Long-Term Potentiation (LTP) in the Central Amygdala (CeA) Is Enhanced After Prolonged Withdrawal From Chronic Cocaine and Requires CRF1 Receptors

Abstract

The amygdala is part of the brain reward circuitry that plays a role in cocaine-seeking and abstinence in animals and cocaine craving and relapse in humans. Cocaine-seeking is elicited by cocaine-associated cues, and the basolateral amygdala (BLA) and CeA are essential in forming and communicating drug-related associations that are thought to be critical in long-lasting relapse risk associated with drug addiction. Here we simulated a cue stimulus with high-frequency stimulation (HFS) of the BLA-CeA pathway to examine mechanisms that may contribute to drug-related associations. We found enhanced long-term potentiation (LTP) after 14-day but not 1-day withdrawal from 7-day cocaine treatment mediated through N-methyl-d-aspartate (NMDA) receptors (NRs), L-type voltage-gated calcium channels (L-VGCCs), and corticotropin-releasing factor (CRF)(1) receptors; this was accompanied by increased phosphorylated NR1 and CRF(1) protein not associated with changes in NMDA/AMPA ratios in amygdalae from cocaine-treated animals. We suggest that these signaling mechanisms may provide therapeutic targets for the treatment of cocaine cravings.

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Long-Term Potentiation (LTP) in the Central Amygdala (CeA) Is Enhanced
After Prolonged Withdrawal From Chronic Cocaine and Requires
CRF
1
Receptors
Yu Fu, Sebastian Pollandt, Jie Liu, Balaji Krishnan, Kathy Genzer, Luis Orozco-Cabal, Joel P. Gallagher,
and Patricia Shinnick-Gallagher
Department of Pharmacology and Toxicology, University of Texas, Medical Branch, Galveston, Texas
Submitted 5 April 2006; accepted in final form 26 October 2006
Fu Y, Pollandt S, Liu J, Krishnan B, Genzer K, Orozco-Cabal
L, Gallagher JP, Shinnick-Gallagher P. Long-term potentiation
(LTP) in the central amygdala (CeA) is enhanced after prolonged
withdrawal from chronic cocaine and requires CRF
1
receptors. J
Neurophysiol 97: 937–941, 2007. First published November 1,
2006; doi:10.1152/jn.00349.2006. The amygdala is part of the brain
reward circuitry that plays a role in cocaine-seeking and abstinence in
animals and cocaine craving and relapse in humans. Cocaine-seeking
is elicited by cocaine-associated cues, and the basolateral amygdala
(BLA) and CeA are essential in forming and communicating drug-
related associations that are thought to be critical in long-lasting
relapse risk associated with drug addiction. Here we simulated a cue
stimulus with high-frequency stimulation (HFS) of the BLA–CeA
pathway to examine mechanisms that may contribute to drug-related
associations. We found enhanced long-term potentiation (LTP) after
14-day but not 1-day withdrawal from 7-day cocaine treatment me-
diated through N-methyl-D-aspartate (NMDA) receptors (NRs), L-
type voltage-gated calcium channels (L-VGCCs), and corticotropin-
releasing factor (CRF)
1
receptors; this was accompanied by increased
phosphorylated NR1 and CRF
1
protein not associated with changes in
NMDA/AMPA ratios in amygdalae from cocaine-treated animals. We
suggest that these signaling mechanisms may provide therapeutic
targets for the treatment of cocaine cravings.
INTRODUCTION
The amygdala is essential in forming stimulus–reward asso-
ciations and associational processing of conditioned cues
(Aggleton 1992; Shinnick-Gallagher et al. 2003). Drug-asso-
ciated cues can induce craving in cocaine users and alter neural
activity in the amygdala (Childress et al. 1999), and electrical
stimulation of the basolateral amygdala (BLA) can reinstate
drug-seeking in animals (Hayes et al. 2003). Drug-cue associ-
ations are not well understood, but the mechanisms may be
similar to forms of synaptic plasticity and the induction and
expression of cocaine sensitization, a model for long-term
neuroadaptations important in addiction (De Vries et al. 1999;
Kalivas and Alesdatter 1993; Robinson and Berridge 1993).
Antagonizing N-methyl-D-aspartate (NMDA) receptors (NRs)
in the amygdala can prevent and block locomotor sensitizing
effects of chronic cocaine (Kalivas and Alesdatter 1993), and
amygdala NR1 protein levels are increased after acute and
chronic cocaine (Turchan et al. 2003). Likewise, activation of
L-type calcium channels mimics the induction (Lin et al. 2001)
and antagonists block expression of cocaine sensitization
(Pierce et al. 1998). Furthermore, corticotropin-releasing factor
(CRF) systems in the amygdala play a significant role in
cocaine addiction (Sarnyai et al. 2001). In cocaine-treated
animals, CRF release in the amygdala is enhanced during acute
withdrawal (Richter and Weiss 1999) and in response to a
cocaine challenge (Richter et al. 1995). Amygdala CRF im-
munolabeling decreases after short-term, but increases after
long-term withdrawal from chronic cocaine (Zorrilla et al.
2001). Furthermore, cocaine-induced locomotor activity is
blocked by intracerebroventricular injection of a CRF antago-
nist (Sarnyai et al. 1992). These data provide strong rationale
for testing the role of CRF receptors in synaptic plasticity in the
central amygdala (CeA). This study shows that specific cocaine
treatment and withdrawal paradigms resulted in enhanced syn-
aptic plasticity, that NR, L-type calcium channels, and CRF
1
were required for long-term potentiation (LTP) in the BLA–
CeA pathway, and that phosphorylated-NR1 (P-NR1) and
CRF
1
protein but not synaptic potentials were increased after
withdrawal from chronic cocaine.
METHODS
Cocaine HCl was a gift from the National Institute of Drug Abuse.
Male Sprague-Dawley albino rats (Harlan, 4 – 6 wk) were injected
daily with cocaine (15 mg/kg, ip) or saline (0.1 ml/kg, ip), once or
twice per day for 1 or 2 wk to assess how duration and frequency of
cocaine treatment and withdrawal time influence synaptic plasticity.
Behavioral sensitization measuring the progressive locomotor stimu-
lant properties resulting from chronic cocaine treatment was analyzed
with a photocell apparatus before and on the first and last days of
cocaine or saline treatment (Fig. 1E) as a measure of cocaine’s
effectiveness. After 7 days, locomotor activity was increased signif-
icantly over 1-day activity in the cocaine-treated (F
1,120
⫽260.07,
P⬍0.001) but not in the saline-treated (P⬎0.05) group. No
significant differences were observed between animals injected once
per day for 7 days or twice daily for 14 days. Coronal brain slices (500
␮
m) were prepared and incubated at room temperature for 1 h with
oxygenated, modified artificial cerebrospinal fluid (ACSF) solution (in
mM): 119 NaCl, 3.0 KCl, 1.2 NaH
2
PO
4
, 1.2 MgSO
4
, 2.5 CaCl
2
,25
NaHCO
3
, and 11.5 glucose. They were then submerged in a chamber
(1.0 ml, 2.5 ml/min) at 30 ⫾1°C for another hour before recording.
BLA fibers were stimulated with concentric electrodes (50 k⍀) using
150-
␮
s pulses of varying intensity (3–15 V) at 0.05 Hz, and field
excitatory postsynaptic potentials (fEPSPs) were recorded in the
capsula/medial CeA with tungsten electrodes (2–5 M⍀). fEPSP mag-
Address for reprint requests and other correspondence: P. Shinnick-Gal-
lagher, 301 University Blvd., Galveston, TX 77555-1031 (E-mail:
psgallag@utmb.edu).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
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J Neurophysiol 97: 937–941, 2007.
First published November 1, 2006; doi:10.1152/jn.00349.2006.
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nitude was adjusted to 30% of maximum response and baseline
recorded, and LTP was induced using high-frequency stimulation
(HFS) consisting of five trains of stimuli (100 Hz for 1 s, 3-min
intervals). fEPSPs were recorded at 0.05 Hz for another hour, and
their slopes were normalized to baseline values. A one- or two-
tailed unpaired t-test or one-way ANOVA with appropriate post
hoc tests were used for statistical analysis; nequals the number of
slices. Methodologies for patch recording (Liu et al. 2004) and
Western blot analysis (Zinebi et al. 2003) were similar to that reported
previously.
RESULTS
Amygdala slices were prepared, and LTP was assessed in
the BLA–CeA pathway (Fig. 1, A–D). We first tested the
influence of varying cocaine administration paradigms and
withdrawal time on LTP. Animals received cocaine or saline
either once per day for 7 days or twice per day for 14 days,
followed by either 1 or 14 days of withdrawal. Input– output
relationships were similar in all treatment groups (Fig. 1D). In
slices from animals treated with cocaine twice per day for 14
days and a 14-day withdrawal, fEPSP slopes after HFS
(203.5 ⫾11.7%, n⫽10) were significantly enhanced com-
pared with fEPSPs obtained from control animals (144.2 ⫾
4.7%, n⫽10, P⬍0.001). When treatment duration and
frequency were reduced to 7 days of cocaine once per day,
HFS-LTP (202.1 ⫾12.1%, n⫽12) remained significantly
enhanced compared with saline-treated animals (160.1 ⫾
9.0%, n⫽12; P⬍0.05) after 14 days of withdrawal. LTP was
not significantly different between 7- and 14-day cocaine
treatment groups. However, when withdrawal time was re-
duced to 1 day in animals receiving cocaine twice per day for
14 days, the resulting LTP (168.3 ⫾13.7%, n⫽7) was not
significantly different from saline controls (140.8 ⫾4.3%, n⫽9,
P⬎0.05), indicating that withdrawal time was crucial in
enhancing LTP, whereas treatment duration or frequency had
no significant impact. Subsequent experiments used the 7-day
treatment (once per day) and 14-day withdrawal paradigm.
Previously, we showed that HFS-LTP in the BLA–CeA
pathway depends on NRs and L-VGCCs (Fu and Shinnick-
Gallagher 2005). To examine whether induction mechanisms
were altered in cocaine-enhanced LTP (Fig. 2), slices were
superfused with the NMDA antagonist APV (50
␮
M) in ACSF
or the L-VGCC antagonist nimodipine (NIM, 10
␮
M) 15 min
before HFS. APV blocked LTP both in cocaine (control:
202.1 ⫾12.1%, n⫽12; APV: 110.4 ⫾2.4%, n⫽5, P⬍
0.001) and saline (control: 160.1 ⫾9.0%, n⫽12; APV:
107.7 ⫾7.4%, n⫽5, P⬍0.005) groups. Similarly, NIM
blocked LTP in cocaine-treated (control: 202.1 ⫾12.1%, n⫽
12; NIM: 104.0 ⫾11.8%, n⫽5, P⬍0.001) and saline-treated
(control: 160.1 ⫾9.0%, n⫽12; NIM: 109.0 ⫾7.7%, n⫽5,
P⬍0.005) groups. These data indicated that NMDA receptors
and L-VGCCs are necessary for LTP induction by HFS in
cocaine and saline treatment groups.
FIG. 1. Long-term potentiation (LTP) at the basolateral
amygdala (BLA)– central amygdala (CeA) pathway was en-
hanced after 2-wk (B) but not 24-h (A) withdrawal from chronic
cocaine without changes in single field excitatory postsynaptic
potential (fEPSP) responsiveness (D). Aand B: traces above
indicated fEPSPs before and after high-frequency stimulation
(HFS)-LTP at the times indicated in the bottom graphs, showing
summary data of LTP time-course. C: plot of last 10 fEPSPs
(mean ⫾SE) 1 h after LTP induction showed enhanced LTP
after 7- and 14-day cocaine tratment and 14-day withdawal but
not after 14-day treatment and 24-h withdrawal. Time-course of
7-day treatment and 14-day withdrawal is shown in Figs. 2 and
3. D: input– output relationships are not altered in any treatment
paradigm. E: horizontal locomotor activity is enhanced after 7
days of cocaine treatment, suggesting behavior sensitization.
Calibrations are the same in Aand B.
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Because CRF has been implicated in the pathophysiology of
drug addiction (Sarnyai et al. 2001), we also examined whether
CRF receptors modulate HFS-LTP (Fig. 3). The selective
CRF
1
antagonist NBI27914 (250 nM) blocked HFS-LTP in
cocaine (control: 202.1 ⫾12.1%, n⫽12; NBI: 114.0 ⫾7.4%,
n⫽5, P⬍0.001) and saline (control: 160.1 ⫾9.0%, n⫽12;
NBI: 119.9 ⫾2.8%, n⫽5, P⬍0.05) groups; astressin2-B, a
selective CRF
2
antagonist, did not significantly affect HFS-
LTP in either group (saline: 164 ⫾25.1%, n⫽6, P⬎0.05;
cocaine: 191 ⫾26.3%, n⫽6, P⬎0.05). These data indicated
an obligatory role for CRF
1
in synaptic plasticity in the
BLA–CeA pathway.
To further study the mechanisms contributing to cocaine-
enhanced LTP, we analyzed amygdala protein levels using
Western blots (7 animals/group; Fig. 3C). NR1 protein was not
quite significantly elevated (P⫽0.07) and P-NR1 protein was
significantly increased (P⬍0.03) in cocaine withdrawn ani-
mals, whereas the L-VGCC
␣
1C subunit (Ca
V
1.2, P⬎0.2)
was not altered, suggesting that signaling through NMDA may
be altered after cocaine treatment. However, NMDA/AMPA
ratios measured at ⫺20mV were not changed in cocaine-
treated animals (saline: 0.097 ⫾⫺0.015, cocaine: 0.110 ⫾
0.019, n⫽6/group), indicating that increased phosphorylated
NR protein was not reflected in the ratio at this synapse. In
agreement with our electrophysiological results, CRF
1
protein
levels were significantly increased after cocaine treatment (P⬍
0.04), whereas CRF
2
remained unchanged (P⬎0.35).
DISCUSSION
Our studies show for the first time that LTP in the BLA–CeA
pathway was enhanced after long- but not short-term with-
drawal from chronic cocaine, that HFS-induced LTP was
modulated endogenously by CRF
1
, and that elevated P-NR1
and CRF
1
protein may contribute to cocaine-enhanced LTP.
The withdrawal-induced enhancement of LTP may be related
to the neuroadaptive effects associated with behavioral sensi-
tization that can persist for 2 wk (Kalivas et al. 1988) and that
FIG. 2. LTP in the BLA pathway is dependent on N-methyl-
D-aspartate (NMDA) receptors (Aand B) and L-type voltage-
gated calcium channels (L-VGCCs) (Cand D) in slices 14 days
after 7-day treatment with either saline (left) or cocaine (right).
In each panel, numbered traces show responses before and after
HFS at times indicated in graph in slices from saline (Aand C)-
and cocaine (Band D)-treated animals in presence and absence
of APV (Aand B) or nimodipine (NIM; Cand D). Graphs below
show summary date of LTP time-course in slices from saline (A
and C)- and cocaine (Band D)-treated groups in the presence
and absence of APV (Aand B) or NIM (Cand D). The same
control data are plotted for saline (A,C, and Fig. 3C) and
cocaine (B,D, and Fig. 3D). Calibrations in B–D are the same
as in A.
FIG. 3. LTP in BLA–CeA pathway is dependent on corti-
cotropin-releasing factor (CRF)
1
receptors in saline- and co-
caine-treated populations and P-NR1, and CRF
1
protein is
increased in cocaine-treated populations. Aand B: numbered
top traces recorded in slices from saline (A)- and cocaine
(B)-treated groups show fEPSPs before and after HFS-induced
LTP at times indicated in the bottom graphs, which show
summary data for LTP time-course. C: Western blots for NR1
(Santa Cruz), P-NR1 (Upstate), and CRF1 (Santa Cruz) pro-
tein (top blots) and corresponding actin (Santa Cruz) protein
(bottom blots) are expressed as optical density ratios in the
summary graphs below. The same control data are plotted for
saline (Cand Fig. 2, Aand C) and cocaine (Dand Fig. 2, Band
D).
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1
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may have a component of associative contextual conditioning
(Carey and Gui 1998). Markers for BLA neuronal activity
increase in animals exposed to a cocaine environment (Brown
et al. 1992; Neisewander et al. 2000; Thomas et al. 2003) even
after 4-mo withdrawal (Ciccocioppo et al. 2001). Thus stimu-
lating the BLA may simulate neuronal activity during cue
exposure after the animal has been sensitized.
Cocaine-enhanced LTP in the BLA–CeA pathway was crit-
ically dependent on withdrawal, whereas baseline fEPSP re-
sponsiveness was unchanged. After 4- to 6-day withdrawal
after 5-day cocaine treatment, hippocampal LTP was enhanced
(Thompson et al. 2002), but after 100-day withdrawal and at
higher self-administered cocaine doses, LTP was reduced
(Thompson et al. 2004); these effects were also not correlated
with an altered fEPSP amplitude. Conversely, at an intralateral
amygdala (LA) synapse, an increased baseline response and
reduced LTP were observed with cocaine treatment (15 mg/kg,
3 times per day, 1-h intervals for 7 days) and 1- to 3-day
withdrawal, but the effect dissipated within 9 days; this reduc-
tion in LTP was interpreted as occlusion caused by the facili-
tated baseline EPSP response (Goussakov et al. 2006). Func-
tionally, these data indicated that long-lasting effects of co-
caine were consistently revealed with HFS. Although
disparities in findings suggest that changes in synaptic facili-
tation and plasticity are dependent on brain area, synapse, and
treatment paradigm, the studies provide insight into the relative
persistence of the effects of cocaine treatment.
HFS-LTP at the BLA–CeA synapse is dependent on NMDA
receptors and L-VGCCs. After 2-wk withdrawal from chronic
cocaine, NR2B and NR1 subunits are upregulated in other
brain areas (Loftis and Janowsky 2000). Here we report a
similar increase in P-NR1 protein in the amygdala, which
could contribute to the enhanced HFS-LTP after chronic co-
caine. However, changes in NMDA/AMPA ratios were not
detected, suggesting that the increased P-NR1 proteins may not
be accessible to transmitter evoked with single stimuli at this
synapse.Cocaine withdrawal also increases calcium entry
through L-VGCCs (Nasif et al. 2005), and L-VGCC antago-
nists block establishment of conditioned locomotion by co-
caine (Reimer and Martin-Iverson 1994), suggesting that
greater L-VGCC activity in cocaine withdrawn animals could
contribute to the cocaine-enhanced HFS-LTP. However, it is
unlikely that increased L-VGCC activity contributed to the
cocaine-enhanced LTP because
␣
1C subunit protein was un-
changed in the cocaine group. CRF
2
receptor activation poten-
tiated NMDA responses in ventral tegmental area neurons
(Ungless et al. 2003) but CRF
2
was not involved in HFS-LTP
in the BLA–CeA pathway, and amygdala CRF
2
protein was
not increased with chronic cocaine. These data suggest that
L-type VGCCs or CRF
2
receptors may not play a role in the
cocaine-enhanced LTP, whereas increased P-NR1 protein may
contribute to enhanced HFS-LTP but not to singly evoked
EPSPs at the BLA–CeA synapse.
Although the CRF
1
antagonist did not affect baseline fEPSPs,
subsequent HFS failed to induce LTP in slices from cocaine
and saline groups, indicating that CRF
1
receptors are required
for LTP induction. We previously showed that exogenous CRF
directly enhanced mEPSC frequency in the CeA, suggesting a
presynaptic increase in glutamate release (Liu et al. 2004).
Repetitively stimulating cerebellar afferents is known to re-
lease CRF (Tian and Bishop 2003), and afferent stimulation
(foot-shock) can increase endogenous CRF release in the CeA
and BLA (Roozendaal et al. 2002). These results suggested that
HFS could enhance endogenous CRF release in the CeA. CRF
priming enhances HFS-induced LTP (Blank et al. 2002), CRF
itself can induce LTP in the hippocampus (Wang et al. 1998),
and at LA–CeA (Pollandt et al. 2006) and BLA–CeA (Fu et al.
2004) synapses, and CRF-induced LTP is enhanced after
chronic cocaine. Furthermore, both CRF
1
protein (Radulovic et
al. 1998) and mRNA (Chalmers et al. 1995) are found in the
BLA, and CRF
1
receptors are located on excitatory type
terminals in the CeA (Chalmers et al. 1995), suggesting an
anatomical basis for a CRF
1
-mediated effect on glutamate
release. The block of HFS-LTP by the CRF
1
antagonist,
increase in CRF
1
protein, and enhanced responsiveness to CRF
in the BLA–CeA pathway (Fu et al. 2004) after cocaine
withdrawal suggests that endogenously released CRF acting
through CRF
1
receptors contributes to the enhanced LTP in
cocaine. CRF is known to enhance locally evoked GABA
inhibition in the CeA through CRF
1
receptors (Nie et al. 2004).
With GABA inhibition intact, we previously found that low
CRF concentrations inhibited evoked excitatory postsynaptic
currents (EPSCs) ⬃40%, whereas in the presence of GABA
antagonists, CRF inhibited miniature EPSCs by only 20% (Liu
et al. 2004), indicating that one half of CRF-induced inhibition
of evoked EPSCs may be caused by CRF-induced GABA
release. However, HFS-LTP in this pathway is not significantly
altered by GABA antagonists (Fu and Shinnick-Gallagher
2005), and GABA antagonists did not affect NBI inhibition of
HFS-LTP (data not shown). Altogether the results suggest that
an HFS-induced increase in CRF release in the presence of
GABA antagonists resulted in facilitated glutamate release,
which prevailed over an inhibitory effect and induced LTP.
Furthermore, our data suggest that increases in P-NR1 and
CRF
1
protein and/or their downstream signaling mechanisms
may contribute to the cocaine-enhanced LTP at the BLA–CeA
synapse.
ACKNOWLEDGMENTS
The authors thank K. Schmidt for helpful comments on the manuscript.
GRANTS
This work was supported by National Institute of Drug Abuse Grants
DA-017727 to P. Shinnick-Gallagher and DA-011991 to J. P. Gallagher.
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Report
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