Available via license: CC BY-NC-SA 4.0
Content may be subject to copyright.
Behavioral/Systems/Cognitive
Cocaine Experience Controls Bidirectional Synaptic
Plasticity in the Nucleus Accumbens
Saı¨d Kourrich,
1
Patrick E. Rothwell,
1,2
Jason R. Klug,
1
and Mark J. Thomas
1,2
1
Departments of Neuroscience and Psychology and Institute of Human Genetics, and
2
Graduate Program in Neuroscience, University of Minnesota,
Minneapolis, Minnesota 55455
Plasticity of glutamatergic synapses is a fundamental mechanism through which experience changes neural function to impact future
behavior. In animal models of addiction, glutamatergic signaling in the nucleus accumbens (NAc) exerts powerful control over drug-
seeking behavior. However, little is known about whether, how or when experience with drugs may trigger synaptic plasticity in this key
nucleus. Using whole-cell synaptic physiology in NAc brain slices, we demonstrate that a progression of bidirectional changes in gluta-
matergic synaptic strength occurs after repeated in vivo exposure to cocaine. During a protracted drug-free period, NAc neurons from
cocaine-experienced mice develop a robust potentiation of AMPAR-mediated synaptic transmission. However, a single re-exposure to
cocaine during extended withdrawal becomes a potent stimulus for synaptic depression, abruptly reversing the initial potentiation. These
enduring modifications in AMPAR-mediated responses and plasticity may provide a neural substrate for disrupted processing of drug-
related stimuli in drug-experienced individuals.
Key words: AMPAR; NMDAR; metaplasticity; synaptic scaling; long-term depression; psychostimulant; addiction
Introduction
Neural circuits are thought to encode information via synaptic
plasticity, a persistent upregulation or downregulation in the ef-
ficacy of excitatory synaptic transmission. Previous evidence sug-
gests that synaptic plasticity in reward circuits is hijacked by ad-
dictive drugs to produce the pathological behaviors that
characterize addiction (Hyman et al., 2006). The neural circuit
that mediates these behaviors includes the nucleus accumbens
(NAc). Excitatory synaptic transmission in NAc appears to be
particularly important, as manipulation of NAc glutamatergic
signaling controls drug-seeking behavior in animal models of
addiction (Kalivas, 2004; Self et al., 2004). Medium-spiny projec-
tion neurons (MSNs), the principal cells of the NAc, contain
abundant glutamatergic synapses and are known targets of long-
lasting molecular and cellular adaptations to addictive drugs
(Nestler, 2001). However, the hypothesis that in vivo drug expe-
rience triggers persistent changes in excitatory synaptic function
in NAc has not been thoroughly examined.
Previous studies indicate that repeated in vivo cocaine can
reduce AMPAR EPSCs in MSNs in the NAc shell (Thomas et al.,
2001). Thus, cocaine treatment has the capacity to engage endog-
enous synaptic plasticity mechanisms in NAc. This synaptic de-
pression appears to play an important role in behavioral changes
caused by drugs, as a peptide that disrupts AMPAR endocytosis
interferes with behavioral sensitization to amphetamine (Breb-
ner et al., 2005). However, repeated in vivo psychostimulant ex-
posure increases the number of dendritic spines on NAc MSNs
(Robinson and Kolb, 2004), cell surface expression of AMPARs
in NAc (Boudreau and Wolf, 2005), and the behavioral response
to AMPA infusion into NAc (Pierce et al., 1996; Cornish and
Kalivas, 2000; Suto et al., 2004). These results suggest psycho-
stimulants may potentiate glutamatergic synapses in NAc MSNs.
How can we reconcile data supporting a potentiation with
data supporting a depression? In general, studies consistent with
NAc synaptic depression include a “challenge” injection of psy-
chostimulant after a drug-free period to measure the persistence
of drug-induced behavioral adaptations, whereas those consis-
tent with synaptic potentiation do not. We hypothesize that an
animal’s recent history of drug experience alters the direction of
plasticity at NAc excitatory synapses. Drug re-exposure during
abstinence can induce relapse to drug-seeking in human addicts
and animal models (Shaham et al., 2003). Thus, examination of
this factor may not only unite some seemingly disparate experi-
mental findings, but perhaps help us to understand the brain’s
response to relapse-inducing stimuli. To investigate this issue, we
made whole-cell recordings in acute NAc brain slices from
cocaine-treated mice. Based on the fact that NAc shell is an im-
portant locus of persistent cocaine-induced adaptations (Self et
al., 2004) and on electrophysiological results from a previous
study (Thomas et al., 2001), we performed all recordings in NAc
shell neurons. We report two major findings. First, repeated co-
caine exposure followed by an extended drug-free period (with-
drawal) triggers a persistent potentiation of NAc excitatory syn-
apses. Second, during extended withdrawal, an additional
cocaine exposure becomes a potent stimulus for initiating NAc
Received Dec. 20, 2006; revised June 11, 2007; accepted June 11, 2007.
This work was supported by National Institute on Drug Abuse Grants R01 DA019666 (M.J.T.) and T32 DA07234
(P.E.R.) and the Whitehall Foundation (M.J.T.). We thank Drs. Marina Wolf, Peter Kalivas, Reed Carroll, and Paul
Mermelstein for helpful comments on a previous version of this manuscript. We also thank Bonnie LaCroix for expert
technical assistance.
Correspondence should be addressed to Dr. Mark J. Thomas, University of Minnesota, 6-145 Jackson Hall, 321
Church Street Southeast, Minneapolis, MN 55455. E-mail: tmhomas@umn.edu.
DOI:10.1523/JNEUROSCI.1859-07.2007
Copyright © 2007 Society for Neuroscience 0270-6474/07/277921-08$15.00/0
The Journal of Neuroscience, July 25, 2007 •27(30):7921–7928 • 7921
synaptic depression. This signals a dramatic switch in the direc-
tion of experience-dependent synaptic plasticity in animals with a
history of cocaine exposure.
Materials and Methods
Behavior. Male C57BL/6J mice (24 –28 d old) received five once-daily
injections of either cocaine (15 mg/kg, i.p.) or saline (0.9% NaCl). Mice
were habituated for 20 min in activity boxes (Applied Concepts, Ann
Arbor, MI) before injection. Immediately after each injection, horizontal
locomotor activity, measured as “crossovers” from one side of the box to
the other, was monitored for 40 min. In Figure 5B, mice in the saline- and
cocaine-challenged groups were handled and injected with saline 2– 4
times (1 per day) during the withdrawal period to mitigate any potential
effects of stress during the challenge injection procedure.
Electrophysiology. Sagittal slices of the NAc shell (240
m) were pre-
pared as described previously (Thomas et al., 2001). Slices recovered in a
holding chamber for at least 1 h before use. During recording they were
superfused with ACSF (22–23°C) saturated with 95% O
2
/5% CO
2
and
containing (in mM) 119 NaCl, 2.5 KCl, 1.0 NaH
2
PO
4
, 1.3 MgSO
4
, 2.5
CaCl
2
, 26.2 NaHCO
3
and 11 glucose. Picrotoxin (100
M) was added to
block GABA
A
receptor-mediated IPSCs. Cells were visualized using
infrared-differential interference contrast optics. Medium spiny neurons
were identified by their morphology and high resting membrane poten-
tial (⫺75 to ⫺85 mV). To assess excitatory synaptic transmission, neu-
rons were voltage clamped at ⫺80 mV using a Multiclamp 700A ampli-
fier (Molecular Devices, Foster City, CA). Electrodes (3–5 M⍀)
contained (in mM) 117 cesium gluconate, 2.8 NaCl, 20 HEPES, 0.4
EGTA, 5 tetraethylammonium-Cl, 2 MgATP, and 0.3 MgGTP, pH 7.2–
7.4 (285–295 mOsm). Series resistance (10 –40 M⍀) and input resistance
were monitored on-line witha4mVdepolarizing step (100 ms) given
with each afferent stimulus. Afferents were stimulated at 0.1 Hz by a glass
monopolar microelectrode filled with ACSF and placed at the prelimbic
cortex–NAc border. Data were filtered at 2 kHz, digitized at 5 kHz, and
collected and analyzed using custom software (Igor Pro; Wavemetrics,
Lake Oswego, OR). AMPAR/NMDAR ratios were computed from EP-
SCs at ⫹40 mV with and without 50
MD-AP-5 as described previously
(Thomas et al., 2001). NMDAR EPSC decay time constants were calcu-
lated from averaged currents (those used to obtain AMPAR/NMDAR
ratio) by fitting to double exponential equations. Weighted mean decay
time constants were calculated to compare between groups (Rumbaugh
and Vicini, 1999). Miniature EPSCs (⬎300 per cell) were collected in the
presence of either tetrodotoxin (1.5
M) or lidocaine hydrochloride
(0.6 – 0.8 mM). Dual-component mEPSCs were collected in the addi-
tional presence of 20
Mglycine, in the absence of added Mg
2⫹
and at a
holding potential of ⫺65 mV. Quantal events were analyzed using Mini-
analysis software (Synaptosoft, Decatur, GA) and verified by eye. For
each cell, a random stretch of 200 mEPSCs was used to construct cumu-
lative probability plots and to calculate mean mEPSC amplitudes. Cur-
rent–voltage (I–V) experiments (see Figs. 1D,4B,5B) and paired-pulse
experiments (see Fig. 2D) were performed in the presence of 50
M
D-AP-5. Internal solution for I–V experiments contained 0.1 mMsperm-
ine (see Fig. 1D) only holding potentials were corrected for liquid junc-
tion potential.
Statistics. In all experiments, data acquisition and analysis were per-
formed blindly. On ⬎90% of recording days, a similar amount of data
were collected from cocaine and saline groups. Results are presented as
mean ⫾SEM. Statistical significance was assessed using two-tailed Stu-
dent’s ttests or ANOVA and Newman–Keuls post hoc tests for paired-
pulse experiments (see Fig. 2 D) and data presented in Figures 4Band 5B.
Traces in figures have had stimulus artifacts removed and are averages of
20 –25 consecutive responses.
Results
Cocaine treatment increases synaptic strength in NAc
shell MSNs
We used a standard paradigm for cocaine treatment (five once-
daily injections of 15 mg/kg, i.p.) (Fig. 1A) that produced clear
behavioral sensitization (38.2 ⫾6.4 vs 183.3 ⫾16.2 crossovers on
days 1 vs 5, measured in a subset of subjects; t
(1,28)
⫽8.30; p⬍
0.001). To examine long-lasting physiological effects of cocaine
exposure, we prepared acute NAc brain slices from cocaine- and
saline-treated mice 10 –14 d after the last injection. We first mea-
sured the ratio of peak AMPAR- to peak NMDAR-mediated
evoked synaptic current in whole-cell recordings from MSNs in
the NAc shell. This ratio has proven to be a sensitive assay for the
detection of differences in glutamatergic synaptic strength be-
tween cells in different slices from different animals (Hsia et al.,
1998; Thomas et al., 2001; Ungless et al., 2001; Saal et al., 2003;
Borgland et al., 2004; Dong et al., 2004; Faleiro et al., 2004; Du-
mont et al., 2005; Bellone and Luscher, 2006; Clem and Barth,
2006). We observed a 40% increase in the AMPAR/NMDAR ra-
tio in cells from cocaine- versus saline-treated mice (Fig. 1C)
(1.58 ⫾0.06 vs 1.13 ⫾0.07; t
(1,13)
⫽4.62; p⫽0.0005).
AMPARs lacking an edited GluR2 subunit show inward recti-
fication mediated by intracellular polyamines (Cull-Candy et al.,
2006). Thus, an inclusion or exclusion of synaptic GluR2-lacking
record
10-14 days
5
cocaine or saline
+40 mV
-80 mV
NMDA
AMPA
saline
cocaine
1234
A
C
-80 -40 40
-1.0
-0.5
0.5
1.0
V(mV)
Norm. I
AMPA
sal
coc
D
Treatment
Day
B
0.0
0.8
1.2
1.6
2.0
sal coc
AMPAR/NMDAR ratio
Figure 1. Repeated cocaine administration increases NAc excitatory synaptic strength. A,
Experimental timeline. B, Sample EPSCs from saline- (sal) and cocaine-treated (coc) animals.
Calibration: 100 ms, 20 pA. C, AMPAR/NMDAR ratio values from neurons in saline- (open circles;
n⫽8 cells, 5 mice) and cocaine-treated mice (filled circles; n⫽7 cells, 6 mice). Hash marks
indicate mean values. D, Left, Examples of evoked AMPA-mediated EPSCs at membrane poten-
tials from ⫺80 mV to ⫹40 mV. Calibration: 50 pA, 20 ms. Right, I–V relationship for AMPAR
EPSCs in saline- and cocaine-treated mice (n⫽8 cells, 5 mice in each group). The lines repre-
sent the linear regression (r⫽0.99 for each group). Error bars represent SEM.
7922 •J. Neurosci., July 25, 2007 •27(30):7921–7928 Kourrich et al. •Cocaine Induces Bidirectional Synaptic Plasticity
AMPARs would be represented as a change in the AMPAR/
NMDAR ratio as measured at a positive potential. Although we
pharmacologically isolated AMPAR EPSCs and provided a de-
fined concentration of intracellular polyamines (0.1 mMsperm-
ine), we did not detect a difference in either the reversal potential
(2.09 ⫾2.91 mV for saline vs 0.85 ⫾3.77 mV for cocaine) or the
rectification index, which we measured by dividing the EPSC
amplitude at ⫹40 mV by the amplitude at ⫺80 mV (0.55 ⫾0.06
for saline and 0.54 ⫾0.06 for cocaine) (Fig. 1D). This suggests
that the cocaine-induced increase in AMPAR/NMDAR ratio
does not reflect a change in the presence of GluR2-lacking
AMPARs at the synapse.
Cocaine treatment increases AMPAR mEPSC amplitude
and frequency
To determine the source of the AMPAR/NMDAR ratio increase
in cocaine-treated mice, we recorded miniature AMPAR EPSCs
(mEPSCs) in NAc MSNs. The mean amplitude distribution of
quantal events in the cocaine group was shifted to the right com-
pared with the saline group (Fig. 2B) and the mean amplitude
was significantly increased (Fig. 2C)(t
(1,17)
⫽2.42; p⫽0.027).
These results suggest that the increase in AMPAR/NMDAR ratio
is attributable, at least in part, to increased AMPAR function
and/or number. The frequency of mEPSCs was also increased in
the cocaine group (Fig. 2C)(t
(1,17)
⫽2.56; p⫽0.020). A fre-
quency increase is classically interpreted as an enhancement of
presynaptic function. However, the responses to paired-pulse
stimulation, a standard paradigm to test for changes in glutamate
release probability ( p
r
), were not affected in the cocaine group
(Fig. 2D), arguing against a global change in p
r
. The increase in
mEPSC frequency could simply indicate that a larger number of
events are rising above the amplitude detection threshold in the
cocaine group. However, given that cocaine exposure induces
new dendritic spine formation (Robinson and Kolb, 2004), our
results would also be consistent with activity at these putative
additional synaptic contacts.
No cocaine-induced changes in synaptic NMDAR function
To test for changes in NMDAR function, we compared the mean
amplitude of NMDAR-mediated mEPSCs between groups. Be-
cause of inherent difficulties in measuring “pure” NMDAR-
mediated mEPSCS in NAc MSNs (Thomas et al., 2001), we mea-
sured a mean NMDAR mEPSC amplitude for each cell using a
subtraction method. We recorded under zero-Mg
2⫹
conditions
to measure a mean dual-component mEPSC, followed by record-
ing in the NMDAR antagonist, D-AP-5 (50
M), to measure the
mean AMPAR mEPSC. Digital subtraction of the mean AMPAR
mEPSC from the mean dual component mEPSC yielded a mean
NMDAR mEPSC. We did not detect a significant difference in the
mean amplitude of NMDAR mEPSCs in cocaine-treated mice
(Fig. 3A) (1.93 ⫾0.24 mV for saline vs 2.02 ⫾0.31 mV for
cocaine). The kinetics of NMDAR EPSC decay can be altered by
changes in the types of NR2 subunits incorporated into synaptic
NMDARs (Monyer et al., 1994); however, we found no difference
between groups in this parameter (Fig. 3B) (95.8 ⫾8.2 ms for
saline vs 96.3 ⫾6.6 ms for cocaine). Thus, we are not able to
detect any cocaine-induced alteration of NMDAR function
and/or number.
Development of cocaine-induced synaptic plasticity is a
function of withdrawal duration and dosing schedule
Previous studies have identified cocaine-induced changes in NAc
AMPARs and/or AMPAR involvement in cocaine sensitization
that only emerge during extended withdrawal (Pierce et al., 1996;
Li et al., 1997; Churchill et al., 1999; Boudreau and Wolf, 2005).
To determine whether withdrawal time is a critical parameter for
cocaine-induced NAc synaptic potentiation, we first examined
AMPAR/NMDAR ratio in mice 24 h after a repeated injection
paradigm (15 mg/kg daily for 5 d) (Fig. 4A). Whereas there is no
significant difference between injection-naive mice and saline-
injected mice, we find a significant decrease in mean AMPAR/
NMDAR ratio in cocaine-treated mice (Fig. 4B). This decrease is
not accompanied by any change in the synaptic I–V curve (Fig.
4B) or NMDAR decay kinetics (data not shown), arguing against
widespread changes in subunit composition for synaptic AM-
PARs or NMDARs. This decrease in AMPAR/NMDAR ratio dur-
ing early withdrawal starkly contrasts with the robust potentia-
tion in AMPAR/NMDAR ratio observed during extended
withdrawal (Fig. 1), strongly suggesting that synaptic potentia-
tion is not present during early withdrawal, but develops as a
function of the duration of withdrawal.
To understand the effect of dosing schedule on the develop-
ment of cocaine-induced synaptic plasticity, we first tested the
idea that a single injection of cocaine might be sufficient to induce
synaptic plasticity. In ventral tegmental area dopamine neurons,
for example, it is well established that a single, modest dose of
cocaine (15 mg/kg, i.p.) is sufficient to induce robust synaptic
010 20 30
0.0
0.2
0.4
0.6
0.8
1.0
sal
coc
mEPSC Amplitude (pA)
Cumulative probability
*
0
2
4
6
8
8
9
10
11
12
sal coc
0
*
sal coc
mEPSC A mplit ude (pA)
mEPSC Frequency (Hz)
01000 2000
0.0
0.2
0.4
0.6
0.8
1.0
Inter-event Interval (ms)
Cumulative probability
A
C
B
0 50 100 150 200
0.6
0.8
1.0
1.2
1.4
sal
coc
Interstimulus inte rval (ms)
Mean pair ed-pulse r atio
D
sa line
cocaine
Figure 2. Repeated cocaine administration increases the amplitude and frequency of
AMPAR mEPSCs without changing the paired-pulse ratio. A, Sample traces of mEPSCs from
neurons in saline- (sal) and cocaine-treated (coc) groups. Calibration: 100 ms, 20 pA. B, Cumu-
lative probability for mEPSC amplitude (left) and mEPSC interevent interval (right) obtained in
saline- (gray line; n⫽12 cells, 6 mice) and cocaine-treated mice (black line; n⫽7 cells, 4
mice). C, Mean values for mEPSC amplitude and frequency. *p⬍0.05. D, Mean paired-pulse
ratio values in saline- (n⫽10 cells, 6 mice) and cocaine-treated (n⫽9 cells, 4 mice) mice are
shown for different interstimulus intervals (two-way ANOVA, F
(1,68)
⫽1.907, p⬎0.05). Error
bars represent SEM.
Kourrich et al. •Cocaine Induces Bidirectional Synaptic Plasticity J. Neurosci., July 25, 2007 •27(30):7921–7928 • 7923
potentiation (Ungless et al., 2001). We found that neither a single
injection of 15 mg/kg cocaine nor 40 mg/kg cocaine (the highest
dose which does not induce seizures, in our hands) induced any
change in the mean AMPAR/NMDAR ratio after 24 h of with-
drawal (Fig. 4D), suggesting that these treatments do not induce
synaptic plasticity in NAc during early withdrawal. Given the
time dependence for the emergence of NAc synaptic potentiation
with repeated cocaine, we also tested whether a single 40 mg/kg
injection would produce potentiation after7dofwithdrawal. We
did not observe any significant difference at this time point either
(Fig. 4D). Together, these data suggest that a single cocaine in-
jection is not sufficient to induce synaptic plasticity in NAc
MSNs. Thus, both the duration of drug withdrawal and the dos-
ing schedule are important factors in the induction and the di-
rection of this synaptic plasticity.
Cocaine history determines the direction of cocaine-induced
synaptic plasticity
In human addicts and animal models, a single drug exposure in
drug-experienced individuals can reinstate drug-seeking behav-
ior, even after a protracted drug-free period (Shaham et al.,
2003). Manipulations of NAc glutamate signaling exert powerful
control over reinstatement of drug-seeking as well as the expres-
sion of behavioral sensitization to cocaine (Kalivas, 2004). Thus,
we hypothesized that experience-elicited plasticity of NAc gluta-
matergic synapses may be differentially engaged by cocaine re-
exposure in cocaine-experienced versus drug-naive mice. After
repeated cocaine injection and 10 –14 d of withdrawal, mice were
either left undisturbed (no challenge) or injected with saline or
80
60
40
20
0
2.01.51.00.5
s
zero Mg
2+
+ APV
zero Mg
2+
dual
AMPA
NMDA
A
0
2
4
6
sal coc
NMDAR mEPSC (pA)
B
80
60
40
20
0
2.01.51.00.5
s
saline cocaine
0
50
100
150
200
sal coc
NMDAR EPSC decay τw (ms)
Figure3. Repeatedcocaineadministration does not affect synaptic NMDARfunction.A,Top,
Samples of mEPSCs recorded at ⫺65 mV in zero Mg
2⫹
solution in the absence (top) and
presence (bottom) of D-APV (50
M) in a cocaine-treated mouse. Calibration: 100 ms, 20 pA.
Bottom,Sampleaveragedtraces of mEPSCs obtained in each condition plus thesubtractedtrace
that yielded an average NMDAR mEPSC. Calibration: 10 ms, 2 pA. Bottom right, Mean NMDAR
mEPSCamplitudevaluesforindividualneurons[n⫽5cells,4 mice for saline (sal); n⫽12 cells,
6 mice for cocaine (coc)]. Hash marks indicate group means. B, Left, Sample traces of NMDAR
EPSCs from saline- and cocaine-treated mice (in gray) are shown with a superimposed double
exponential curve (in black). Calibration: 500 ms, 20 pA. Right, Weighted decay time constant
(
w
)valuesofevoked NMDAR EPSCs from saline- (n⫽8 cells, 5mice)andcocaine-treated(n⫽
7 cells, 6 mice) mice. Hash marks indicate group means. Error bars represent SEM.
0.0
0.4
0.8
1.2
1.6
sal coc sal coc sal coc
AMPAR/NMDAR ratio
A
*
*
0.0
0.6
0.8
1.0
1.2
1.4
1.6
naïve
sal
coc
AMPAR/NMDAR ratio
B
-80 -40 40
-1.0
-0.5
0.5
1.0
naïve
sal
coc
V(mV)
Norm. IAMPA
C
D
15 mg/kg
early
withdrawal
40 mg/kg
early
withdrawal
40 mg/kg
extended
withdrawal
coc or sal
12345
Treatment
Day 24h pos t-injection
coc or sal
Treatment
Day 24h pos t
(early)
17d post
(extended)
record
record record
Figure 4. Cocaine-induced NAc synaptic potentiation is absent during early withdrawal and
does not develop after a single cocaine exposure. A, Timeline for experiments in B.B, Left,
Mean AMPAR/NMDAR ratio from naive mice (n⫽16 cells, 5 mice), saline-treated mice (sal;
n⫽18 cells, 5 mice), and cocaine-treated mice (coc; n⫽21 cells, 6 mice; ANOVA, F
(2,53)
⫽
4.843, p⫽0.012; Student–Newman–Keuls post hoc test, *p⬍0.05). Right, I–V relationship
for AMPAR EPSCs in naive, saline-treated, and cocaine-treated mice. The lines represent the
linear regression (r⫽0.99 for each group). C, Timeline for experiments in D.D, Left, Mean
AMPAR/NMDAR ratio from saline- and cocaine-treated mice (15 mg/kg early withdrawal, n⫽
6cells,4miceineach group; 40 mg/kg early withdrawal, n⫽11 cells, 6 mice for saline andn⫽
7 cells, 4 mice for cocaine; 40 mg/kg extended withdrawal, n⫽11 cells, 5 mice for saline and
n⫽12 cells, 5 mice for cocaine). Error bars represent SEM.
7924 •J. Neurosci., July 25, 2007 •27(30):7921–7928 Kourrich et al. •Cocaine Induces Bidirectional Synaptic Plasticity
cocaine 24 h before electrophysiological study. Consistent with
our previous experiment (Figs. 1, 2), we find that repeated co-
caine treatment followed by extended withdrawal results in ro-
bust synaptic potentiation relative to an experimentally naive
control group (Fig. 5B). However, this new potentiated baseline
level of AMPAR-mediated transmission is reversed by a single
additional cocaine injection but not by saline (Fig. 5B). This in-
dicates that the cocaine history specifically altered the response to
cocaine re-exposure. Previous work has demonstrated that this
cocaine-induced decrease in AMPAR/NMDAR ratio reflects a
reduction in AMPAR function and/or number, and was not as-
sociated with any detectable change in NMDAR function and/or
number (Thomas et al., 2001). Here, we report the additional
findings that this AMPAR/NMDAR ratio decrease in the cocaine-
challenged group is not accompanied by any change in the AM-
PAR EPSC I–V relationship (Fig. 5C), nor
any change in decay time constants of syn-
aptic NMDARs (data not shown).
In contrast to drug-experienced mice, a
single cocaine injection in drug-naive mice
(i.e., mice that received repeated saline in-
jections according to the schedule in Fig.
5A) did not induce any significant change
in the AMPAR/NMDAR ratio (1.49 ⫾
0.093 for saline and 1.38 ⫾0.105 for co-
caine; t
(1,18)
⫽0.788; p⫽0.441) (Fig. 5D).
These data are summarized in Figure 5D,
with values for cocaine-challenged animals
normalized to saline-challenged controls.
These results demonstrate the ability of a
single cocaine exposure to differentially
modify glutamatergic synaptic strength on
NAc MSNs in drug-experienced versus
drug-naive animals.
Discussion
Our results indicate that in vivo cocaine ex-
erts dynamic bidirectional control over ex-
citatory synaptic strength in NAc, a struc-
ture known for its involvement in
producing drug-seeking behavior. These
data provide direct evidence of experience-
dependent changes in NAc synaptic
strength, little of which has been collected
to date. Several previous studies have dem-
onstrated that cocaine exposure can alter
the capacity of NAc synapses to undergo
synaptic plasticity that is triggered by the
experimenter (Fourgeaud et al., 2004; Yao
et al., 2004; Goto and Grace, 2005; Martin
et al., 2006). In general, however, these
studies were not purposefully designed to
assess whether NAc synaptic strength is
modified directly by cocaine experience.
Thus, this issue has remained open for
speculation. Our data add to a growing
body of evidence that cocaine experience
drives endogenous synaptic plasticity in
the mesolimbic dopamine system.
We find that cocaine experience pro-
duces a potentiation that develops during
drug withdrawal, and an abrupt depres-
sion that follows a single drug re-exposure.
Thus, repeated in vivo cocaine establishes a
new elevated baseline level of excitatory synaptic transmission in
the NAc and converts a cocaine injection, an ineffective stimulus
in drug-naive mice, into a potent stimulus for synaptic depres-
sion. This information may unify interpretations of intriguing
results which had seemed mutually incompatible. For example,
extended withdrawal from repeated cocaine exposure increases
cell-surface expression of AMPAR subunits in NAc tissue (Bou-
dreau and Wolf, 2005) as well as dendritic spine density in NAc
MSNs (Robinson and Kolb, 2004), both of which are consistent
with a synaptic potentiation. However, in studies where cocaine
withdrawal was interrupted by cocaine re-exposure 1 d before
sampling, AMPAR-mediated mEPSCs in NAc MSNs were atten-
uated and the induction of in vitro long-term depression was
occluded (Thomas et al., 2001). Our present results indicate that
-40
-20
0
20
sal chal
coc chal
Repeated
saline
Repeated
cocaine
AMPAR/NMDAR rat io
(% sal chal)
-80 -40 40
-1.0
-0.5
0.5
1.0
coc-coc
coc-nochal/
coc-sal
V(mV)
Norm. I
AMPA
A
*
*
0
0.8
1.0
1.2
1.4
1.6
##
--
-- --
coc coc coc
sal coc
Treatment
Challenge
naive
coc-nochal
coc-sal
coc-coc
AMPAR/NMDAR ratio
B
C
coc or sal
10-14 days
1 2345
Treatment
Day
*challenge*
coc
or
sal
record record
D
naïve
coc-sal coc-coc
coc-nochal
NMDA
AMPA
Figure 5. Cocaine exposure history determines whether NAc excitatory synapses exhibit potentiation or depression. A, Exper-
imental timeline. B, Left,Sample EPSCs from naive and cocaine-treated mice. Calibration: 100 ms, 20 pA. Right, Mean AMPAR/
NMDAR ratio in naive (n⫽6 cells, 3 mice), coc-nochal (coc treatment with no challenge; n⫽8 cells, 5 mice), coc-sal (coc
treatment with sal challenge; n⫽11 cells, 6 mice), and coc-coc (coc treatment with coc challenge; n⫽13 cells, 6 mice) groups.
#
Significantly different from each bar labeled with an asterisk (ANOVA, F
(3,29)
⫽8.167, p⫽0.0004; Student–Newman–Keuls
post hoc test, p⬍0.05). C,I–V relationship for AMPAR EPSCs in coc-nochal/coc-sal and coc-coc mice. Data from coc-nochal and
coc-salhavebeenpooledbecausethere is no significant difference between groups. The lines represent thelinearregression(r⫽
0.99 for each group). D, Summary graph indicating percentage decrease of AMPAR/NMDAR ratio in cocaine-challenged mice
relative to saline-challenged controls. Animals that had no previous drug experience (repeated saline; n⫽13 cells, 6 mice for
saline challenge, and n⫽7 cells, 5 mice for cocaine challenge) showed no significant depression. Drug-experienced animals
(coc-coc vs coc-sal; normalized to coc-sal) exhibited significant depression. Error bars represent SEM.
Kourrich et al. •Cocaine Induces Bidirectional Synaptic Plasticity J. Neurosci., July 25, 2007 •27(30):7921–7928 • 7925
a single additional cocaine exposure in drug-experienced animals
can determine whether NAc glutamatergic synapses exhibit de-
pression or potentiation.
Cocaine experience-elicited synaptic potentiation in NAc
A possible mechanism for the potentiation is suggested by an
intriguing line of experiments by Wolf et al. (2004) examining
AMPAR surface expression in cultured NAc neurons. In these
experiments, transient activation of dopamine receptors in-
creases surface-level AMPARs. This raises the possibility that in
vivo, the transient activation of dopamine receptors during co-
caine exposure may increase NAc AMPAR surface levels and en-
hance EPSCs. However, the story is not likely to be so straight-
forward. For example, dopamine receptor activation inhibits
AMPAR EPSCs in NAc slices (Nicola et al., 2000), an effect that is
enhanced with repeated cocaine administration (Beurrier and
Malenka, 2002). Furthermore, the day after discontinuing re-
peated cocaine injections, neither the synaptic potentiation (Fig.
4B) nor the increased level of surface AMPARs (Boudreau and
Wolf, 2005) is present. The fact that the potentiation takes time to
develop during withdrawal suggests it is not directly related to the
ability of dopamine receptor activation to drive AMPAR inser-
tion into the membrane.
Another possible mechanism for the potentiation is homeo-
static synaptic scaling: an alteration in synaptic responses
throughout a cell that compensates for chronic changes in activ-
ity (Turrigiano and Nelson, 2004). For example, by suppressing
activity in visual cortex through visual deprivation, AMPAR EP-
SCs can be upregulated in a cell-wide manner (Desai et al., 2002).
Repeated in vivo cocaine is known to reduce intrinsic excitability
of NAc MSNs (Zhang et al., 1998; Hu et al., 2004; Dong et al.,
2006). Thus, decreased excitability after drug cessation could
trigger synaptic scaling mechanisms to augment excitatory syn-
aptic strength. Another possibility, raised by Boudreau and Wolf
(2005), is that the decreased levels of extracellular glutamate
known to occur in NAc after repeated cocaine (Pierce et al., 1996;
Baker et al., 2003) may engage synaptic scaling. However it may
be triggered, the scaling phenomenon typically involves changes
in number (as opposed to purely changes in function) of synaptic
AMPARs (Turrigiano and Nelson, 2004). Cocaine-elicited syn-
aptic potentiation in NAc appears to be consistent with this
mechanism. For example, repeated cocaine exposure increases
surface expression of AMPARs, a portion of which are associated
with synapses (Boudreau and Wolf, 2005).
The functional significance of cocaine-induced NAc synaptic
potentiation is not yet clear. However, viral vector-mediated
overexpression of AMPAR subunits in NAc is sufficient to mod-
ify reward-related behaviors such as cocaine conditioned-place
preference (Kelz et al., 1999) intracranial self-stimulation (Tod-
tenkopf et al., 2006), and stress-induced reinstatement of
cocaine-seeking behavior (Sutton et al., 2003). Once we under-
stand the degree to which this overexpression can artificially po-
tentiate excitatory synaptic strength on MSNs, we will have a
framework within which to understand how cocaine-induced
changes in NAc synaptic strength can affect behavioral output of
reward circuits.
Cocaine experience-induced metaplasticity?
A single cocaine injection in drug-experienced animals during an
extended drug-free period triggers a synaptic depression whereas
the same treatment in drug-naive animals does not. Thus, re-
peated cocaine dramatically alters an animal’s response to subse-
quent cocaine during extended withdrawal. This type of shift has
been referred to as metaplasticity, a condition in which the his-
tory of activity in a given neuron or synapse alters the magnitude
or direction of plasticity in response to subsequent stimulation
(Abraham and Bear, 1996; Bear, 2003). A compelling example of
metaplasticity comes from visual deprivation experiments. Re-
duction in activity of visual cortical neurons can shift the re-
sponse of these neurons to a given evoked stimulus from long-
term depression to long-term potentiation (LTP) (Kirkwood et
al., 1996; Bear, 2003). As in other forms of metaplasticity, re-
peated cocaine experience appears to shift the threshold neces-
sary for generating a plastic response, in this case, synaptic de-
pression. Our data indicate that multiple cocaine exposures are
necessary to decrease the AMPAR/NMDAR ratio in mice that
had previously been drug-naive. However, a single cocaine re-
exposure is sufficient for NAc synaptic depression in drug-
experienced, “abstinent” mice. Although the degree of overlap in
the mechanisms for any synaptic depression elicited under these
two conditions will require additional study, it is clear that co-
caine experience and withdrawal lowers the threshold (i.e., the
number of drug exposures necessary) for cocaine-induced NAc
synaptic depression.
What are potential mechanisms for this threshold shift? In
visual cortical metaplasticity, changes in the subunit composition
of synaptic NMDARs, an enhanced inclusion of NR2B-
containing receptors, prolong calcium entry and facilitate LTP
induction (Quinlan et al., 1999a,b; Philpot et al., 2001). NR2B
expression in NAc is reported to be decreased at 24 h after re-
peated cocaine and increased after 2 weeks of withdrawal (Loftis
and Janowsky, 2000). Thus, we examined NMDAR EPSC decay
kinetics, an indicator for addition or loss of synaptic NR2B-
containing receptors (Monyer et al., 1994; Vicini et al., 1998;
Rumbaugh and Vicini, 1999; Schilstrom et al., 2006). We did not
observe any changes in this parameter. This does not rule out a
potential change in NR2B-containing receptors that are extra-
synaptic (van Zundert et al., 2004; Kohr, 2006). However, the lack
of change in NMDAR EPSC decay kinetics strongly suggests that
the mechanism for cocaine-induced metaplasticity is not directly
shared with other known forms of in vivo metaplasticity.
Another possible mechanism for the reduced synaptic depres-
sion threshold is suggested by the fact that cocaine treatment
enhances NAc glutamate release after cocaine re-exposure during
extended withdrawal (Pierce et al., 1996; Reid and Berger, 1996).
Coupled with our finding of enhanced AMPAR EPSCs, this sug-
gests cocaine re-exposure in cocaine-treated animals triggers su-
praphysiological activation of NAc glutamate transmission. In-
tense glutamate signaling can induce AMPAR endocytosis and
synaptic depression in vitro, most commonly through prolonged
NMDAR activation (Carroll et al., 1999; Beattie et al., 2000;
Mangiavacchi and Wolf, 2004). The involvement of AMPAR en-
docytosis in the synaptic depression described here seems a likely
possibility. For example, the delivery of an AMPAR-endocytosis-
blocking peptide into NAc interfered with the expression of be-
havioral sensitization to amphetamine (Brebner et al., 2005).
These results offer potential clues to the mechanism of cocaine-
elicited NAc synaptic depression. They also suggest that this de-
pression is a key factor in long-lasting behavioral modification by
addictive drug exposure.
Conclusion
Our results define prominent features of cocaine-induced synap-
tic plasticity in a key neural circuit for reward and drug-seeking
behavior. An important future direction will be to determine
whether these alterations may be pathogenic mediators that con-
7926 •J. Neurosci., July 25, 2007 •27(30):7921–7928 Kourrich et al. •Cocaine Induces Bidirectional Synaptic Plasticity
tribute to addiction, or perhaps homeostatic adaptations that
counteract it. For example, the increase in NAc synaptic efficacy
measured here may be a balancing factor against deleterious ad-
aptations, in which case its reversal during a drug re-exposure
may gate a signal for drug-seeking behavior. There is increasing
evidence that inhibition of NAc MSNs (GABAergic projection
neurons) promotes reward-seeking behavior (Kelley, 2004; Taha
and Fields, 2006), perhaps by disinhibiting “downstream” re-
gions such as the ventral pallidum (McFarland and Kalivas, 2001;
Tindell et al., 2005) and lateral hypothalamus (Harris et al.,
2005). Understanding the role of cocaine-induced NAc synaptic
plasticity in addiction will require detailed examination of this
phenomenon in relationship to animal behavior in models of
addiction. The present results should help bridge the divide be-
tween our rapidly expanding knowledge base of molecular neu-
roadaptations to cocaine and the reorganization of brain reward
circuits that results in addiction.
References
Abraham WC, Bear MF (1996) Metaplasticity: the plasticity of synaptic
plasticity. Trends Neurosci 19:126–130.
Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW
(2003) Neuroadaptations in cystine-glutamate exchange underlie co-
caine relapse. Nat Neurosci 6:743–749.
Bear MF (2003) Bidirectional synaptic plasticity: from theory to reality. Phi-
los Trans R Soc Lond B Biol Sci 358:649–655.
Beattie EC, Carroll RC, Yu X, Morishita W, Yasuda H, von Zastrow M,
Malenka RC (2000) Regulation of AMPA receptor endocytosis by a sig-
naling mechanism shared with LTD. Nat Neurosci 3:1291–1300.
Bellone C, Luscher C (2006) Cocaine triggered AMPA receptor redistribu-
tion is reversed in vivo by mGluR-dependent long-term depression. Nat
Neurosci 9:636–641.
Beurrier C, Malenka RC (2002) Enhanced inhibition of synaptic transmis-
sion by dopamine in the nucleus accumbens during behavioral sensitiza-
tion to cocaine. J Neurosci 22:5817–5822.
Borgland SL, Malenka RC, Bonci A (2004) Acute and chronic cocaine-
induced potentiation of synaptic strength in the ventral tegmental area:
electrophysiological and behavioral correlates in individual rats. J Neuro-
sci 24:7482–7490.
Boudreau AC, Wolf ME (2005) Behavioral sensitization to cocaine is asso-
ciated with increased AMPA receptor surface expression in the nucleus
accumbens. J Neurosci 25:9144–9151.
Brebner K, Wong TP, Liu L, Liu Y, Campsall P, Gray S, Phelps L, Phillips AG,
Wang YT (2005) Nucleus accumbens long-term depression and the ex-
pression of behavioral sensitization. Science 310:1340–1343.
Carroll RC, Beattie EC, Xia H, Luscher C, Altschuler Y, Nicoll RA, Malenka
RC, von Zastrow M (1999) Dynamin-dependent endocytosis of iono-
tropic glutamate receptors. Proc Natl Acad Sci USA 96:14112–14117.
Churchill L, Swanson CJ, Urbina M, Kalivas PW (1999) Repeated cocaine
alters glutamate receptor subunit levels in the nucleus accumbens and
ventral tegmental area of rats that develop behavioral sensitization. J Neu-
rochem 72:2397–2403.
Clem RL, Barth A (2006) Pathway-specific trafficking of native AMPARs by
in vivo experience. Neuron 49:663–670.
Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus ac-
cumbens mediates relapse in cocaine addiction. J Neurosci 20:RC89.
Cull-Candy S, Kelly L, Farrant M (2006) Regulation of Ca
2⫹
-permeable
AMPA receptors: synaptic plasticity and beyond. Curr Opin Neurobiol
16:288–297.
Desai NS, Cudmore RH, Nelson SB, Turrigiano GG (2002) Critical periods
for experience-dependent synaptic scaling in visual cortex. Nat Neurosci
5:783–789.
Dong Y, Saal D, Thomas M, Faust R, Bonci A, Robinson T, Malenka RC
(2004) Cocaine-induced potentiation of synaptic strength in dopamine
neurons: behavioral correlates in GluRA(⫺/⫺) mice. Proc Natl Acad Sci
USA 101:14282–14287.
Dong Y, Green T, Saal D, Marie H, Neve R, Nestler EJ, Malenka RC (2006)
CREB modulates excitability of nucleus accumbens neurons. Nat Neuro-
sci 9:475–477.
Dumont EC, Mark GP, Mader S, Williams JT (2005) Self-administration
enhances excitatory synaptic transmission in the bed nucleus of the stria
terminalis. Nat Neurosci 8:413–414.
Faleiro LJ, Jones S, Kauer JA (2004) Rapid synaptic plasticity of glutamater-
gic synapses on dopamine neurons in the ventral tegmental area in re-
sponse to acute amphetamine injection. Neuropsychopharmacology
29:2115–2125.
Fourgeaud L, Mato S, Bouchet D, Hemar A, Worley PF, Manzoni OJ (2004)
A single in vivo exposure to cocaine abolishes endocannabinoid-
mediated long-term depression in the nucleus accumbens. J Neurosci
24:6939–6945.
Goto Y, Grace AA (2005) Dopamine-dependent interactions between lim-
bic and prefrontal cortical plasticity in the nucleus accumbens: disruption
by cocaine sensitization. Neuron 47:255–266.
Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypotha-
lamic orexin neurons in reward seeking. Nature 437:556–559.
Hsia AY, Malenka RC, Nicoll RA (1998) Development of excitatory cir-
cuitry in the hippocampus. J Neurophysiol 79:2013–2024.
Hu XT, Basu S, White FJ (2004) Repeated cocaine administration sup-
presses HVA-Ca
2⫹
potentials and enhances activity of K⫹channels in rat
nucleus accumbens neurons. J Neurophysiol 92:1597–1607.
Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addic-
tion: the role of reward-related learning and memory. Annu Rev Neurosci
29:565–598.
Kalivas PW (2004) Glutamate systems in cocaine addiction. Curr Opin
Pharmacol 4:23–29.
Kelley AE (2004) Ventral striatal control of appetitive motivation: role in
ingestive behavior and reward-related learning. Neurosci Biobehav Rev
27:765–776.
Kelz MB, Chen J, Carlezon Jr WA, Whisler K, Gilden L, Beckmann AM,
Steffen C, Zhang YJ, Marotti L, Self DW, Tkatch T, Baranauskas G, Sur-
meier DJ, Neve RL, Duman RS, Picciotto MR, Nestler EJ (1999) Expres-
sion of the transcription factor deltaFosB in the brain controls sensitivity
to cocaine. Nature 401:272–276.
Kirkwood A, Rioult MC, Bear MF (1996) Experience-dependent modifica-
tion of synaptic plasticity in visual cortex. Nature 381:526–528.
Kohr G (2006) NMDA receptor function: subunit composition versus spa-
tial distribution. Cell Tissue Res 326:439–446.
Li Y, Vartanian AJ, White FJ, Xue CJ, Wolf ME (1997) Effects of the AMPA
receptor antagonist NBQX on the development and expression of behav-
ioral sensitization to cocaine and amphetamine. Psychopharmacology
(Berl) 134:266–276.
Loftis JM, Janowsky A (2000) Regulation of NMDA receptor subunits and
nitric oxide synthase expression during cocaine withdrawal. J Neurochem
75:2040–2050.
Mangiavacchi S, Wolf ME (2004) Stimulation of N-methyl-D-aspartate re-
ceptors, AMPA receptors or metabotropic glutamate receptors leads to
rapid internalization of AMPA receptors in cultured nucleus accumbens
neurons. Eur J Neurosci 20:649–657.
Martin M, Chen BT, Hopf FW, Bowers MS, Bonci A (2006) Cocaine self-
administration selectively abolishes LTD in the core of the nucleus ac-
cumbens. Nat Neurosci 9:868–869.
McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced
reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663.
Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH (1994) Devel-
opmental and regional expression in the rat brain and functional proper-
ties of four NMDA receptors. Neuron 12:529–540.
Nestler EJ (2001) Molecular basis of long-term plasticity underlying addic-
tion. Nat Rev Neurosci 2:119–128.
Nicola SM, Surmeier J, Malenka RC (2000) Dopaminergic modulation of
neuronal excitability in the striatum and nucleus accumbens. Annu Rev
Neurosci 23:185–215.
Philpot BD, Sekhar AK, Shouval HZ, Bear MF (2001) Visual experience and
deprivation bidirectionally modify the composition and function of
NMDA receptors in visual cortex. Neuron 29:157–169.
Pierce RC, Bell K, Duffy P, Kalivas PW (1996) Repeated cocaine augments
excitatory amino acid transmission in the nucleus accumbens only in rats
having developed behavioral sensitization. J Neurosci 16:1550–1560.
Quinlan EM, Philpot BD, Huganir RL, Bear MF (1999a) Rapid, experience-
dependent expression of synaptic NMDA receptors in visual cortex in
vivo. Nat Neurosci 2:352–357.
Quinlan EM, Olstein DH, Bear MF (1999b) Bidirectional, experience-
dependent regulation of N-methyl-D-aspartate receptor subunit compo-
Kourrich et al. •Cocaine Induces Bidirectional Synaptic Plasticity J. Neurosci., July 25, 2007 •27(30):7921–7928 • 7927
sition in the rat visual cortex during postnatal development. Proc Natl
Acad Sci USA 96:12876–12880.
Reid MS, Berger SP (1996) Evidence for sensitization of cocaine-induced
nucleus accumbens glutamate release. NeuroReport 7:1325–1329.
Robinson TE, Kolb B (2004) Structural plasticity associated with exposure
to drugs of abuse. Neuropharmacology 47 [Suppl 1]:33–46.
Rumbaugh G, Vicini S (1999) Distinct synaptic and extrasynaptic NMDA
receptors in developing cerebellar granule neurons. J Neurosci
19:10603–10610.
Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress
trigger a common synaptic adaptation in dopamine neurons. Neuron
37:577–582.
Schilstrom B, Yaka R, Argilli E, Suvarna N, Schumann J, Chen BT, Carman M,
Singh V, Mailliard WS, Ron D, Bonci A (2006) Cocaine enhances
NMDA receptor-mediated currents in ventral tegmental area cells via
dopamine D5 receptor-dependent redistribution of NMDA receptors.
J Neurosci 26:8549–8558.
Self DW, Choi KH, Simmons D, Walker JR, Smagula CS (2004) Extinction
training regulates neuroadaptive responses to withdrawal from chronic
cocaine self-administration. Learn Mem 11:648–657.
Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement
model of drug relapse: history, methodology and major findings. Psycho-
pharmacology (Berl) 168:3–20.
Suto N, Tanabe LM, Austin JD, Creekmore E, Pham CT, Vezina P (2004)
Previous exposure to psychostimulants enhances the reinstatement of
cocaine seeking by nucleus accumbens AMPA. Neuropsychopharmacol-
ogy 29:2149–2159.
Sutton MA, Schmidt EF, Choi KH, Schad CA, Whisler K, Simmons D, Kara-
nian DA, Monteggia LM, Neve RL, Self DW (2003) Extinction-induced
upregulation in AMPA receptors reduces cocaine-seeking behaviour. Na-
ture 421:70–75.
Taha SA, Fields HL (2006) Inhibitions of nucleus accumbens neurons en-
code a gating signal for reward-directed behavior. J Neurosci 26:217–222.
Thomas MJ, Beurrier C, Bonci A, Malenka RC (2001) Long-term depres-
sion in the nucleus accumbens: a neural correlate of behavioral sensitiza-
tion to cocaine. Nat Neurosci 4:1217–1223.
Tindell AJ, Berridge KC, Zhang J, Pecina S, Aldridge JW (2005) Ventral
pallidal neurons code incentive motivation: amplification by mesolimbic
sensitization and amphetamine. Eur J Neurosci 22:2617–2634.
Todtenkopf MS, Parsegian A, Naydenov A, Neve RL, Konradi C, Carlezon Jr
WA (2006) Brain reward regulated by AMPA receptor subunits in nu-
cleus accumbens shell. J Neurosci 26:11665–11669.
Turrigiano GG, Nelson SB (2004) Homeostatic plasticity in the developing
nervous system. Nat Rev Neurosci 5:97–107.
Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine expo-
sure in vivo induces long-term potentiation in dopamine neurons. Nature
411:583–587.
van Zundert B, Yoshii A, Constantine-Paton M (2004) Receptor compart-
mentalization and trafficking at glutamate synapses: a developmental
proposal. Trends Neurosci 27:428–437.
Vicini S, Wang JF, Li JH, Zhu WJ, Wang YH, Luo JH, Wolfe BB, Grayson DR
(1998) Functional and pharmacological differences between recombi-
nant N-methyl-D-aspartate receptors. J Neurophysiol 79:555–566.
Wolf ME, Sun X, Mangiavacchi S, Chao SZ (2004) Psychomotor stimulants
and neuronal plasticity. Neuropharmacology 47 [Suppl 1]:61–79.
Yao WD, Gainetdinov RR, Arbuckle MI, Sotnikova TD, Cyr M, Beaulieu JM,
Torres GE, Grant SG, Caron MG (2004) Identification of PSD-95 as a
regulator of dopamine-mediated synaptic and behavioral plasticity. Neu-
ron 41:625–638.
Zhang XF, Hu XT, White FJ (1998) Whole-cell plasticity in cocaine with-
drawal: reduced sodium currents in nucleus accumbens neurons. J Neu-
rosci 18:488–498.
7928 •J. Neurosci., July 25, 2007 •27(30):7921–7928 Kourrich et al. •Cocaine Induces Bidirectional Synaptic Plasticity
