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 Previous Article
The Journal of Neuroscience, March 15, 1999, 19(6):2401-2411
Dissociation in Effects of Lesions of the Nucleus Accumbens Core
and Shell on Appetitive Pavlovian Approach Behavior and the
Potentiation of Conditioned Reinforcement and Locomotor Activity by
D-Amphetamine
John A.
Parkinson1,
Mary C.
Olmstead2,
Lindsay
H.
Burns3,
Trevor W.
Robbins1, and
Barry J.
Everitt1
1 Department of Experimental Psychology, University of
Cambridge, Cambridge, United Kingdom CB2 3EB, 2 Department
of Psychology, Queens University, Kingston Ontario, Canada, K7L 3N6,
and 3 Neurex, Menlo Park, California, 94025-1012
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ABSTRACT |
Dopamine release within the nucleus accumbens (NAcc) has been
associated with both the rewarding and locomotor-stimulant effects of
abused drugs. The functions of the NAcc core and shell were investigated in mediating amphetamine-potentiated conditioned reinforcement and locomotion. Rats were initially trained to associate a neutral stimulus (Pavlovian CS) with food reinforcement (US). After
excitotoxic lesions that selectively destroyed either the NAcc core or
shell, animals underwent additional CS-US training sessions and then
were tested for the acquisition of a new instrumental response that
produced the CS acting as a conditioned reinforcer (CR). Animals were
infused intra-NAcc with D-amphetamine (0, 1, 3, 10, or 20 µg) before each session. Shell lesions affected neither Pavlovian nor
instrumental conditioning but completely abolished the potentiative
effect of intra-NAcc amphetamine on responding with CR. Core-lesioned
animals were impaired during the Pavlovian retraining sessions but
showed no deficit in the acquisition of responding with CR. However,
the selectivity in stimulant-induced potentiation of the CR lever was
reduced, as intra-NAcc amphetamine infusions dose-dependently increased
responding on both the CR lever and a nonreinforced (control) lever.
Shell lesions produced hypoactivity and attenuated amphetamine-induced
activity. In contrast, core lesions resulted in hyperactivity and
enhanced the locomotor-stimulating effect of amphetamine. These results
indicate a functional dissociation of subregions of the NAcc; the shell
is a critical site for stimulant effects underlying the enhancement of
responding with CR and locomotion after intra-NAcc injections of
amphetamine, whereas the core is implicated in mechanisms underlying
the expression of CS-US associations.
Key words:
ventral striatum; reward; dopamine; psychomotor
stimulant; associative learning; drugs of abuse
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INTRODUCTION |
The mesolimbic dopamine (DA) system
that projects from the ventral tegmental area (VTA) to the nucleus
accumbens (NAcc) has been implicated in the rewarding properties of
intracranial self-stimulation, drugs of abuse, and natural reinforcers
(for review, see Wise and Bozarth, 1987 ; Robbins and Everitt, 1996).
Although there is general agreement that the dopaminergic innervation
of the NAcc contributes to reinforcement processes, the functions of this system remain unclear. It is unlikely that mesolimbic DA simply
mediates primary reinforcement because lesions of this system or
infusions of DA receptor antagonists into the NAcc do not affect
consummatory responses to food, water, or sex (Koob et al., 1978a;
Everitt, 1990; Robbins and Everitt, 1992).
Conversely, there is psychopharmacological, neurochemical, and
electrophysiological evidence that DA release in the NAcc is associated
with anticipatory responses to reinforcing stimuli (Everitt, 1990;
Phillips et al., 1991; Schultz et al., 1992; Williams et al., 1993),
indicating that DA modulates reinforcement signals at the level of the
NAcc (Robbins and Everitt, 1992). In this way, DA release in the NAcc
may enhance behavioral responses during both Pavlovian and instrumental
conditioning by potentiating approach responses to conditioned stimuli
and increasing the control over instrumental behavior of stimuli
associated with reinforcement (conditioned reinforcers; Everitt and
Robbins, 1992; Robbins and Everitt, 1992).
The acquisition of responding with conditioned reinforcement (CR)
provides a powerful means of investigating the contribution of
Pavlovian conditioning to reinforcement-related instrumental behavior.
Conditioned reinforcement is the process whereby a previously conditioned stimulus (CS) acts as the reinforcer for an
instrumental action (Mackintosh, 1974). Responding for a
conditioned reinforcer is potentiated by systemic (Hill, 1970) or
intra-NAcc (Taylor and Robbins, 1984) administration of
D-amphetamine, having behavioral, anatomical, and
neurochemical specificity (Cador et al., 1989; Taylor and Robbins,
1984, 1986). Of particular relevance for this study is that these
effects have been shown to depend critically on DA receptor activation
within the NAcc (Taylor and Robbins, 1986; Wolterink et al., 1993).
Thus, use of this procedure allows the control over behavior by a
conditioned reinforcer and how this control is modified by increasing
dopamine transmission in the nucleus accumbens to be measured, rather
than the ability of an appetitive conditioned stimulus to affect new
learning per se.
In addition to its role in reinforcement processes, the NAcc has been
implicated in spontaneous and psychomotor stimulant-potentiated locomotion. Systemic or intra-NAcc infusions of DA receptor agonists increase spontaneous activity (Kelly et al., 1975; Kelley et al., 1989;
Swerdlow and Koob, 1989). This increased activity is blocked by
DA-depleting lesions of the VTA or by previous intra-NAcc
administration of DA receptor antagonists (Kelly et al., 1975;
Wolterink et al., 1993). Dopamine depletion from the NAcc or VTA
generally produces hypoactivity (Koob et al., 1978b), whereas cell body
lesions of the entire NAcc produce a significant increase in
spontaneous locomotor activity (Kelly and Roberts, 1983; Kafetzopoulos,
1986; Everitt et al., 1991).
The NAcc is a heterogeneous structure (Graybiel and Ragsdale, 1978;
Jongen-Relo et al., 1993). It can be separated anatomically into core
and shell subdivisions (Zaborszky et al., 1985; Voorn et al., 1989)
situated in the dorsolateral and ventromedial regions of the nucleus,
respectively, that can be dissociated immunocytochemically (Graybiel
and Ragsdale, 1978; Voorn et al., 1994) and on the basis of their
differential patterns of connectivity (Groenewegen et al., 1987;
Berendse and Groenewegen, 1990; Zahm and Heimer, 1990, 1993; Hurley et
al., 1991; Berendse et al., 1992; Wright et al., 1996).
The distinct pattern of core and shell output targets, with the core
projecting to pallidal structures and the shell, in addition, projecting to more limbic domains, such as the lateral hypothalamus (Zahm and Heimer, 1990), suggests that the two regions may mediate different behavioral processes. Recently, functional dissociations of
the NAcc shell and core have been provided using both excitotoxic lesions and excitatory amino acid modulation of the two NAcc subregions selectively (Maldonado-Irizarry and Kelley, 1995; Kelley et al., 1997).
By using excitotoxic lesions that selectively destroy neurons in either
the NAcc core or shell, we have investigated the functions of these two
subregions in the processes underlying CR and its potentiation by
stimulant drugs and also in mediating the locomotor stimulant effects
of D-amphetamine.
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MATERIALS AND METHODS |
Subjects
Ninety-five male Lister hooded rats (Olac, Bicester, UK) were
housed in pairs in a temperature-controlled (21°C) room on a 12 hr
light/dark cycle. After recovery from surgery, animals were placed on a
restricted feeding schedule and maintained at ~85% of their
free-feeding weight. Water was available ad libitum in the
home cages. All animals used in these studies were treated in
accordance with the United Kingdom 1986 Animals (Scientific Procedures)
Act (project license PPL 80/00668).
Surgery
Animals in the locomotor activity study received bilateral
lesions of the NAcc core or shell before any behavioral testing. Animals in the CR study received lesions after the Pavlovian CR training sessions. Before surgery, rats were anesthetized with Avertin
[2,2,2-tribromoethanol, 2-methylbutan-2-ol, Dulbecco "A" PBS
tablets, and ddH20 in tertiary amyl alcohol (Sigma, Poole, UK); 10 ml/kg body weight] and secured in a Kopf stereotaxic
instrument with the incisor bar set at  3.3 mm. Fifteen animals for
the CR study and eighteen animals for the activity study received NAcc core lesions, induced by infusing 0.5 µl of quinolinic acid (0.09 M) over 3 min at the following site: anteroposterior (AP),
+1.2 mm; lateral (L), ±1.8 mm; and dorsoventral (DV), 7.1 mm from dura. The pipette was removed 2 min after the infusion. Fourteen animals for the CR study and twelve animals for the activity study received NAcc shell lesions that were induced by infusing ibotenic acid
(0.06 M) at three different sites. The coordinates,
infusion volume, infusion time, and diffusion time for each injection
were as follows: (1) AP, +1.6 mm; L, ± 1.1 mm; DV, 6.4 mm; 0.1 µl; 1 min; 2 min; (2) AP, +1.6 mm; L, ±1.1 mm; DV, 6.9 mm; 0.1 µl; 1 min; 1 min; (3) AP, +1.6 mm; L, ±1.1 mm; DV, 7.9 mm; 0.2 µl; 2 min; 1 min. Twelve rats (six core and six shell) for the CR study and twenty-four (12 core and 12 shell) for the activity study
received NAcc sham lesions induced by infusing vehicle using the
coordinates and infusion parameters described above.
All neurotoxin injections were made through a single burr hole using
either a 1 or 5 µl SGE (Baton Rouge, LA) syringe (26 gauge
code, 1BR-OC-7/0.47) with a custom-made glass micropipette attached to
the end. Initially, pipettes (Intracel Ltd.) measured 1.2 mm external
diameter and 0.69 mm internal diameter by 10 cm in length and were
pulled using a Stoelting App-1 all-purpose Puller, model 52500, giving
a final tip diameter of 50-100 µm and a length of 12 mm.
Micropipettes were attached to the syringe using Araldite epoxy resin
(CIBA) to ensure an airtight seal. All animals were given injections of
glucose-saline (5-10 ml, i.p.) after surgery to aid recovery. There
was no significant animal loss in the first week after surgery.
Animals in the CR study were also implanted bilaterally with stainless
steel guide cannulae (22 gauge) 2 mm dorsal to the intended injection
site in the NAcc (AP, +1.6 mm; ML, ±1.5 mm; DV, 4.1 mm) during the
same surgery as that in which the lesions were made. Cannulae were
fixed to the skull with dental cement, and stainless steel screws and
were closed with stainless steel stylets. All animals were allowed to
recover for 2 weeks before behavioral testing began.
Drugs and infusions
D-Amphetamine sulfate (Sigma) was dissolved in
sterile PBS, pH 7.2, for intracerebral infusions and in sterile 0.9%
saline for systemic injections. Intracerebral infusions were made
through 29 gauge cannulae that extended 2 mm beyond the guide cannulae tips and were attached to an infusion pump (Harvard Apparatus) by
polyethylene tubing. Infusions were in a volume of 0.5 µl per side
over 60 sec with a 60 sec diffusion period. Before the first drug
infusion, all animals were given a preliminary infusion of PBS and
returned to their home cages so that any behavioral effects of tissue
damage mechanically induced by the injection cannulae would occur
before the test session.
Apparatus
Conditioned reinforcement training and testing took place in
sound-attenuated operant chambers (26.5 × 22 × 20 cm) that
were fitted with two retractable levers and a sucrose dipper situated between the levers (Med Associates). The operant chambers could be
illuminated by a ceiling house light, and external noise was masked by
ventilating fans mounted on the side of each box. Access to the dipper
was allowed through a magazine (3.8 cm from the side and 5.5 cm from
the grid floor) that could be illuminated with a tray light. The
apparatus was controlled and data were collected by BBC or Acorn
Archimedes microcomputers (Acorn Computers, Cambridge, UK) running the
control languages Spider or Arachnid (Genes Cognition, Cambridge, UK).
Locomotor activity was tested in individual wire photocell cages
(40 × 25 × 18 cm) that were transected by two parallel
infrared photocell beams 6 cm from the cage ends and 1 cm from the cage floor. Beam breaks were registered in 10 min bins on-line by a BBC
Master Series microcomputer equipped with a Spider extension (Genes
Cognition). All testing was conducted in the dark phase of the
light/dark cycle.
Behavioral procedures
Conditioned reinforcement. Forty-one animals
underwent Pavlovian conditioning sessions in which the presentation of
a CS (5 sec illumination of the tray light and house light off)
preceded the US (5 sec elevation of the dipper filled with a 10%
sucrose solution). The CS-US pairing was presented 30 times per
session on a variable interval (VI), 60 sec schedule of reinforcement. All animals received 20 training sessions. The frequency and duration of magazine entries were detected by infrared beams that transected the
entrance. The number of magazine entries during the VI, CS, and US
periods was recorded, and a measure of discriminated approach was
determined for each animal. Discriminated approach was calculated as
the mean number of magazine entries during the CS period as a ratio of
the mean number of magazine entries during the total trial period,
excluding the duration of US presentation (CS + VI). Animals were given
four retraining sessions when they had recovered from surgery to ensure
a stable baseline of responding before the start of the test phase.
In Pavlovian to instrumental transfer test sessions, sucrose was not
available, i.e., animals were tested in extinction. The two levers were
introduced into the chambers, and depression of one lever (CR) resulted
in the presentation of the CS (under a random ratio 2 schedule),
whereas depression of the second lever had no programmed consequences
(NCR). The ability of the CS to selectively increase responding on the
CR lever provides a measure of the conditioned reinforcing properties
of the CS (Mackintosh, 1974). The assignment of CR and NCR levers was
counterbalanced within groups. Immediately before each of five tests,
animals were infused intra-NAcc with D-amphetamine (0, 1, 3, 10, or 20 µg). All drug doses were administered in a Latin square
design. The number of responses on each lever, as well as the number of magazine entries, were recorded during each 30 min test. All test sessions were separated by 48 hr. For statistical analyses, the responses on the CR and NCR lever were square root-transformed to
maintain homogeneity of variance (Winer, 1971). Furthermore, the
homogeneity of variance across groups in repeated-measures design
ANOVAs was assessed by the Mauchly Sphericity test. When data sets
significantly violated this requirement for a repeated-measures design
ANOVA, the Greenhouse Geisser Epsilon correction parameter for degrees
of freedom (Geisser and Greenhouse, 1959; Winer, 1971) was used
to calculate a more conservative p value for each
F ratio. Finally, when appropriate, further analyses of
three-way ANOVA interactions was undertaken using weighted
mean-adjusted (pooled) Mean Square Error terms as described by Winer
(1971).
Locomotor activity. Thirty-six animals were tested for
locomotor responses to systemic injections of
D-amphetamine. They were given four 2 hr sessions in the
activity cages to measure spontaneous locomotor activity and
habituation to the cages. After this, all animals received 0, 0.5, 1.5, and 5.0 mg/kg of D-amphetamine (administered in ascending
order of concentration) systemically (intraperitoneally), on
separate days, and their activity levels were measured for 2 hr.
Histological assessment of lesions
At the completion of behavioral testing, animals were killed
under deep barbiturate anesthesia and perfused intracardially with
0.9% saline followed by 4% paraformaldehyde (PFA). The brains were
removed and post-fixed for 1 hr in PFA and then stored in a 20% w/v
sucrose solution for 12-15 hr.
Coronal sections (40 µm) were cut through the forebrain on a freezing
microtome. Every third section was stained for immunocytochemical analysis using antibodies raised against substance P and Calbindin 28 K. These sections were quenched for 5 min at room temperature in a
solution of 10% methanol, 10% concentrated hydrogen peroxide, and
80% distilled water. After two 5 min washes in 0.05 M
Tris-buffered saline (TBS; pH 7.4), the sections were subjected to
blocking with 1% goat serum (NGS) in TBS containing 0.2% Triton X-100
(TTBS) for 1 hr before being transferred without washing into a
solution containing the primary antibody in the following dilution:
monoclonal anti-Calbindin-D (mouse) antibody (Sigma) 1:500 and 1% NGS
in TTBS; anti-substance P antibody 1:1000 with 1% NGS in TTBS.
Sections were left overnight at room temperature on a shaker and then
washed thoroughly in TBS. Sections were then incubated in goat
anti-mouse (biotinylated) at a dilution of 1:200, or goat anti-rabbit
(biotinylated) at a dilution of 1:50, with 1% NGS in TBS for 3 hr,
then given three 5 min washes in TBS before a further 1 hr incubation
with the avidin-biotin-peroxidase complex (ABC; Vector Laboratories, Burlingame, CA) at a dilution of 1:200 with 1% NGS in TBS (this solution was mixed 30 min before use). The sections were then washed
once in TBS and twice in Tris nonsaline (TNS) before treatment with the
chromogen diaminobenzidine (DAB): 10 mg/ml DAB and 0.67 µl/ml 30%
hydrogen peroxide in TNS. Sections were incubated for ~5 min until
the required intensity of reaction was attained. After a final rinse in
TBS, sections were mounted on gelatinized slides, allowed to dry
overnight, and then dehydrated in ascending alcohols and coverslipped.
Alternate sections were mounted on gelatin-coated glass slides, then
stained for Nissl substance using cresyl violet. The combined Nissl
staining and immunocytochemistry allowed visualization of the NAcc core
and shell regions. Calbindin is prevalent within the core subregion,
whereas substance P immunoreactivity is relatively more intense in the
shell (Voorn et al., 1989; Zahm and Brog, 1992). Thus,
immunocytochemistry highlights the core and shell subregions during
histological analysis, whereas staining with cresyl violet stain
enables assessment of the extent and nature of excitotoxin-induced
neuronal damage as well as gliosis-associated intracerebral infusions
of quinolinic or ibotenic acids.
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RESULTS |
Histological assessment
Figures 1 and
2 show schematic representations of
lesions of the NAcc core and shell, respectively, based on the
stereotaxic atlas of the rat brain by Paxinos and Watson (1998).
Delineation of the NAcc core and shell was also based on
immunocytochemical and histological analyses of the striatum (Voorn et
al., 1989; Zahm and Brog, 1992; Jongen-Relo et al., 1993, 1994; Heimer
et al., 1995). NAcc shell lesions, resulting from infusions of ibotenic acid, destroyed all, or a great majority of, neurons in the caudal, mediodorsal shell (sometimes termed the septal pole), thus leaving the
medial rostral pole and also the entire ventral and ventrolateral aspects of the shell intact (see Fig. 3 for photomicrograph of the
lesion). Neuronal loss typically extended in an anteroposterior direction from +1.7 to +0.48 mm anterior to bregma and from the base of
the lateral ventricle dorsally, to the ventral portions of the medial
shell occasionally reaching the region of the olfactory tubercle. There
was, in some cases, unilateral damage to the lateral septum or to
the medial NAcc core. Animals with bilateral damage to any structures
extraneous to the shell, including especially the medial core, were
excluded from any further analysis. Finally, there was no evidence of
damage to the ventral pallidum or the nucleus of the vertical limb of
the diagonal band of Broca in any animals.
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Figure 1.
Schematic representation of excitotoxic
lesions to the NAcc core. Shaded areas represent the
smallest (black) and largest
(gray) extent of neuronal damage in a single
animal. Coronal sections are +2.7 mm anterior through +0.48 mm
posterior to bregma (Paxinos and Watson, 1998).
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Figure 2.
Schematic representation of excitotoxic
lesions to the NAcc shell. Shaded areas represent the
smallest (black) and largest
(gray) extent of neuronal damage in a single
animal. Coronal sections are +2.7 mm anterior through +0.48 mm
posterior to bregma (Paxinos and Watson, 1998).
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Figure 3.
Photomicrographs showing cresyl violet-stained
coronal sections through the nucleus accumbens (~+1.2 mm from
bregma). A, Sham lesion; B, nucleus
accumbens shell lesion. C, High magnification of the
sham lesion section shown in A; D, high
magnification of the shell lesion section shown in B.
The lesioned area is indicated by the dotted lines.
Scale bars: A, 1 mm; C, 500 µm.
Arrowheads show identical landmarks in A
and B, and C and D.
aca, Anterior commissure; Acbc, nucleus
accumbens core; Acbsh, nucleus accumbens shell;
LV, lateral ventricle.
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Lesions of the NAcc core resulting from infusions of quinolinic acid
encompassed most of the core subregion. Figure
4 shows photomicrographs of a
representative coronal section from an NAcc core lesion and a sham
control stained with cresyl violet. Neuronal loss and associated
gliosis extended, in an anteroposterior direction, rostrally from +2.5
to +0.5 mm anterior to bregma. Generally, the lesion did not extend
ventrally or caudally into ventral pallidum or olfactory tubercle.
Neuronal damage was often caused to ventral parts of the overlying
caudate putamen, although this was usually unilateral in nature.
Similarly, neuronal loss was occasionally seen in the lateral or
ventrolateral shell. Animals with bilateral damage of this kind were
excluded from further analysis of the behavioral data. Finally, animals
with any damage to the medial and dorsomedial shell were excluded
from the behavioral analysis.
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Figure 4.
Photomicrographs showing cresyl violet-stained
coronal sections through the nucleus accumbens (~+1.2 mm from
bregma). A, Sham lesion; B, nucleus
accumbens core lesion. The lesioned area is indicated by the
dotted lines. Scale bar: A, 1 mm.
aca, Anterior commissure; Acbc, nucleus
accumbens core; Acbsh, nucleus accumbens shell;
ICjM, major islands of calleja; LV,
lateral ventricle; Pir, piriform cortex.
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During experimental testing, implanted cannulae became detached from
the head mountings of some subjects. The data from these animals were
not included in the subsequent statistical analyses (four core, two
shell, and four sham animals). Similarly, the data from animals with
lesions that were incomplete or extended beyond the target area, as
revealed by histological examination, were also discarded (six core and
11 sham). Twenty-two animals remained in the CR study, seven
shell-lesioned, seven core-lesioned, and eight sham-lesioned. Forty-six
animals remained in the locomotor study, six shell-lesioned, 16 core-lesioned, and 24 sham-lesioned.
Conditioned reinforcement
Pavlovian conditioning
The effects of NAcc core and shell lesions on discriminated
approach during CS-US training sessions are shown in Figure
5. Discriminated approach was calculated
as the number of approaches during the CS period as a ratio of
approaches during the total CS and VI period. An increase in this ratio
across sessions indicates that responses during the CS period are
increasing relative to responses during the VI period. ANOVA of the
four presurgical Pavlovian sessions (comparing the three experimental
groups before surgery) showed that there were no differences in this
measure of discriminated approach between the three groups either
through a main effect of lesion (F(2,19) = 0.52; p = 0.6) or through a lesion × session
interaction (F(6,57) = 0.33; p = 0.92). However, all animals demonstrated Pavlovian learning as
expressed as an increase in conditioned responding over sessions
(F(3,57) = 22.28; p = 0.0001).
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Figure 5.
Effect of NAcc core and shell lesions on
Pavlovian-discriminated approach. The mean ± SEM ratio of approach
responses during the CS relative to the CS plus VI period is shown for
four presurgical and four postsurgical sessions for core-, shell-, and
sham-lesioned animals.
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ANOVA comparing postsurgery discriminated approach revealed a
significant lesion × surgery interaction
(F(6,57) = 2.9; p < 0.05).
Post hoc analysis of simple interactions demonstrated that animals with core lesions
exhibited a reduced level of discriminated approach relative to shell-
and sham-lesioned animals during the postsurgery conditioning sessions
(p < 0.05). Furthermore, whereas shell- and
sham-lesioned animals showed a significant increase in discriminated
approach over the four trials (p < 0.05),
core-lesioned animals showed no significant change in their approach
behavior (p = 0.13).
Baseline activity (overall magazine entries during the session), as
measured by the total frequency and duration of magazine entries, was
not affected by either lesion (duration: lesion × session
interaction, F(2,22) = 2.26, p = 0.13; main effect of lesion, F(2,22) = 3.04, p = 0.09; frequency: lesion × session interaction, F(2,22) = 0.13, p = 0.73; main effect of lesion, F(2,22) = 1.49;
p = 0.25), demonstrating the specific discriminated nature of the core lesion deficit.
Acquisition of a new response with conditioned reinforcement
The effects of NAcc core and shell lesions on the acquisition of
responding with CR are shown in Figures 6
and 7. The actual mean number of
responses over the 30 min testing periods made by sham-lesioned animals
varied from 56.6 and 10.5 (for CR and NCR levers, respectively) after
saline to 208 and 19.9 at the 20 µg D-amphetamine dose.
Responses made by core-lesioned animals similarly ranged from 52.1 and
19.6 (CR and NCR after saline infusion) to 121.2 and 30.2 (after 20 µg D-amphetamine), whereas those for shell-lesioned
animals ranged from 36.9 and 12.2 (CR and NCR, respectively) to 43.8 and 13.9 (after 20 µg D-amphetamine).
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Figure 6.
Effect of NAcc core lesions on the acquisition of
responding with CR. Data points represent the mean square root ± SEM
responses on the lever producing the conditioned reinforcer
(CR) and the control lever (NCR) for
sham- and core-lesioned animals after intra-NAcc injections of
D-amphetamine (0, 1, 3, 10, and 20 µg).
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Figure 7.
Effect of NAcc shell lesions on the acquisition of
responding with CR. Data points represent the mean square root ± SEM
responses on the lever producing the conditioned reinforcer
(CR) and the control lever (NCR) for
sham- and shell-lesioned animals after intra-NAcc injections of
D-amphetamine (0, 1, 3, 10, and 20 µg).
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The data were square root-transformed to maintain homogeneity of
variance. ANOVA comparing CR and NCR responses for each group across
D-amphetamine doses revealed statistical significance for all interactions, including lesion × lever × dose
(F(5,50) = 4.14; p < 0.005),
lesion × lever (F(2,19) = 11.08;
p < 0.005), lesion × dose
(F(8,76) = 3.85; p < 0.005),
and lever × dose (F(3,50) = 9.17;
p < 0.0001). All three main effects were also
statistically significant: lesion (F(2,19) = 8.41; p < 0.005), lever
(F(1,19) = 137.55; p < 0.0001),
and dose (F(4,76) = 9.85; p < 0.0001). Because of the three-way interaction, the nature of these
effects was investigated further by post hoc analysis of
simple interactions and simple main effects by studying the factors of
lever and dose separately in each experimental group.
These post hoc analyses revealed that sham-lesioned animals
made significantly more responses on the CR than the NCR lever and
indicated that these animals further showed a dose-dependent increase
in responding on the CR lever but not the NCR lever (lever × dose
interaction, F(4,76) = 15.33; p < 0.05).
The analysis of core-lesioned animals produced significant main effects
of lever (F(1,19) = 24.58; p < 0.05) and dose (F(4,19) = 3.72;
p < 0.05), revealing that the stimulant effects of
intra-NAcc D-amphetamine and the control over behavior by
CR were intact. However, core-lesioned animals did not show a
significant lever × dose interaction
(F(4,76) = 2.06; p = ns),
suggesting that the interaction of CR and its potentiation by
amphetamine was absent. There was a dose-dependent increase in
responding, but this was not selective for the CR lever.
Shell-lesioned animals were not impaired in responding with CR (main
effect of lever, F(1,19) = 21.38;
p < 0.05). However, the stimulant effects of
intra-NAcc D-amphetamine were abolished after shell lesions
(main effect of dose, F(4,19) = 0.39;
p = ns; lever × dose interaction,
F(4,76) = 0.84; p = ns).
In summary, sham-lesioned animals responded more on the CR lever at all
doses of D-amphetamine, and this response was selectively potentiated in a dose-dependent manner. Core-lesioned animals were not
significantly impaired in the acquisition of a new response with CR. Moreover, intra-NAcc infusions of D-amphetamine
produced a significant stimulation of responding. However, the stimulus control over responding on the CR and NCR levers after intra-NAcc D-amphetamine was impaired in these animals.
Shell-lesioned animals were completely unimpaired in the acquisition of
a new response with CR, but these lesions abolished the potentiative
effect of intra-NAcc D-amphetamine. Thus, the CS
successfully acted as a conditioned reinforcer for operant lever
pressing in all groups. D-amphetamine selectively
potentiated responding with CR in sham-lesioned animals only, whereas
there was less control over this behavior by the conditioned reinforcer
after NAcc core lesions and a complete abolition of the potentiative
effects of D-amphetamine in animals with NAcc shell lesions.
Discriminated approach to the magazine during CR testing
ANOVAs were used to compare the duration and frequency of magazine
entries during CR testing. Under control vehicle treatment there was a
significant main effect of lesion on duration of magazine entries
(F(2,21) = 4.31; p < 0.05)
caused by the fact that core-lesioned animals spent significantly more
time at the magazine than either sham- or shell-lesioned animals.
Statistical analysis of the effect of D-amphetamine on the
duration of magazine approaches revealed a significant lesion × dose interaction (F(8,84) = 8.15;
p < 0.0001) as the duration of approaches was reduced
in both the core- and sham-lesioned animals equivalently and
dose-dependently, whereas the shell-lesioned group showed a
dose-dependent increase in approach duration.
Analysis of the frequency of magazine entries revealed no significant
group differences after saline injections
(F(2,21) = 2.73; p = 0.09).
Comparisons of the effect of D-amphetamine on the frequency
of magazine approaches showed no significant lesion × dose
interaction (F(3,32) = 1.95; p = 0.14) or main effect of dose (F(2,32) = 0.8;
p = 0.43). The significant main effect of lesion
(F(2,21) = 5.16; p < 0.05) was
caused by a reduced frequency of approaches made by shell-lesioned
animals across doses of D-amphetamine relative to both
sham- and core-lesioned animals.
In summary, core-lesioned animals showed an increase in the duration of
magazine approach under saline treatment. Furthermore, compared with
both sham- and core-lesioned animals, animals with NAcc shell lesions
showed a general reduction in the frequency of magazine entries and a
dose-dependent increase in the duration of magazine entry after
D-amphetamine injections, perhaps reflecting an overall
reduction in locomotor activity by these animals.
Locomotor activity
Figure 8 shows the activity levels
of shell-, core-, and sham-lesioned animals during habituation sessions
and after each drug injection. ANOVA comparing locomotor scores of the
three groups across habituation sessions revealed no lesion × session interaction (F(4,93) = 0.59;
p = 0.69). Activity levels of all three groups declined
over the four habituation sessions (main effect of session,
F(2,93) = 39.03; p < 0.001),
but there was also a significant main effect of lesion
(F(2,42) = 8.97; p = 0.001).
Post hoc tests revealed that this was caused by the
increased activity of core-lesioned animals compared with both sham-
and shell-lesioned animals.
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Figure 8.
Effect of NAcc core and shell lesions on
spontaneous and D-amphetamine-induced locomotion.
Vertical bars represent the mean ± SEM photocell beam
breaks for each group during habituation sessions (Hab)
and after systemic injections of D-amphetamine
(saline, 0.5, 1.5, 5.0 mg/kg).
|
|
A one-way ANOVA comparing activity levels after saline injections
revealed a significant effect of lesion (F(2,43) = 6.81; p = 0.003), and post hoc tests
indicated that the core-lesioned group's activity was significantly
higher than that of shell- and sham-lesioned groups (which were not
different from one another). Because of this baseline difference, a
multivariate analysis of covariance was undertaken to compare activity
levels after the three systemic drug injections, using the activity
levels after saline injections as the covariates. This analysis
revealed that activity levels after injections of 0.5 and 1.5 mg/kg
D-amphetamine differed significantly from saline
(F(1,41) = 17.31; p < 0.001 and
F(1,41) = 14.20; p = 0.001, respectively), but not after the 5.0 mg/kg D-amphetamine
injection (F(1,41) = 0.62; p = 0.44). Thus, activity was significantly elevated in all groups after 0.5 and
1.5 mg/kg injections but not after 5.0 mg/kg. There was also a
lesion × drug interaction (F(2,41) = 7.11;
p = 0.002) at the 1.5 mg/kg dose. Post hoc
analysis of this interaction revealed that the activity scores of the
core-lesioned rats were significantly higher than both shell- and
sham-lesioned groups, whereas the shell-lesioned group showed
significantly lower locomotor activity scores than shams. A
repeated-measures ANOVA using the percentage change from baseline
activity levels corroborated the results from the multivariate analysis
of covariance.
Ratings of stereotypy were taken (ranging from 0 to 8; see Mittleman et
al., 1991) at 30, 60, 90, and 120 min during the final (5.0 mg/kg) test
session. For example, a score of 0 was given for inactivity (of
behavior), 2 for continuous locomotor activity, 4 for continuous
stereotypy over a wide area, and 6 for pronounced, continuous
stereotypy in a restricted area. Average stereotypy scores for each
group over the 2 hr session are shown in Table 1. Because of the nature of these data,
nonparametric tests were used to analyze stereotypy ratings. Thus, a
Kruskal-Wallis one-way ANOVA assessed group differences at each of the
four time points. There were no significant group differences at any
time point (critical value for  2 at p < 0.05 = 5.99; calculated values were 5.22 at 30 min, 0.19 at 60 min, 1.09 at 90 min, and 0.18 at 120 min). Thus, whereas all animals
demonstrated stereotypy after a systemic injection of 5.0 mg/kg
D-amphetamine, there were no differences between groups.
In summary, animals with lesions of the core were more active than
their sham-lesioned controls during a test of spontaneous locomotor
activity. Furthermore, their locomotor response to systemic D-amphetamine was significantly enhanced relative to sham
controls. Thus, lesions of the core produced an enhancement of the
locomotor potentiative effects of D-amphetamine. In
contrast, rats with lesions of the shell were less active than
sham-lesioned controls during the measurement of spontaneous locomotor
activity, and the potentiative effects of systemic
D-amphetamine were significantly attenuated in these
animals (at the 1.5 mg/kg dose).
| |
DISCUSSION |
To investigate the possibly dissociable functions of the NAcc core
and shell, we have developed excitotoxic amino acid-induced lesions
that selectively destroy these two regions and investigated their
effects on two fundamental effects of psychomotor stimulant drugs; the
potentiation of conditioned reinforcement and locomotor hyperactivity,
as well as appetitive Pavlovian behavior and the acquisition of
instrumental responding with CR. Lesions of the NAcc shell completely
abolished the potentiation of instrumental behavior with CR after
intra-NAcc infusions of D-amphetamine. Shell lesions also
produced locomotor hypoactivity and attenuated D-amphetamine-induced increases in locomotor activity. By
contrast, in core-lesioned animals, intra-NAcc
D-amphetamine infusions dose-dependently increased
responding on CR and NCR (control) levers, thus demonstrating intact
stimulant potentiation combined with a reduction of stimulus control.
Core lesions also produced locomotor hyperactivity and enhanced the locomotor-stimulating effect of systemic
Damphetamine. NAcc shell lesions affected neither
Pavlovian conditioning nor CR as assessed in the acquisition of a new
response procedure. In contrast, NAcc core lesions impaired
discriminated approach to a Pavlovian-conditioned stimulus but did not
affect the acquisition of a new instrumental response with CR.
These findings indicate basic interactions between the
dopamine-dependent effect of stimulants such as amphetamine and
associative information that we have shown to be dependent on limbic
afferents to the NAcc (Cador et al., 1989). They also indicate that
different aspects of the learned control over appetitive behaviors are
mediated by distinct regions within the NAcc, as revealed here by
demonstrating a double dissociation between the effects of lesions of
the NAcc shell and core on responses to amphetamine and associative
learning mechanisms.
Effects of NAcc shell and core lesions on responses
to amphetamine
NAcc shell lesions completely abolished the potentiative effects
of intra-NAcc D-amphetamine on the control over behavior by
a conditioned reinforcer. Shell lesions also resulted in hypoactivity during the habituation sessions to locomotor activity cages and attenuated the stimulant effect of systemic D-amphetamine.
These results suggest that a major property of stimulant drugs to
potentiate both the impact of motivationally relevant environmental
cues on instrumental behavior and locomotor activity rely critically on
the integrity of the NAcc shell.
These findings are consistent with reports of changes in DA
transmission selectively within the NAcc shell (relative to the NAcc
core or the dorsal striatum), in response to intravenous infusions of
several drugs of abuse (Pontieri et al., 1995, 1996; Carlezon and Wise,
1996; Tanda et al., 1997) and selective increases in energy metabolism
as measured by 2-deoxyglucose autoradiography in the NAcc shell
produced by such drugs (Pontieri et al., 1994; Orzi et al., 1996).
Highly palatable, preferred foods also increase DA selectively in the
NAcc shell (Tanda et al., 1994) as do Pavlovian CSs paired with food
(Phillips et al., 1993; Wilson et al., 1995). Such observations
(Robbins and Everitt, 1992) have led authors to suggest a role for NAcc
DA in incentive motivation (Phillips and Fibiger, 1987) and reward
(Wise and Bozarth, 1987) and more specifically, a role for DA in the
shell in the attribution of incentive properties to CSs (DiChiara,
1998), with drugs of abuse usurping this process, thereby producing
abnormal "incentive learning". Although the NAcc shell is clearly
implicated in aspects of responding to both drug-related and natural
reinforcers, the present findings of intact Pavlovian and instrumental
conditioning in NAcc shell-lesioned animals suggest that, rather than
an associative or incentive motivational role, a key function of the
dopaminergic innervation of the NAcc shell is to potentiate ongoing
instrumental responding in the presence of motivationally significant stimuli.
Lesions of the central nucleus of the amygdala (CeA) also block the
potentiative effects of intra-NAcc D-amphetamine on
responding with CR (Burns et al., 1993; Robledo et al., 1996). Although
the CeA does not project directly to the NAcc, it may influence
striatal DA function via its projections to midbrain DA neurons (Simon et al., 1979; Wallace et al., 1992; Han et al., 1997). Alternatively, the NAcc shell and CeA may be functionally related as part of the
continuum known as the extended amygdala (Heimer et al., 1991; Alheid
et al., 1995). Dopamine-depleting lesions of the amygdala (Simon et
al., 1988), as well as infusions of D1 receptor antagonists (Hurd et al., 1997) both profoundly alter dopamine concentration or
release in the NAcc, indicating the tight functional relationship between these components of the extended amygdala.
Lesions of the ventral subiculum block the potentiative effects of
D-amphetamine on locomotor activity and abolish the effects of intra-NAcc D-amphetamine without affecting the impact of
the CR on instrumental performance (Burns et al., 1993), much like the
shell lesions in the present study. This similarity in the functional
effects of NAcc shell and ventral subiculum lesions is significant in
the context of the strong preferential glutamatergic projection from
the ventral subiculum to that part of the NAcc shell (septal pole) that
was lesioned here (Fig. 2). Thus, information reaching the NAcc
concerned with the nature and direction of behavior, which depends on
the integrity of the basolateral amygdala (BLA) (Cador et al.,
1989; Burns et al., 1993), presumably via its projections to both the
NAcc core and shell (Groenewegen et al., 1987) may be
"gain-amplified" by dopamine transmission in the shell in a way
that is critically dependent on the integrity of its glutamatergic inputs arising from the ventral subiculum (Burns et al., 1993; Blaha et
al., 1997; Brudzynski and Gibson, 1997).
Although NAcc core lesions did not affect the acquisition of responding
with CR under control (saline) conditions, the interaction between
intra-NAcc D-amphetamine and responding with CR appears to
depend on the integrity of the NAcc core. It is of interest, therefore,
that animals with lesions of the BLA show similar, although greater,
impairments in the same task, including a loss of control over
responding for the CR under control conditions (Cador et al., 1989;
Burns et al., 1993). Similarities in the effects of NAcc and BLA
manipulations have been reported previously (Everitt et al., 1989,
1991; Everitt and Robbins, 1992) and have led us to suggest that the
integrity of the BLA is critical for stimulus-reward information to
gain influence over voluntary behavior (Everitt et al., 1991; Burns et
al., 1993; Robbins and Everitt, 1996). Thus, limbic corticostriatal
circuits involving the BLA and NAcc core may be essential for the
influence of associative stimulus-reward information on goal-directed
action. The effects of NAcc shell lesions to abolish the potentiative
effects of intra-NAcc D-amphetamine, whereas NAcc
core lesions disrupt discriminative control after intra-NAcc
infusions of Damphetamine are reminiscent of models of
striatal function based on separate striatal zones being responsible
for behavioral "choice" and "vigour" (Kelly and Moore, 1976;
Robbins and Everitt, 1982; Koshikawa et al., 1996). Such models can now
be refined both behaviorally and neuroanatomically on the basis of the
functional dissociations revealed in the present and related studies
(Balleine and Killcross, 1994; Kelley et al., 1997) and the neuronal
interactions known to occur in shell and core compartments of the
striatum determined by the pattern of termination of discrete limbic
cortical afferents (Pennartz et al., 1994).
NAcc core lesions also resulted in increased spontaneous
locomotor activity and an enhanced response to systemic
Damphetamine. This may reflect motoric response
disinhibition after core lesions resulting from reductions in
inhibitory striatal GABAergic outflow to several striatal output target
structures directly concerned with the control of locomotor activity
(Alexander and Crutcher, 1990) that are also further susceptible to the
effects of DA release within remaining parts (shell) of the NAcc.
Similar mechanisms may underlie the significant increase in responding
on the NCR control lever during the conditioned reinforcement procedure.
Effects of NAcc shell and core lesions on associative
learning mechanisms
Animals with lesions of the NAcc shell were not impaired
in Pavlovian conditioning as assessed by their discriminated approach to a Pavlovian CS+, or in the acquisition of responding with CR. Intra-NAcc infusions of D-amphetamine also dose-dependently
increased magazine approach duration, relative to NAcc core- and
sham-operated groups, supporting further the selective effects of
D-amphetamine in the NAcc core on the mechanisms subserving
discriminated approach. Thus, the NAcc shell does not appear to be
significantly involved in associative learning mechanisms assessed in
this study. Lesions of the NAcc core, by contrast, retarded the
expression of the CS-US association such that animals in this group
showed a decrease in levels of discriminated approach relative to
prelesion performance. It may seem paradoxical that core-lesioned
animals who showed a deficit in discriminated approach subsequently
acquired responding with CR. However, Kelley et al. (1997) reported
similar effects with blockade of NMDA receptors in the NAcc.
Furthermore, we have demonstrated previously that disruptions in the
formation of a CS-US association do not necessarily produce deficits
in the acquisition of a new response for the Pavlovian-paired stimulus
(Olmstead et al., 1998) and vice versa (Burns et al., 1993). Our
results confirm, therefore, that the neural mechanisms through which
conditioned reinforcers control instrumental behavior are dissociable
neurally from processes that mediate the expression of a CS-US
relationship through Pavlovian approach behavior (Cador et al., 1989;
Burns et al., 1993).
Implications for the functions of the nucleus accumbens
There are two major findings in this study: (1) the NAcc shell
mediates both the potentiation by D-amphetamine of the
control over instrumental responding by conditioned reinforcers and of locomotor activity; (2) the NAcc core is involved in the conditioned preparatory aspects of Pavlovian associative learning and may also
modulate the associative control over instrumental responding after
intra-NAcc D-amphetamine. These results, therefore,
indicate that there is functional specificity within the NAcc and its
associated circuitries. The potentiative effects on behavior of
D-amphetamine are critically dependent on the NAcc shell,
whereas the expression or potentiation of Pavlovian conditioned
responses generated by the presentation of incentive stimuli (Rescorla
and Solomon, 1967; Dickinson and Balleine, 1994) depends on the
integrity of the NAcc core. Furthermore, control over goal-directed
actions and incentive motivation per se may depend on functional
interactions between limbic cortical structures, including
the BLA, cingulate, and prefrontal cortex, which may
interface with different striatal zones (Cador et al., 1989;
McAlonan et al., 1993; Bussey et al., 1997; Floresco et al.,
1997). Thus, different limbic corticostriatal afferents passing through
the NAcc within ventral striatopallidal circuits may be involved in
qualitatively different functional processes but may undergo similar
modulation at the level of the NAcc.
| |
FOOTNOTES |
Received Sept. 16, 1998; revised Jan. 7, 1998; accepted Jan. 10, 1999.
This work was supported by a Medical Research Council Programme Grant
(G9537855) to B.J.E., T.W.R., and A. Dickinson. J.A.P. was supported by
a Biotechnology and Biological Sciences Research Council research
studentship and an Oon Khye Beng Ch'hia Tsio Scholarship.
Correspondence should be addressed to Barry J. Everitt, Department of
Experimental Psychology, University of Cambridge, Downing Street,
Cambridge, UK CB2 3EB.
| |
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Top
Abstract
Introduction
