percentage of
mean of three points before cocaine ± SEM). Subdivisions were the
medial two, central two, and lateral two trajectories, independent of
depth. *Significantly different from the other two groups at
p < 0.05, numbers in
parentheses indicate number of observations.
M, Medial; C, central; L,
lateral.
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The most anterior placement of probes was at a level at which both
caudate and putamen were discernable [corresponding to plate 31, interaural coordinate 28.65 mm of the Paxinos et al. (2000) rhesus
monkey stereotaxic atlas]. The most posterior was at the point of
crossing of the anterior commissure (plate 49, interaural coordinate
18.75 mm). Along the rostral to caudal gradient, there was not a
significant difference in basal or cocaine-activated levels as
determined by parcelling the striatum into three sections between its
beginning and the crossing of the anterior commissure.
Two minute microdialysis sampling during cocaine and
cue exposure
Because the rate of change in extracellular DA may be important in
cocaine reward and the initial "rush" associated with intravenous administration, a rapid sampling procedure was used to monitor the
increase in extracellular DA resulting from cocaine
self-administration. Figure 7 illustrates
the impact of a 0.5 mg/kg self-administered dose of cocaine on
extracellular striatal DA when examined at 2 min intervals. By one-way
repeated measures ANOVA, the increase in DA was significant
(p < 0.0001) in each animal. For animals 103 and 32, dialysis samples were collected without correcting for the dead
volume between the probe and collection vial, whereas for animals 47 and 49, there was a time lag to correct for the dead volume in the
outlet line. Thus, for animals 103 and 32, the initial postcocaine
sample was diluted by the dead volume, making the time course seen with
animals 103 and 32 a temporally more accurate picture of the
immediate postinfusion impact on extracellular DA.
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Figure 7.
Microdialysis measurements of DA at 2 min
intervals. Extracellular DA (percentage of mean of three points before
t = 0 ± SEM) response to 0.5 mg/kg
self-administered cocaine, saline, or no cue presentation. For animals
103 and 32, the first postcocaine sample was diluted by the dead volume
of the outlet lines.
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Results for studies in which no cue was presented indicate no
change in DA levels over time
Also illustrated in Figure 7 is a cue exposure study in which the
response to a "surprise" substitution of saline for cocaine was
examined. The infusion conditions were identical to those for cocaine,
including onset of the discriminative stimulus, its offset, and the
sound of the infusion pump. As for the cocaine infusions presented in
Figure 7, the animal had no drug on board at the time of the infusion.
There was no increase in DA after contingent infusion of saline in
either sensorimotor or mesolimbic striatum, as can be seen in Figure
8, in which the regional responses are
collapsed across all animals, as shown by repeated measures ANOVA
across time with region as a between-groups factor
(F(18,171) = 1.073; p = 0.38). Examining the data collapsed across groups and animals,
one-way repeated measures ANOVA showed no change over time
(F(9,189) = 1.25; p = 0.27).
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Figure 8.
Extracellular striatal dopamine during
"surprise" saline substitution for cocaine. Regional responses are
collapsed across animals, with no significant increase in any region or
differences between the regions. Ventromedial, central striatum, and
dorsolateral striatum are as shown in Figure 4.
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In a separate series of studies in three of the animals, it was
determined whether there were any changes in extracellular DA
associated with longer periods of active drug-seeking behavior. A cue
similar to the one normally indicating cocaine availability was used.
The normal cue indicating cocaine availability was a horizontally
placed red and green light, whereas in this case a vertically placed
red and green light, (centered on the same point as the horizontal
pair) was used. The cue was presented for 10 min, during which time
there was no consequence to the lever pressing. Figure
9 indicates that the cue had saliency in that it engendered rapid and prolonged lever pressing by the animals. Pooled across all animals and trials, mean responses in the 10 min
before cue presentation was 5 ± 2 (n = 10), in
the 10 min cue presentation period the mean number of responses was
260 ± 82 (n = 10), with the difference
significant (p < 0.01 by t test). Microdialysis sampling revealed that the cue exposure resulted in no
significant increase in extracellular DA (Fig.
10). Probe placements included both
central and ventromedial striatum, with no significant increase in
either region, as shown in the bottom panel of Figure 10. For that
data, repeated measures ANOVA across time with region as a between
groups factor showed no difference between the two regions
(F(1,9) = 1.43; p = 0.18). Examining the data collapsed across groups and animals, one-way
repeated measures ANOVA showed no change over time
(F(9,108) = 0.804; p = 0.61).
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Figure 9.
Lever pressing during extended cue exposure.
Representative cumulative response diagrams during exposure to visual
cue to which cocaine responding generalized. Extended
arrow shows time during which cue was present in each
diagram.
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Figure 10.
Extracellular striatal DA during extended
drug-seeking behavior. DA levels in each animal during the 10 min cue
exposure period. Probe placements include both sensorimotor and
mesolimbic striatum. The bottom panel shows data from
the two striatal regions examined, collapsed across animals. There was
no significant increase in either region. Ventromedial and central
striatum are as shown in Figure 4.
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Cocaine plasma levels after self-administration
The vascular access port allowed blood withdrawal in addition to
drug infusion. Plasma samples were collected over time and analyzed by
liquid chromatography (Jatlow and Nadim, 1990). Figure 11 illustrates that peak levels were
seen in the first sample obtained, at 2 min after injection. Comparison
of the observed plasma levels with those from human laboratory studies
indicates that they are consistent with those associated with
subjective reports of cocaine-induced euphoria (Javaid et al., 1978;
Foltin and Fischman, 1991) and DA transporter occupancy (Volkow et al.,
1997).
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Figure 11.
Plasma cocaine levels. After self-administration
of 0.5 mg/kg of cocaine HCl, plasma was obtained from blood drawn at
the indicated times from the vascular access port. Shown are means ± SEM.
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DISCUSSION |
This report is the first to demonstrate the impact of
self-administered cocaine on extracellular DA in a nonhuman primate. There is a rapid increase in striatal extracellular DA in response to
self-administered cocaine. No apparent DAergic response was observed
after substitution of saline for cocaine or during an extended period
of lever pressing engendered by a cue to which cocaine seeking behavior
generalized. At the 0.5 mg/kg dose of cocaine used, sampling of plasma
cocaine levels after self-administration indicated that drug levels
were comparable to those seen in human laboratory studies of cocaine
reward in which significant euphoria was reported.
Impact of self-administered cocaine on extracellular DA
It has recently been demonstrated (Volkow et al., 1997) that in
humans there is a significant correlation between occupancy of the DA
transporter and intensity of subjective effects of intravenous cocaine
at doses (0.3-0.6 mg/kg) comparable to that used in the present study
(0.5 mg/kg). Thus, the results herein complement that imaging study by
providing a high temporal resolution measure of the impact of that
transporter occupancy on extracellular DA in a closely related species.
The close parallel between the time course of the subjective effects of
intravenous cocaine (Breiter et al., 1997; Volkow et al., 1997) and the
impact on extracellular DA we have observed is consistent with the idea
that increased extracellular DA is a primary mediator of cocaine reward
in human and nonhuman primates.
An important aspect of the present study is the ability to investigate
rapid changes in neurotransmitter levels in response to the
rapid increase in plasma (Paly et al., 1982; Foltin and Fischman, 1991;
Nobiletti et al., 1994) and brain (Fowler et al., 1992; Bradberry et
al., 1993; Volkow et al., 1997) levels of cocaine seen with intravenous
or smoked routes of administration. As has been noted previously, the
rapidity of changes in plasma levels significantly impacts the strength
of reinforcement (Balster and Schuster, 1973; Panlilio et al., 1998). A
previous study in the rodent has also used microdialysis with fast
sampling methodology in cocaine self-administering animals (Wise et
al., 1995). That work was done within a paradigm of free-ranging
self-administration to investigate what internal neurochemical changes
trigger cocaine self-administration when in the midst of a
self-administration session. In the present study, we have examined the
response of a drug-free brain to an initial dose of cocaine or to cues
that signal its availability.
Impact of cocaine-associated cues on extracellular DA
The cue paradigms we have used were designed primarily to address
two questions: whether there is a conditioned component to the
cocaine-induced increase in extracellular DA we have seen and whether
animals actively involved in drug-seeking behavior show increases in
either mesolimbic or sensorimotor-associated striatum. No conditioned
component of the DA response was apparent, as indicated by the lack of
a change after saline substitution. Although we reproduced all of the
exteroceptive stimuli associated with cocaine when saline was
substituted, the interoceptive cues associated with cocaine were
absent, and a study in rats suggests that those interoceptive cues can
contribute to the ability of cocaine to elicit an increase in
extracellular DA (Fontana et al., 1993).
Because the saline substitution paradigm was one in which there was a
"mismatch" between the predicted reward (cocaine) and what the
animal received (saline), it also was considered possible that there
would have been a decrease in extracellular DA, consistent with
electrophysiological studies of DA neuronal activity using nondrug
rewards (Mirenowicz and Schultz, 1996; Schultz, 1998). However, there
was no apparent decrease in DA levels in response to saline infusion.
Because the time to reach contingency was relatively brief (see mean
response rates in Table 1; animals 103 and 32 worked under an FR10,
whereas animals 49 and 47 worked under an FR30), it is possible that an
increased release of DA during responding could have been offset by a
decrease after saline infusion, resulting in no apparent change when
integrated over the sampling period. Thus, the studies with longer
periods of responding were conducted. In them, active responding
persisted for longer than the microdialysis sampling intervals of 2 min. There were not any detectable increases in extracellular DA
associated with more prolonged periods of drug-seeking behavior. It is
possible that DA neuronal activity in response to drug versus nondrug
rewards differs or that the very brief alterations in activity
(Mirenowicz and Schultz, 1996; Schultz, 1998) are too short-lasting to
be detected by microdialysis methods. There is also the possibility that alterations in DA neuronal activity do not result in measurable increases by microdialysis methods, although the very consistent measurement of stress-induced increases in extracellular DA in accumbens and prefrontal cortex in rats would argue against this (Keefe
et al., 1993; Jedema and Moghaddam, 1994; Westerink, 1995).
The cue paradigms used could be considered to model the situation of a
drug-free individual confronted with environmental cues associated with
cocaine availability. Because priming doses (de Wit and Stewart, 1981),
stressors (Erb et al., 1996), and drug cues (de Wit and Stewart, 1981)
trigger relapse in animal models, and stressors (Keefe et al., 1993)
and priming doses are known to cause increased release of DA, it has
been hypothesized that cues also may trigger relapse via increased DA
release (Stewart et al., 1984). The present data do not support such a
hypothesis in nonhuman primates, nor did studies designed to
specifically examine this question in the self-administering rat
(Neisewander et al., 1996) or those using investigator administration
of cocaine (Brown and Fibiger, 1992). More recent work by Erb et al.
(1998) also suggests different circuitry may be involved in
a stress and cocaine-induced relapse. However, there are other
reports of microdialysis studies in rodents in which cocaine-predictive discriminative stimuli (Weiss and Ciccocioppo, 1999) or sexual stimuli
(Pfaus et al., 1990) have been reported to cause small but significant
increases in extracellular DA in nucleus accumbens, the equivalent of
mesolimbic striatum examined in the present study. The difference
between those results and the present suggest the mechanisms for
cue-induced behaviors in nonhuman primates may be significantly
different from the rodent.
A concern that could be raised about the present studies is that the
visual cue used is not serving as a true conditioned cue, but is only
causing a general activation of behavior. There was only one lever on
the operant panel, thus it was not possible to determine if the
increased lever pressing was only associated with an active versus an
inactive lever. However, for many months responses on the lever were
only associated with cocaine reward, and there was an extremely high
degree of association of lever pressing with the presence of the visual
cue. For three of the four animals, the difference in response rate was
more than two orders of magnitude greater during visual cue
presentation, and for the fourth animal it was one order of magnitude
greater. Thus, it appears that the lack of changes observed are not a
consequence of insufficient salience of the cue.
Anatomical subdivisions of primate striatum
An important issue is that of the anatomical placement of probes
in the present study. In the rat, reinforcing effects of increased DA
neurotransmission appear to be limited to the nucleus accumbens, a
region defined by limbic inputs from hippocampus, amygdala, and
prefrontal cortex (Kelley and Domesick, 1982; Kelley et al., 1982;
Phillipson and Griffiths, 1985), and whose DAergic input arises
primarily from the ventral tegmental area (Fallon and Moore, 1978).
However, in the primate, the situation is much less restrictive in
terms of the origin of both DAergic and limbic inputs. There is broader
distribution of these inputs across the ventral striatum, making
distinctions between the nucleus accumbens adjacent ventral caudate and
putamen somewhat arbitrary (Lynd-Balta and Haber, 1994a; Haber and
McFarland, 1999). Our placements included regions encompassing what
would be considered both the mesolimbic ventral striatum and the
sensorimotor dorsolateral striatum. A greater responsiveness to
cocaine-induced increases in extracellular DA was observed in
ventromedial and medial striatum. It was also observed that basal
extracellular DA levels were significantly lower in the ventromedial
striatum. Detailed mapping of tissue levels of DA have not been
published, however unpublished studies indicate that tyrosine
hydroxylase staining is less intense in ventral striatum (S. N. Haber, personal communication). There is also reduced level of
DA uptake site density in ventral striatum (Haber and McFarland, 1999),
consistent with a reduced density of innervation. The enhanced
responsiveness of DA to cocaine in the medial subdivision where there
were no differences in basal DA (Fig. 6) indicates that the enhanced
responsiveness is not simply related to lower basal levels.
The medial and ventromedial regions are those that are targets
primarily of orbitofrontal and medial prefrontal cortex, as opposed to
dorsolateral prefrontal cortex, which projects primarily to what we
have defined as the "central" subdivision in Figures 5 and 6
(Lynd-Balta and Haber, 1994a; Haber and McFarland, 1999). Orbitofrontal
cortex is known to subserve reward evaluative functions (Rolls, 1996;
Rolls et al., 1996; Tremblay and Schultz, 1999). However, dorsolateral
prefrontal cortex is also activated by cocaine and cocaine cues in
imaging studies (Grant et al., 1996; Breiter et al., 1997; Maas et al.,
1998), leaving the role of different cortical inputs in the enhanced
responsiveness of medial and ventromedial striatum unclear. That
enhanced responsiveness is consistent with reports of increased
responsiveness of nucleus accumbens DA to psychostimulants in the
rodent. However, the degree of difference in responsiveness between
sensorimotor (dorsolateral) striatum and mesolimbic (ventromedial)
striatum was less in the primate than has been reported in rodents
(Carboni et al., 1989).
In summary, rapid and pronounced increases in striatal extracellular DA
in response to self-administered cocaine were observed, with a time
course that closely follows that of human subjective effects of
intravenous cocaine. There was no apparent DAergic response after
substitution of saline in the self-administered infusion or during
extended periods of drug-seeking behavior, suggesting that exposure to
specific environmental cocaine-associated cues does not activate
release of DA in sensorimotor or mesolimbic striatum, the latter being
equivalent to the nucleus accumbens in the rodent.
| |
FOOTNOTES |
Received Jan. 4, 2000; revised Feb. 23, 2000; accepted Feb. 25, 2000.
This work was supported by National Institutes of Health Grants
DA 08073, DA04060, DA10331, and the Yale Veteran's Administration Alcoholism Research Center. The excellent technical assistance of
Christopher Baccei, Shawna Ellis, Haleh Nadim, and Cindy Rodriguez is
also gratefully acknowledged.
Correspondence should be addressed to Dr. Charles Bradberry, West Haven
Veteran's Administration Hospital/116A2, 950 Campbell Avenue, West
Haven, CT 06516. E-mail: charles.bradberry{at}yale.edu.
Dr. Barrett-Larimore's present address: Department of Psychology,
Morgan State University, Baltimore, MD.
| |
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I. Boileau, A. Dagher, M. Leyton, R. N. Gunn, G. B. Baker, M. Diksic, and C. Benkelfat
Modeling Sensitization to Stimulants in Humans: An [11C]Raclopride/Positron Emission Tomography Study in Healthy Men
Arch Gen Psychiatry,
December 1, 2006;
63(12):
1386 - 1395.
[Abstract]
[Full Text]
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N. D. Volkow, G.-J. Wang, F. Telang, J. S. Fowler, J. Logan, A.-R. Childress, M. Jayne, Y. Ma, and C. Wong
Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction.
J. Neurosci.,
June 14, 2006;
26(24):
6583 - 6588.
[Abstract]
[Full Text]
[PDF]
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L. J. M. J. Vanderschuren, P. Di Ciano, and B. J. Everitt
Involvement of the Dorsal Striatum in Cue-Controlled Cocaine Seeking
J. Neurosci.,
September 21, 2005;
25(38):
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[Abstract]
[Full Text]
[PDF]
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F. J. Vocci, J. Acri, and A. Elkashef
Medication Development for Addictive Disorders: The State of the Science
Am J Psychiatry,
August 1, 2005;
162(8):
1432 - 1440.
[Abstract]
[Full Text]
[PDF]
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L. J. Porrino, D. Lyons, H. R. Smith, J. B. Daunais, and M. A. Nader
Cocaine Self-Administration Produces a Progressive Involvement of Limbic, Association, and Sensorimotor Striatal Domains
J. Neurosci.,
April 7, 2004;
24(14):
3554 - 3562.
[Abstract]
[Full Text]
[PDF]
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K. McFarland, S. B. Davidge, C. C. Lapish, and P. W. Kalivas
Limbic and Motor Circuitry Underlying Footshock-Induced Reinstatement of Cocaine-Seeking Behavior
J. Neurosci.,
February 18, 2004;
24(7):
1551 - 1560.
[Abstract]
[Full Text]
[PDF]
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S. R. Vorel, C. R. Ashby Jr, M. Paul, X. Liu, R. Hayes, J. J. Hagan, D. N. Middlemiss, G. Stemp, and E. L. Gardner
Dopamine D3 Receptor Antagonism Inhibits Cocaine-Seeking and Cocaine-Enhanced Brain Reward in Rats
J. Neurosci.,
November 1, 2002;
22(21):
9595 - 9603.
[Abstract]
[Full Text]
[PDF]
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C. W. Bradberry
Book Review: Dynamics of Extracellular Dopamine in the Acute and Chronic Actions of Cocaine
Neuroscientist,
August 1, 2002;
8(4):
315 - 322.
[Abstract]
[PDF]
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R. Ito, J. W. Dalley, T. W. Robbins, and B. J. Everitt
Dopamine Release in the Dorsal Striatum during Cocaine-Seeking Behavior under the Control of a Drug-Associated Cue
J. Neurosci.,
July 15, 2002;
22(14):
6247 - 6253.
[Abstract]
[Full Text]
[PDF]
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S. J. Cragg, C. J. Hille, and S. A. Greenfield
Functional Domains in Dorsal Striatum of the Nonhuman Primate Are Defined by the Dynamic Behavior of Dopamine
J. Neurosci.,
July 1, 2002;
22(13):
5705 - 5712.
[Abstract]
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W.-K. Park, A. A. Bari, A. R. Jey, S. M. Anderson, R. D. Spealman, J. K. Rowlett, and R. C. Pierce
Cocaine Administered into the Medial Prefrontal Cortex Reinstates Cocaine-Seeking Behavior by Increasing AMPA Receptor-Mediated Glutamate Transmission in the Nucleus Accumbens
J. Neurosci.,
April 1, 2002;
22(7):
2916 - 2925.
[Abstract]
[Full Text]
[PDF]
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P. W. Czoty, B. C. Ginsburg, and L. L. Howell
Serotonergic Attenuation of the Reinforcing and Neurochemical Effects of Cocaine in Squirrel Monkeys
J. Pharmacol. Exp. Ther.,
March 1, 2002;
300(3):
831 - 837.
[Abstract]
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U. Shalev, J. W. Grimm, and Y. Shaham
Neurobiology of Relapse to Heroin and Cocaine Seeking: A Review
Pharmacol. Rev.,
March 1, 2002;
54(1):
1 - 42.
[Abstract]
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Q. Wu, M. E. A. Reith, M. J. Kuhar, F. I. Carroll, and P. A. Garris
Preferential Increases in Nucleus Accumbens Dopamine after Systemic Cocaine Administration Are Caused by Unique Characteristics of Dopamine Neurotransmission
J. Neurosci.,
August 15, 2001;
21(16):
6338 - 6347.
[Abstract]
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G. S. Berns, S. M. McClure, G. Pagnoni, and P. R. Montague
Predictability Modulates Human Brain Response to Reward
J. Neurosci.,
April 15, 2001;
21(8):
2793 - 2798.
[Abstract]
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K. C. Bradley and R. L. Meisel
Sexual Behavior Induction of c-Fos in the Nucleus Accumbens and Amphetamine-Stimulated Locomotor Activity Are Sensitized by Previous Sexual Experience in Female Syrian Hamsters
J. Neurosci.,
March 15, 2001;
21(6):
2123 - 2130.
[Abstract]
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S. J. Cragg, C. J. Hille, and S. A. Greenfield
Dopamine Release and Uptake Dynamics within Nonhuman Primate Striatum In Vitro
J. Neurosci.,
November 1, 2000;
20(21):
8209 - 8217.
[Abstract]
[Full Text]
[PDF]
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R. Ito, J. W. Dalley, S. R. Howes, T. W. Robbins, and B. J. Everitt
Dissociation in Conditioned Dopamine Release in the Nucleus Accumbens Core and Shell in Response to Cocaine Cues and during Cocaine-Seeking Behavior in Rats
J. Neurosci.,
October 1, 2000;
20(19):
7489 - 7495.
[Abstract]
[Full Text]
[PDF]
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C. W. Bradberry
Acute and Chronic Dopamine Dynamics in a Nonhuman Primate Model of Recreational Cocaine Use
J. Neurosci.,
September 15, 2000;
20(18):
7109 - 7115.
[Abstract]
[Full Text]
[PDF]
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TOP
ABSTRACT
INTRODUCTION
