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proposed to underlie learning and memory (12), and changes in
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do2). These findings support the proposal that sensitization of
appetitive effects of AMPH and other psychostimulants
motes the pursuit and self-administration of these drugs and
y underlie the transition from casual drug use to compulsive
g taking and abuse (2,3).
A number of long-lasting neuroadaptations have been iden-
ed that provide neural correlates for the expression of these
sitized behaviors. A drug challenge administered weeks to
nths after psychostimulant exposure induces enhanced dopa-
ne (DA) and glutamate overflow in the nucleus accumbens
Acc) (2,4,5). Notably, terminals releasing these transmitters
m synaptic contacts on the same dendritic spines of medium
ny neurons in the NAcc (6), and these spines have been
orted to undergo long-lasting increases in density, an effect
spine morphology and density in particular have been linked to
the formation of learned associations (13,14). The induction of
drug-induced sensitization necessarily involves exposure to the
drug in association with a complex of environmental stimuli,
conditions that favor the formation of associations between the
drug and these stimuli when the drug is administered systemi-
cally (15). Thus, it is possible that the increases in spine density,
dendritic length, and dendritic branching observed in the NAcc
following systemic exposure to psychostimulants may reflect
associative drug conditioning rather than nonassociative drug
sensitization (15). Indeed, we show here that exposure to
amphetamine in the ventral tegmental area (VTA), a procedure
that sensitizes drug-induced locomotion and NAcc DA overflow
but does not produce drug conditioning (16–18), fails to increase
spine density, dendritic length, or dendritic branching in the
NAcc.
Methods and Materials
Subjects
Male Sprague-Dawley rats (Harlan Sprague-Dawley, Madison,
Wisconsin) weighing 250–300 g on arrival were individually
housed with food and water freely available in a reverse cycle
room (12-hour light–12-hour dark). Animals were allowed to
acclimate to these conditions for 3–4 days before the start of any
procedures. All testing was conducted during the dark period of
m the Committee on Neurobiology (BFS, PV) and Department of Psychi-
atry and Behavioral Neuroscience (CJ-M, PV), The University of Chicago,
Chicago, Illinois; Department of Pharmacology (LMT), Columbia Univer-
sity, New York, New York; Department of Neuroscience (GG, YL, BK),
University of Lethbridge, Lethbridge, Canada.
dress reprint requests toPaulVezina, Ph.D.,Departmentof Psychiatry and
Behavioral Neuroscience, The University of Chicago, 5841 S. Maryland
Avenue, MC 3077, Chicago, IL 60637; E-mail: pvezina@yoda.bsd.uchicago.
edu.
eivedNovember 25, 2008; revisedDecember 18, 2008; acceptedDecem-
ber 19, 2008.
BIOL PSYCHIATRY 2009;65:835–8406-3223/09/$36.00
i:10.1016/j.biopsych.2008.12.020 © 2009 Society of Biological Psychiatrymphetamine-Induced Cha
orphology in Rat Forebrai
ssociative Drug Conditioni
onassociative Drug Sensiti
yan F. Singer, Lauren M. Tanabe, Grazyna Gorny, C
yan Kolb, and Paul Vezina
ckground: Systemic exposure to amphetamine (AMPH) leads to
ndritic morphology in rat forebrain. It remains unknown whether t
tive drug sensitization, two forms of plasticity produced by system
thods: We compared the behavioral, neuronal, and morphologic
exposure to AMPH applied to the ventral tegmental area (VTA
umbens (NAcc) DA overflow but do not produce drug conditionin
sults: Both IP and VTAAMPH exposure sensitized locomotion and
omotion. Importantly, whereas IP AMPH exposure increased spine
A AMPH produced the opposite effects. A similar differentiation of
nclusions: Together these findings suggest that the morphologic
ditioning rather than nonassociative drug sensitization. The decre
bility of these infusions to support conditioning.
y Words: Conditioning, dendritic spines, dopamine release, lo-
otion, nucleus accumbens, sensitization
xposure to amphetamine (AMPH) leads to long-lasting
sensitization of its psychomotor stimulant effects so that
reexposure to the drug weeks to months later produces
hanced locomotor responding as well as enhanced workes in Dendritic
orrespond to
Rather than
tion
maine Jake-Matthews, Yilin Li,
umber of long-lasting neuroadaptations including changes in
changes relate to associative drug conditioning or to nonasso-
posure to AMPH.
equences of exposing rats to intraperitoneal (IP) AMPH to those
usions that sensitize AMPH-induced locomotion and nucleus
DA overflow, but only IP AMPH exposure produced conditioned
ity and dendritic length and branching in the NAcc, exposure to
ts was observed in cortical areas.
anges seen following IP AMPH exposure reflect associative drug
observed in the NAcc of VTA AMPH exposed rats may reflect the
ompanied by increases in dendritic branching and length
9).
Although a number of findings support a critical role for the
hanced release of DA and glutamate in the NAcc in the
pression of behavioral sensitization by psychostimulants
2,4,5,10), the contribution to sensitization of changes in den-
tic morphology remains unclear and was recently brought into
estion (11). Interestingly, structural changes have long been

the light cycle. Female Sprague-Dawley rats were also used in
some of the dendritic morphology experiments because the
sam
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836 BIOL PSYCHIATRY 2009;65:835–840 B.F. Singer et al.
wwe effects have been reported in males and females (7,8).
In all experiments, rats were tested following exposure to
PH or saline (SAL) administered either intraperitoneally (IP)
into the VTA using AMPH regimens known to produce
omotor and DA sensitization. Thus, approximately half of all
s were surgically prepared with chronic bilateral guide cannu-
aimed at the VTA (Supplement 1). Rats in different groups
re subsequently tested in different experiments to assess the
ility of exposure to IP or VTA AMPH to produce locomotor
sitization, sensitization of in vitro DA release, conditioned
omotion, and changes in dendritic morphology in forebrain
s.
comotor Sensitization
Rats in four groups were exposed to AMPH or SAL either IP or
o the VTA. For systemic AMPH (3.0 mg/kg, IP; n
6) or SAL
0 mL/kg, IP; n
6), five injections were administered. For
A AMPH (2.5 g/.5 L/side; n
7) or SAL (.5 L/side; n
6),
ee bilateral microinjections were made. In both cases, injec-
ns were made every third day. Testing was conducted 2–3
eks following the last exposure injection. In the test, rats were
ced in locomotor chambers (Supplement 1) and allowed to
bituate for 1 hour. All rats were then administered AMPH (1.0
/kg, IP) and their locomotor response measured for 2 hours.
all cases, AMPH (S()-amphetamine sulfate; Sigma, St. Louis,
ssouri) was dissolved in sterile saline. All doses refer to the
ight of the salt.
nsitization of In Vitro DA Release
Rats in four groups were exposed to AMPH or SAL either IP or
o the VTA using the exposure regimens described for loco-
tor sensitization. Testing was conducted 2–3 weeks following
last exposure injection. On the test day, rats were sacrificed
decapitation, their brains were quickly removed, and a
m-thick coronal section containing the NAcc and striatum
s obtained using an ice-cold brain matrix. The NAcc and
atum was dissected from each side (Figure 1G), and sections
re prepared for in vitro release (Supplement 1).
nditioned Locomotion
For both IP and VTA injection routes, rats in three groups
re administered AMPH (1.0 mg/kg IP or 2.5g/.5 L/side in
VTA) or SAL. Rats in one group (Paired) received AMPH in
locomotor activity boxes and, the following day, SAL in their
me cage. Rats in a second group (Unpaired) received SAL in
activity boxes and AMPH in their home cage. Rats in the third
up (Control) received saline in both environments. All ani-
ls were left undisturbed on the third day. This procedure was
eated four times for VTA and five times for IP exposure.
sting for conditioned locomotion was conducted 2–3 weeks
r. On this test, all rats were administered an IP saline injection
d then immediately placed in an activity box where their
omotor response was measured for 1 hour. For VTA expo-
e, n per group was Paired
7, Unpaired
8, and Control

For IP exposure, n per group
8.
ndritic Morphology
Rats in four groups were exposed to AMPH or SAL either IP or
o the VTA. For systemic AMPH (1.0 mg/kg IP; n
9) or SAL

8), seven injections were administered, 1 injection daily. For
A AMPH (2.5 g/.5L/side; n
6) or SAL (.5 L/side; n
5),
ee bilateral microinjections were made, one injection everyw.sobp.org/journalrd day. Rat brains were prepared for Golgi-Cox staining 2–3
eks following the last exposure injection (Supplement 1).
rphologic analyses focused on medium spiny neurons in the
cc. For comparison, neurons in the striatum and three cortical
ions were also analyzed: layer 5 pyramidal neurons in the
frontal cortex (Cg3), layer 3 pyramidal neurons of the parietal
rtex (Par1), and cells in the agranular insular dorsal aspect of
orbital cortex (AID). Dendritic morphology is altered in each
ure 1. Ventral tegmental area (VTA) and intraperitoneal (IP) amphet-
ine (AMPH) similarly enhance AMPH-evoked locomotion and dopamine
) release from forebrain slice. Previous exposure to VTAAMPHenhanced
PH-evoked locomotion (A) and DA release from nucleus accumbens
cc) (B) but not striatal (C) slice. Previous exposure to IP AMPH enhanced
PH-induced locomotion (D) and DA release in both sites (E and F).
ponding to AMPH was tested 2–3 weeks following exposure. Data are
wn as mean ( SEM) 2-hour total locomotor counts and percent of total
released by AMPH. (G) illustration of the NAcc and striatal regions dis-
ted bilaterally in the release experiments. Line drawing depicts the cau-
surface of a coronal hemisection extending 1.2–2.2 mm from the
gma. This figurewaspublished inTheRat Brain in Stereotaxic Coordinates,
pact 3rd ed., Paxinos G and Watson C, Copyright Elsevier, 1997 (37).
mbers at the base of each bar indicate rats per group. ** p .01, ***, p
1, significantly greater than the saline (SAL) exposure condition.

of these regions by systemic AMPH exposure (7–9,19–21). Cells
were selected and drawn using a camera lucida by an individual
bli
mo
(7,
(Su
His
im
bra
pla
ally
an
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for
an
(AN
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a s
1A
Se
com
in
exposure to either VTA [t (13)
3.26, p .01] or IP [t (16)
3.42,
p  .01] AMPH (Figure 1B and 1E). AMPH-evoked DA release
(Fi
[F (
an
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sig
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in t piny n
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B.F. Singer et al. BIOL PSYCHIATRY 2009;65:835–840 837nd to treatment conditions. Three measures of dendritic
rphology were obtained using methods described previously
9,22): spine density, dendritic length, and dendritic branching
pplement 1).
tology
After completion of the experiments, rats with chronically
planted guide cannulae were deeply anesthetized, and their
ins were processed for staining and verification of cannula tip
cements. Only rats with injection cannula tips located bilater-
in the VTA were listed earlier and included in the data
alyses (Supplement 1).
ta Analyses
Total test values obtained on the tests for locomotor sensiti-
ion and in vitro DA release were analyzed by one-tailed t tests
independent samples. The conditioned locomotion data were
alyzed with one-between/one-within analysis of variance
OVA) with groups as the between factor and time as the
thin factor. Post hoc Scheffé comparisons were made accord-
to Kirk (23). Dendritic morphology results were analyzed
ng one-way ANOVA (24).
sults
comotor Sensitization
As expected, compared with SAL-exposed controls, previous
osure to either VTA [t (11)
3.75; p .01] or IP [t (10)
4.52;
.001] AMPH significantly enhanced locomotor responding to
ystemic AMPH challenge administered 2–3 weeks later (Figure
and 1D).
nsitization of In Vitro DA Release
In a manner paralleling the locomotor sensitization findings,
pared with SAL exposed controls, AMPH-evoked DA release
the NAcc was significantly increased 2–3 weeks following
ure 2. Ventral tegmental area (VTA) and intraperitoneal (IP) amphetamine
rphology in the nucleus accumbens (NAcc). VTA AMPH failed to produce co
dritic branching in the NAcc (B–E). IP AMPHproduced conditioned locomo
he NAcc (G–J). The camera lucida drawings are of representative medium s
ditioned locomotor responding to SAL and dendritic morphology were
mbers at the base of each bar indicate hemispheres per group. *p  .05,
omotor conditioning test and the SAL exposure condition for dendritic mos also significantly increased in the striatum following expo-
e to IP [t (17)
3.59, p  .01] but not VTA AMPH [t (12)
.89,
(Figure 1C and 1F). The lack of effect in striatum following
A AMPH exposure is consistent with the fact that this forebrain
ion is not an A10 DA neuron projection field and supports the
egrity and anatomic specificity of the VTA microinjections
de.
Together with the locomotor sensitization results, these find-
s confirm and extend earlier reports showing that exposure to
PH enhances its ability to produce locomotion and to release
from DA terminals in forebrain (18,25,26). They also show
t these effects are produced by either the IP or VTA route of
PH exposure.
nditioned Locomotion
It is well known that pairing systemically administered AMPH
th a distinct environment will lead to the development of an
ociation between that environment and the drug (15). Thus,
ired rats that received IP AMPH in the activity boxes 2–3 weeks
rlier showed a conditioned locomotor response to IP saline in
drug-paired environment compared with Unpaired rats that
eived the same exposure to AMPH but unpaired with the
ivity boxes or Controls not previously exposed to the drug
gure 2F). The ANOVA detected significant effects of group
2,21)
9.21, p  .01] and time [F (5,105)
72.38, p  .001]
d a significant group time interaction [F (10,105)
2.25, p 
]. Post hoc Scheffé tests revealed that Paired rats displayed
nificantly enhanced locomotion compared with the other two
ups over much of the testing period (p  .05–.001). The latter
o groups did not differ significantly from one another.
In contrast to these findings, Paired rats that received VTA-
PH in the activity boxes showed no evidence of conditioned
omotion 2–3 weeks later (Figure 2A). The ANOVA revealed
ly a significant effect of time. These findings are consistent
th previous reports (15–17) showing that exposure to either IP
PH) produce different effects on conditioned locomotion and dendritic
oned locomotion (A) and decreased spine density, dendritic length, and
F) and increased spine density, dendritic length, and dendritic branching
eurons from rats exposed to saline (SAL) or AMPH in the VTA (E) or IP (J).
ed 2–3 weeks following exposure. Data are shown as means ( SEM).
0.01, ***p  .001, significantly different from two other groups for the
ogy.wa
sur
ns]
VT
reg
int
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or
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ter
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the
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838 BIOL PSYCHIATRY 2009;65:835–840 B.F. Singer et al.
wwVTA AMPH produces sensitization, but that unlike with IP
PH, rats exposed to VTA AMPH do not form associations
king the drug and the environment in which it was adminis-
ed.
ndritic Morphology
Experiments were then conducted to determine what changes
dendritic morphology were associated with exposure to IP or
A AMPH 2–3 weeks earlier. Consistent with previous reports
9), exposure to IP AMPH produced significant changes in
NAcc, increasing spine density [F (1,22)
7.2, p  .01],
ndritic length [F (1,31)
4.83, p  .05], and dendritic
nching [F (1,31)
12.97, p  .01] relative to SAL controls
gure 2G–2I). In contrast, exposure to VTA AMPH produced
nificant but opposite effects: decreased spine density
1,18)
31.82, p  .001], dendritic length [F (1,20)
34.48,
.001], and dendritic branching [F (1,20)
20.35, p  .001]
ative to controls (Figure 2B–2D). The differential change in
ne density produced by the two routes of AMPH exposure is
strated in the camera lucida drawings in Figure 2E and 2J. The
ls illustrated and described earlier were selected from the
cc shell. Additional analyses of cells in the NAcc core revealed
ntical effects for all measures (Supplement 1).
Exposure to IP AMPH produces long-lasting increases in
ne density in striatum as well (19). Consistent with the lack of
ect on DA release observed in the striatum (Figure 1C),
osure to VTA AMPH did not significantly alter spine density
this site (Supplement 1), again supporting the integrity and
atomic specificity of the VTA microinjections.
In cortical regions, a similar differentiation between the
g-lasting effects of IP and VTA AMPH exposure was observed
r statistical analyses of all cortical effects, see Supplement 1).
prefrontal cortex, exposure to systemic AMPH produces
ure3.Dendriticmorphologywas altered in cortex 2–3weeks followingexpo
cts observed in the prefrontal (A) and orbital (B) cortices and that both are
era lucida drawings are of representative pyramidal cells from rats expo
mbers at the base of each bar indicate hemispheres per group. *p .05, **
cal dendrites; B, basilar dendrites.w.sobp.org/journalreases in spine density, dendritic length, and dendritic branch-
. These effects are restricted to apical dendrites (7–9). Expo-
e to VTA AMPH 2–3 weeks earlier produced significant but
posite effects: decreased spine density, dendritic length, and
ndritic branching relative to controls (Figure 3A). In addition,
se effects were statistically significant in both basilar and
ical dendrites. In orbital cortex, decreases in spine density in
th apical and basilar dendrites are observed following systemic
PH (20) (effects on dendritic length and branches have not
t been reported). Again, exposure to VTA AMPH produced the
posite effect: significant increases in spine density in both
ects of these neurons relative to controls (Figure 3B). Basilar,
t not apical, dendrites also showed a significant increase in
nching and a trend for increased length in this region. In
rietal cortex, exposure to systemic AMPH decreases spine
nsity in apical and basilar dendrites with no effects observed in
ndritic length and branching (7,9,21). Unlike with the prefron-
and orbital cortex, exposure to VTA AMPH produced the
e effects in spine density in this region as did exposure to
temic AMPH. Basilar, but not apical, dendrites also showed a
nificant decrease in branching and a trend for decreased
gth in this region (Supplement 1).
scussion
A number of reports have proposed a link between the
pression of psychostimulant sensitization and increased spine
nsity, dendritic length, and dendritic branching in the NAcc.
ese findings suggest that such a link may not be justified.
posure to VTA AMPH, which like IP AMPH led to sensitized
omotor activity and DA release in the NAcc, failed to increase
d in fact significantly decreased all three measures of dendritic
rphology in this site. This finding indicates that psychostimu-
to ventral tegmental area (VTA) amphetamine (AMPH). Note thedifferent
site to those reported following intraperitoneal (IP) AMPH (see text). The
o saline (SAL) or AMPH in the VTA. Data are shown as means ( SEM).
1, ***p .001, significantly greater than the SAL exposure condition. A,the
ap
bo
AM
ye
op
asp
bu
bra
pa
de
de
tal
sam
sys
sig
len
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ex
de
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lant sensitization can in fact be expressed even when spine
density, dendritic length, and dendritic branching are reduced in
the
bu
tha
fol
the
no
tem
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ass
int
an
VT
inc
tat
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de
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stu
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ele
de
acc
(30
con
ass
exp
exp
sim
tha
tio
spi
con
me
the
are
Be
pa
change is related to conditioning. However, different effects
following systemic and VTA AMPH were observed in the pre-
fro
the
to
pa
un
the
(in
de
of
tio
pro
to
dru
og
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to
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ini
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an
10
po
on
1.
2.
3.
4.
B.F. Singer et al. BIOL PSYCHIATRY 2009;65:835–840 839NAcc. The additional finding that rats exposed to IP AMPH,
t not VTA AMPH, exhibited conditioned locomotion suggests
t the increases in dendritic morphology observed in the NAcc
lowing systemic exposure to psychostimulants may support
expression of associative drug conditioning rather than
nassociative drug sensitization.
The ubiquity of environmental stimuli surrounding the sys-
ic administration of drugs ensures the formation of associa-
ns between the drug and any number of these stimuli. These
ociations are likely mediated at least in part by DA–glutamate
eractions in VTA innervated forebrain areas such as the NAcc
d the prefrontal and orbital cortices (27). Because the effects of
A AMPH are restricted to the midbrain, where it locally
reases extracellular levels of DA and initiates the neuroadap-
ions that underlie sensitization, it does not acutely stimulate
omotion or increase NAcc DA overflow (28,29) and likely for
se reasons does not produce conditioned effects. Thus, the
rease in spine density, dendritic length, and branching ob-
ved in the NAcc following exposure to IP AMPH may reflect
formation of new drug–stimulus associations, whereas the
crease observed following exposure to VTA AMPH may reflect
inability of these infusions to support conditioning. The idea
t changes in dendritic morphology may underlie learning and
mory is not new (12), and recently, changes in spine mor-
ology and density in hippocampus have been linked to the
mation of learned associations (13,14). Our results suggest
t this kind of structural plasticity may be linked to associative
ditioning in the NAcc as well. Of course, how specific
rphologic changes are produced and how they might affect
generation of drug- and drug-cue-induced behaviors remains
be determined (see later discussion).
The convergence of DA and glutamate inputs onto the
ndritic spines of medium spiny neurons in the NAcc (6)
ports a role for these neurotransmitters in the formation of
g–sensory stimulus associations in this site. Indeed, the
reases in spine density and dendritic branching observed after
osure to AMPH are confined to the distal dendrites of
dium spiny neurons, the primary locus of DA and glutamate
uts to these cells (7–9). It is difficult, without ultrastructural
dies, to establish with certainty whether the increased spine
nsity observed following psychostimulant exposure is neces-
ily accompanied by an increase in synaptic contacts, although
ctron microscopic analyses have shown that the increase in
ndritic surface produced by various learning experiences is
ompanied by increases in the number of synapses per neuron
). Thus, it is conceivable that an increased number of synaptic
tacts in the NAcc mediates information about conditioned
ociations and that this information is used to direct the
ression of sensitization (27,31). Interestingly, exposure to
erimenter- or self-administered psychostimulants leads to
ilar increases in spine density in the NAcc (7,24), suggesting
t this structural change is not related to instrumental condi-
ning. However, in light of the possibility that the increase in
ne density observed in both conditions reflects classically
ditioned associations, it is difficult to conceive that this
asure of dendritic morphology could distinguish between
se two forms of conditioning.
Changes in dendritic morphology are also observed in cortical
as following exposure to either systemic or VTA AMPH.
cause a similar decrease in spine density was observed in
rietal cortex following IP and VTA AMPH, it is unlikely that thisntal and orbital cortices, suggesting that structural changes in
se sites following exposure to systemic AMPH may contribute
conditioned effects. Both of these sites are known to partici-
te in various forms of conditioning (27). Although it remains
known why different changes are observed in spine density in
prefrontal and orbital cortices following exposure to AMPH
crease and decrease, respectively, following systemic AMPH;
crease and increase, respectively, following VTA AMPH), both
these regions constitute primary midbrain DA cortical projec-
n fields; they are well positioned to influence information
cessing in subcortical areas such as the NAcc and, as a result,
affect the generation of appetitive behaviors directed at
g-conditioned stimuli (4,27). Changes in dendritic morphol-
y in these sites may thus lead to the deficits in reversal learning
d reinforcer devaluation, as well as the loss of executive
ntrol of behavior observed following psychostimulant expo-
e (20). Interestingly, exposure to IP AMPH has been reported
inhibit neuronal activity in the prefrontal cortex and excite
ivity in the orbital cortex (32). It is possible that these effects
lect compensatory attempts in these sites to regain executive
ntrol over behavior.
The release by psychostimulants of DA and glutamate onto
processes of medium spiny neurons in the NAcc and
ramidal cells in cortical regions activates extracellular signal-
ulated kinase (ERK), and this kinase is required for the
mation of associations between drugs and environmental
uli (33,34). ERK activity is also essential to the ability of
in-derived neurotrophic factor to increase dendritic spine
nsity and support the formation of long-term memories
,36). Thus, systemically administered psychostimulants may
tiate morphologic changes necessary in forebrain sites to
diate conditioned associations through the coincident activa-
n of neighboring DA and glutamate receptors. VTA AMPH
posure may be unable to produce these effects because it lacks
least one of the necessary components (DA release in fore-
in). Recently, a role for the myocyte enhancer factor 2 (MEF2)
ily of transcription factors was also proposed (11). Psycho-
ulant suppression of MEF2 in the NAcc is required to
rease spine density in this site. Interestingly, this effect is
diated in part through a D1 DA receptor initiated pathway.
This work was supported by grants from the National Insti-
es of Health (Grant No. DA09397 to PV; T32 DA07255 to BFS)
d the Canadian Institutes for Health Research (Grant No.
8712 to BK).
The authors reported no biomedical financial interests or
tential conflicts of interest.
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