 |
 Previous Article | Next Article 
The Journal of Neuroscience, February 1, 2003, 23(3):742
BRIEF COMMUNICATION
Time-Dependent Increases in Brain-Derived Neurotrophic Factor
Protein Levels within the Mesolimbic Dopamine System after Withdrawal
from Cocaine: Implications for Incubation of Cocaine Craving
Jeffrey W.
Grimm1, *,
Lin
Lu1, *,
Teruo
Hayashi2, *,
Bruce T.
Hope1,
Tsung-Ping
Su2, and
Yavin
Shaham1
1 Behavioral Neuroscience Branch and
2 Cellular Neurobiology Branch, Intramural Research
Program/National Institute on Drug Abuse/National Institutes of
Health/Department of Health and Human Services, Baltimore, Maryland
21224
 |
ABSTRACT |
Using a rat model of drug craving, we found that the responsiveness
to cocaine cues progressively increases or incubates over the first
60 d of cocaine withdrawal. Here we studied whether alterations in
brain-derived neurotrophic factor (BDNF) protein levels within the
mesolimbic dopamine system are associated with this incubation
phenomenon. BDNF is involved in synaptic plasticity and was found to
enhance responding for cues associated with natural rewards. Rats were
trained to press a lever to receive intravenous cocaine or oral sucrose
for 6 hr/d for 10 d; each earned reward was paired with a
tone-light cue. Resumption of lever-pressing behavior was then
assessed on days 1, 30, or 90 of reward withdrawal. First, resistance
to extinction was assessed during 6 hr in which lever presses were not
reinforced and the cue was absent. Second, cue-induced reinstatement
was assessed after extinction during 1 hr in which responding led to
cue presentations. Other rats were killed without testing on days 1, 30, and 90 of reward withdrawal, and BDNF and nerve growth factor (NGF)
protein levels were measured in the ventral tegmental area (VTA),
accumbens, and amygdala. Lever pressing during extinction and
cue-induced reinstatement tests of cocaine craving progressively
increased after cocaine withdrawal. Time-dependent changes also were
observed during the tests for sucrose craving, with maximal responding
on day 30. BDNF, but not NGF, levels in the VTA, accumbens, and
amygdala progressively increased after cocaine, but not sucrose,
withdrawal. Time-dependent increases in BDNF levels may lead to
synaptic modifications that underlie enhanced responsiveness to cocaine
cues after prolonged withdrawal periods.
Key words:
amygdala; extinction; nucleus accumbens; reinstatement; relapse; ventral tegmental area
| |
Introduction |
Cocaine addiction is characterized
by high rates of relapse after prolonged abstinence (O'Brien, 1997 ).
This relapse is often associated with reports of craving, a subjective
state induced by re-exposure to stimuli associated with cocaine intake
(Childress et al., 1999). Based on clinical observations, Gawin and
Kleber (1986) hypothesized that cue-induced cocaine craving
progressively increases during drug abstinence. Recently, we described
an analogous phenomenon in a study in which we inferred cocaine craving
from the responsiveness of rats to cocaine cues in two tests performed after withdrawal from drug self-administration (Grimm et al., 2001).
First, resistance to extinction was assessed in the presence of the
house light and the lever, contextual cues that during training had
indicated drug availability, but in the absence of cocaine and a
discrete tone-light cue previously paired with drug injections.
Second, cue-induced reinstatement of cocaine seeking was assessed in a
test wherein responding led to the tone-light cue presentations under
extinction conditions. We found that the responsiveness to cocaine cues
progressively increases or incubates over the first 60 d of
withdrawal. This "incubation of craving" may be mediated by
neuroadaptations within the mesolimbic dopamine (DA) reward system that
are induced by chronic cocaine self-administration and subsequent
withdrawal (Nestler and Aghajanian, 1997; Piazza and Le Moal, 1997;
White and Kalivas, 1998). Some of these neuroadaptations might include
molecular (Nestler, 2001) and morphological (Robinson and Berridge,
2003) changes involved in synaptic plasticity associated with learning
and memory (Hyman and Malenka, 2001).
Brain-derived neurotrophic factor (BDNF) is a growth factor involved in
synaptic plasticity (Thoenen, 1995) and in cellular events thought to
underlie learning and memory processes such as long-term potentiation
(LTP) (Yamada et al., 2002). BDNF colocalizes with tyrosine hydroxylase
in midbrain DA neurons (Seroogy et al., 1994) and therefore, can play a
role in synaptic plasticity of these neurons (Hyman and Malenka, 2001).
BDNF infusions into the substantia nigra, ventral tegmental area (VTA),
and accumbens increase DA utilization and enhance locomotor activity
induced by psychostimulant drugs (for review, see Pierce and Bari,
2001). Accumbens infusions of BDNF also enhance responding for
conditioned stimuli paired with water reward (Horger et al., 1999).
Primarily based on this latter finding, we studied whether alterations
in BDNF protein levels within the mesolimbic DA system are associated with the time-dependent changes in responsiveness to cocaine cues after withdrawal.
We trained rats to lever-press for intravenous cocaine or oral sucrose,
a control condition using nondrug reward. Responsiveness to the
reward-associated cues was then assessed on days 1, 30, or 90 of
withdrawal in tests for resistance to extinction and cue-induced
reinstatement. Other rats were killed without testing after reward
withdrawal, and BDNF and nerve growth factor (NGF) protein levels were
measured using ELISA in the VTA, accumbens, and amygdala. Thus, we
determined long-term changes in BDNF protein levels that are not
influenced by the potential acute induction of BDNF provoked by
re-exposure to a reinforcer-associated environment (Hall et al., 2000).
NGF was used as a control growth factor because it is not colocalized
with midbrain DA neurons (Seroogy et al., 1994) and does not alter
cocaine-induced locomotion (Pierce and Bari, 2001). The VTA, accumbens,
and amygdala are involved in reinstatement of cocaine seeking (Stewart,
2000; Shalev et al., 2002) and responding for conditioned rewards
(Everitt et al., 1999).
| |
Materials and Methods |
Subjects and surgery
Male Long-Evans rats (Charles River, Raleigh, NC;
350-400 gm) were used. Rats were housed in the animal facility and
were maintained on a reversed 12 hr light/dark cycle (lights off at 10 A.M.) with food and water available in the home cage. Procedures followed the Principles of Laboratory Animal Care (National
Institutes of Health publication 86-23, 1996). Rats were surgically
implanted with intravenous catheters (Grimm et al., 2002) under
anesthesia (xylazine plus ketamine, 10 plus 100 mg/kg, i.p.).
Buprenorphine (0.01 mg/kg) was administered before surgery. Catheters
were flushed with saline every 24-48 hr during a 5 d recovery
period and before the drug self-administration sessions.
Sucrose-trained rats underwent intravenous "sham" surgery.
Apparatus
The self-administration boxes, controlled by a Med Associates
(Georgia, VT) system, had two levers located 9 cm above the grid floor,
but only one lever (an active, retractable lever) activated the
infusion pump. Presses on the other lever (an inactive, stationary
lever) were also recorded. The modified cannula on the rat's skull was
connected to a liquid swivel with polyethylene-50 tubing that
was protected by a metal spring and connected to the syringe of the
infusion pump. The sucrose solution was delivered into liquid-drop receptacles.
Procedures
The experiments included three phases. During the training phase
(10 d), rats were trained to lever-press for cocaine or sucrose; each
earned reward was paired with a discrete tone-light cue. During the
withdrawal phase (1-90 d), rats were housed in the animal facility.
During the test day, lever presses were not rewarded. Initially, rats
were allowed to lever-press for six to eight 1 hr sessions
("extinction of lever-pressing behavior") in the absence of the
tone-light cue. Rats were then tested for reinstatement induced by
contingent presentations of this cue during one 1 hr session. In
experiment 2, rats were trained to self-administer cocaine or sucrose
but were not exposed to the test conditions after withdrawal.
Training phase
Rats were trained to self-administer cocaine (supplied by the
National Institute on Drug Abuse; dissolved in saline; 1.0 mg/kg per
infusion; delivered over 4.5 sec) or 10% sucrose solution (0.4 ml per
reward delivery). Rats were housed in the animal facility and were
brought to the self-administration chambers every day. Training was
conducted during six 1 hr daily sessions that were separated by 5 min
for 10 d under a continuous reinforcement schedule (each lever
press is reinforced) with a 40 sec timeout after each earned reward. To
facilitate sucrose training, water was not available on the day before
training. For rats that did not initiate cocaine self-administration,
food was removed from the chambers during the six 1 hr sessions for up
to 5 d. Each session began with the insertion of the active lever
and the illumination of a red house light. Each earned reward was
accompanied by a 5 sec tone-light cue. At the end of each session, the
house light was turned off and the active lever was retracted. The
number of rewards earned was limited to 15 per hour to minimize cocaine
overdose or for preventing the sucrose-trained rats from emptying the syringes.
Withdrawal phase
Rats were housed in the animal facility and were handled three
times per week. In experiment 1, independent groups were then tested
for sucrose or cocaine seeking at the different withdrawal periods. In
experiment 2, rats were neither tested nor exposed to the
self-administration chambers after withdrawal.
Experiment 1: extinction responding and cue-induced reinstatement
of reward seeking
Cocaine-trained rats. Three groups (n = 11-12 per group) of rats were tested for resistance to extinction
and cue-induced reinstatement after 1, 30, or 90 d of withdrawal.
Cocaine-trained rats were connected to the metal spring, but neither
cocaine nor its vehicle (saline) was available during testing. On the
test day, resumption of lever pressing was assessed in two ways. First, resistance to extinction was assessed in the absence of the discrete tone-light cue previously paired with cocaine injections. Rats were
allowed to lever-press for six to eight 1 hr sessions (separated by 5 min intervals when the lever was retracted and the house light was
turned off) until they met an extinction criterion of  15 responses
per session on the active lever. Second, a test for cue-induced
reinstatement was conducted 5 min after the final extinction session.
Each lever press resulted in another presentation of the tone-light
cue that served as a conditioned reinforcer (Robbins et al., 1989)
during this test. A single, noncontingent presentation of the cue was
given at the onset of the test session because toward the end of
extinction, several rats did not approach the lever.
Sucrose-trained rats. Three groups of rats
(n = 10-14) were tested for resistance to extinction
and cue-induced reinstatement after 1, 30, or 90 d of withdrawal
from sucrose under conditions identical to those described above.
Experiment 2: BDNF and NGF protein levels
Rats from six groups (n = 5-7 per group) were
decapitated 1, 30, or 90 d after withdrawal from sucrose or
cocaine self-administration, and their brains were then removed. A
control group of naive rats (n = 5) was also included
in the assays. Brains were rapidly extracted, frozen in  50°C
isopentane, and stored at 80°C. Bilateral tissue punches of the
VTA, accumbens, and amygdala were obtained from ~1 mm coronal
sections cut in a cryostat at 20°C. The coronal sections were
approximately 5.6, +1.8, and 2.3 mm from bregma for the VTA,
accumbens (core and shell), and amygdala (central and basolateral),
respectively (Paxinos and Watson, 1998). Tissue punches were sonicated
in 300 µl of lysis buffer (137 mM NaCl, 20 mM Tris, 1% NP-40, 10% glycerol, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml
aprotinin, 1 µg/ml leupeptin, and 0.5 mM sodium vanadate). The homogenates were incubated at 4°C for 30 min and centrifuged at 12,000 × g for 10 min. The protein
concentrations of the supernatants were determined using the Micro-BCA
assay kit (Pierce, Rockford, IL). Sandwich-style ELISAs
were performed using the BDNF and NGF Emax ImmunoAssay System kit
(Promega, Madison, WI) according to the manufacturer's
instructions (Wang et al., 2000). BDNF and NGF content were
interpolated from standard curve runs for each plate (linear range of
7.8-500 and 16-1000 pg/ml for BDNF and NGF, respectively). BDNF and
NGF protein contents were divided by total protein in each sample to
determine the number of picograms of peptide per microgram of total
protein. For a given brain area and growth factor, samples from the
groups of cocaine- and sucrose-trained rats and the naive control rats were determined in a single run. The intra-assay variability values were 2.46 ± 1.53% (mean ± SD) and 3.43 ± 3.90% for
BDNF and NGF, respectively.
Statistical analyses
Data from the extinction sessions and tests for cue-induced
reinstatement were analyzed separately for total (nonreinforced) active
and inactive lever responses. Data were analyzed separately for the
cocaine- and sucrose-trained rats.
Extinction responding. A mixed-model ANOVA was conducted
using the between-subjects factor of withdrawal period (1, 30, or 90 d) and the within-subjects factor of session (the first six 1 hr sessions during which all rats from all groups were exposed to the
extinction conditions).
Cue-induced reinstatement. Data were analyzed for responses
during the last 60 min extinction session during which rats reached the
extinction criterion (baseline, no cue condition) and for responses
made during the subsequent 1 hr test. A mixed-model ANOVA was conducted
using the between-subjects factor of withdrawal period and the
within-subjects factor of test session (no cue vs cue).
ELISAs. Raw values of protein levels of BDNF and NGF were
analyzed with two-way ANOVAs using the between-subjects factors of
withdrawal period and reward type (cocaine vs sucrose). Post hoc analyses were performed with the Fisher PLSD test, and
significant differences are reported for p < 0.05.
| |
Results |
Rats demonstrated reliable cocaine or sucrose
self-administration, and no significant differences were observed
within the sucrose and cocaine conditions among the groups tested
at the different withdrawal days in experiments 1 and 2. The mean ± SEM (data collapsed for both experiments) number of earned rewards on the last three days of training were 52.9 ± 1.8, 54.4 ± 1.9, and 57.3 ± 1.7, respectively, for the cocaine-trained rats
(n = 55) and 79.4 ± 2.3, 78.1 ± 2.3, and
81.4 ± 1.9, respectively, for the sucrose-trained rats
(n = 53).
Experiment 1: extinction responding and cue-induced reinstatement
of reward seeking
Cocaine-trained rats
Nonreinforced lever pressing during tests for resistance to
extinction and cue-induced reinstatement were significantly higher after 30 and 90 d of withdrawal than on day 1.
Extinction responding. Figure
1A and B
show active-lever responses in the absence of the discrete tone-light
cue during the test for resistance to extinction. Figure
1A also shows inactive-lever responses (a measure of
nonspecific activity and/or response generalization). All rats met the
extinction criterion (15 active-lever responses per hour) within six
to eight sessions. Analysis of active-lever responding revealed
significant effects of withdrawal period
(F(2,31) = 8.5; p = 0.01), session (F(5,155) = 50.6;
p < 0.01) and withdrawal period by session
(F(10,155) = 5.9; p < 0.01). The effect of withdrawal period on inactive-lever responding was
not significant (p > 0.05).
View larger version (16K):
[in this window]
[in a new window]
|
Figure 1.
Cocaine. A, Extinction, total
responses: mean ± SEM responses on the previously active-lever
and inactive-lever responses during the six 60 min sessions of
extinction (conducted in the absence of the discrete tone-light cue
previously paired with cocaine infusions). B,
Extinction, responses per hour: mean active-lever responses at each
session of extinction. C, Cue-induced reinstatement:
mean active-lever responses during the 60 min session that followed the
extinction sessions. During the test for cue-induced reinstatement,
lever presses led to presentations of the tone-light cue. No cue
refers to the last 60 min extinction session on which the rats reached
the extinction criterion. *Different from day 1 withdrawal;
p < 0.05; Fisher PLSD (n = 11-12 per withdrawal period).
|
|
Cue-induced reinstatement. Figure 1C shows
active-lever responses during the 1 hr test session for cue-induced
reinstatement in which lever presses led to the presentation of the
tone-light cue that was previously paired with earned cocaine.
Analysis revealed significant effects of withdrawal period
(F(2,31) = 5.3; p < 0.05), test session (F(1,31) = 52.9;
p < 0.01), and withdrawal period by test session
(F(2,31) = 3.7; p < 0.05). Inactive-lever responses were low (<3 per 1 hr session), and no
group differences were found (p > 0.05).
Sucrose-trained rats
Nonreinforced lever pressing during tests for cue-induced
reinstatement followed an inverted U-shaped function with higher responding on day 30 of withdrawal from sucrose than on days 1 and 90. A similar trend, although not statistically significant, was observed
for extinction responding.
Extinction responding. Figure
2A and B
show active- and inactive-lever responses in the absence of the
discrete tone-light cue during the test for resistance to extinction.
All rats met the extinction criterion (15 active-lever responses per
hour) within six to eight sessions. Analysis of active-lever responding revealed significant effects of session
(F(5,155) = 38.2; p < 0.01) and an approaching significant effect of withdrawal period (F(2,31) = 2.6; p = 0.09). The effect of withdrawal period on inactive-lever responding was
not significant (p > 0.05).
View larger version (15K):
[in this window]
[in a new window]
|
Figure 2.
Sucrose. A, Extinction, total
responses: mean ± SEM responses on the previously active-lever
and inactive-lever responses during the six 60 min sessions of
extinction (conducted in the absence of the discrete tone-light cue
previously paired with sucrose infusions). B,
Extinction, responses per hour: mean active-lever responses at each
session of extinction. C, Cue-induced reinstatement:
mean active-lever responses during the 60 min session that followed the
extinction sessions. During the test for cue-induced reinstatement,
lever presses led to presentations of the tone-light cue. No cue
refers to the last 60 min extinction session on which the rats reached
the extinction criterion. *Different from day 1 withdrawal;
p < 0.05 (n = 10-14 per
withdrawal period).
|
|
Cue-induced reinstatement. Figure 2C shows
active-lever responses during the 1 hr test session for cue-induced
reinstatement in which lever presses led to the presentation of the
tone-light cue previously paired with earned sucrose. Analysis of
active-lever responding revealed significant effects of withdrawal
period (F(2,31) = 5.2;
p < 0.05), test session
(F(1,31) = 43.4; p < 0.01), and withdrawal period by test session
(F(2,31) = 5.9; p < 0.05). Inactive-lever responses were very low (group means of less than
two per 1 hr session), and no group differences were found
(p > 0.05).
Experiment 2: BDNF and NGF protein levels
The data obtained from the ELISAs are presented in Figure
3. The values for the cocaine- and
sucrose-trained rats are presented as the percentage of the mean values
of naive control rats that were not exposed to cocaine or sucrose.
Time-dependent increases in the levels of the BDNF protein, but not the
NGF protein, were observed in the VTA, accumbens, and amygdala after
withdrawal from cocaine. For BDNF in the VTA, analysis revealed
significant effects of reward type
(F(1,24) = 6.5; p < 0.01) and approaching significant effects of withdrawal period
(F(2,24) = 3.3; p < 0.06) and reward type by withdrawal period
(F(1,24) = 3.2; p < 0.06). For BDNF in the accumbens and amygdala, analysis revealed
significant effects of reward type
(F(1,34) = 17.7 and 31.6;
p < 0.01), withdrawal period
(F(2,34) = 9.5 and 9.6;
p < 0.01), and reward type by withdrawal period
(F(2,34) = 4.1 and 6.8;
p < 0.05). No significant effects were observed for
NGF levels in the VTA, accumbens, or amygdala (p > 0.05).
View larger version (20K):
[in this window]
[in a new window]
|
Figure 3.
BDNF and NGF protein levels in VTA
(A), accumbens (B), and
amygdala (C) after reward withdrawal. Data are
presented as the percentage of mean values of naive control rats that
were not exposed to sucrose or cocaine. *Different from the
sucrose-trained groups at each withdrawal day; p < 0.05. #Different from day 1 cocaine withdrawal;
p < 0.05 (n = 5-7 per
group).
|
|
| |
Discussion |
The responsiveness to cocaine cues progressively increases during
tests for resistance to extinction and cue-induced reinstatement and
persists for up to 90 d of withdrawal. Significant time-dependent changes in responsiveness to sucrose cues also were observed during the
test for cue-induced reinstatement, but not for resistance to
extinction, with peak responding after 30 d. Most important, BDNF,
but not NGF, protein levels in the VTA, accumbens, and amygdala progressively increase after withdrawal from cocaine, but not sucrose,
self-administration.
The present behavioral data extend our previous findings of incubation
of both sucrose and cocaine craving as measured in our model (Grimm et
al., 2001, 2002). The reasons for the different time course of
responding for cocaine versus sucrose cues and the less robust effect
on the test for resistance for extinction for sucrose-trained rats are
not known. Potential behavioral mechanisms for differences in magnitude
and duration of the incubation phenomenon in cocaine- versus
sucrose-trained rats, including response rates during training as well
as anhedonia and anxiety during early cocaine withdrawal have been
discussed previously (Grimm et al., 2002). Below we discuss the
potential role of BDNF in the persistent responsiveness to cocaine cues
after withdrawal.
BDNF and incubation of cocaine craving
Although incubation of craving occurs for sucrose and cocaine,
BDNF protein levels in the VTA, accumbens, and amygdala progressively increase after cocaine, but not sucrose, withdrawal. This increase in
BDNF levels had a time course similar to that of responding for cocaine
cues. Based on these data, we speculate that BDNF-mediated synaptic
plasticity may be involved in the persistent responsiveness to cocaine
cues after withdrawal. In this regard, it is of significance that both
BDNF levels and cue responding were substantially elevated on day 90 of
cocaine withdrawal, a time point at which responsiveness to sucrose
cues was similar to that observed on day 1. BDNF is involved in the
control of dendritic morphology (McFarlane, 2000). Thus, the higher
levels of BDNF observed here may produce morphological changes in brain
areas innervated by DA neurons; these changes have been hypothesized
recently to be involved in compulsive drug use (Robinson and Berridge,
2003). This hypothesis is based on the observations that exposure to
cocaine or amphetamine leads to persistent morphological changes in
neurons within the mesocorticolimbic DA terminal regions, such as
increases in dendritic branching and density of dendritic spines on
medium spiny neurons in the nucleus accumbens shell and on pyramidal
cells in the prefrontal cortex (Robinson and Kolb, 1999; Robinson et
al., 2001). The present data also are potentially relevant to those
from recent reports of cocaine-induced LTP in the VTA (Ungless et al.,
2001) and long-term depression (LTD) in the accumbens (Thomas et al.,
2001). LTP and LTD are cellular processes thought to be involved in
learning and memory processes, and are dependent on BDNF activity
(Yamada et al., 2002). However, the degree to which cocaine-induced LTP or LTD within the mesolimbic DA system is involved in incubation of
cocaine craving is not known in the absence of data on the time course
of these effects after withdrawal.
Finally, Horger et al. (1999) reported that BDNF infusions into the VTA
and accumbens enhance cocaine-induced locomotor sensitization. Horger
et al. (1999) also found that accumbens infusions of BDNF enhance
responding for a conditioned water reward, an effect similar to that
observed after repeated exposure to systemic cocaine injections (Taylor
and Horger, 1999). These observations are of potential relevance to the
phenomenon of incubation of craving because the time course of enhanced
responsiveness to cocaine cues is somewhat similar to that of the
expression of psychostimulant sensitization after withdrawal (Kalivas
and Stewart, 1991; Robinson and Berridge, 1993). For example,
time-dependent changes in the magnitude of amphetamine-induced
psychomotor activity during tests for the expression of sensitization
after withdrawal were observed for up to 1 year, with lower activity
during early withdrawal (Robinson and Berridge, 1993). The degree that
neuronal mechanisms underlying psychostimulant locomotor sensitization
are involved in incubation of cocaine craving, however, is not known.
Many studies on the expression of locomotor sensitization in
cocaine-experienced rats reported that locomotor activity is sensitized
during both early (first several days) and late (several weeks)
withdrawal (Henry and White, 1995). However, the mechanisms underlying
cocaine-induced locomotor sensitization during early withdrawal (e.g.,
subsensitivity of D2 autoreceptors in the VTA) are different from the
ones mediating cocaine sensitization during late withdrawal (e.g., D1
receptor supersensitivity, enhanced DA and glutamate neurotransmission in the accumbens) (White and Kalivas, 1998). Thus, it is possible that
the neuroadaptations associated with sensitized locomotor activity
during late withdrawal also are involved in the persistence of
responsiveness to cocaine cues observed here.
Concluding remarks
Time-dependent changes in responsiveness to reward cues after
withdrawal are observed in both cocaine- and sucrose-trained rats, and were previously found with heroin-trained rats in a test for resistance to extinction (Shalev et al., 2001). Time-dependent changes in responsiveness to cues also were reported after exposure to
aversive events, a phenomenon termed "incubation of fear" (Houston et al., 1999). Here we report time-dependent alterations in BDNF protein levels within the mesolimbic DA system after withdrawal from
cocaine, but not sucrose, self-administration. Therefore, neuronal
mechanisms other than alterations in BDNF levels are likely to be
involved in the incubation phenomenon that is observed with cues
previously paired with appetitive or aversive stimuli. We speculate,
however, that the persistence of responding to cocaine, but not to
sucrose, cues after prolonged withdrawal may involve BDNF-mediated
synaptic plasticity induced by cocaine self-administration and
subsequent withdrawal. These synaptic modifications may underlie cue-induced cocaine craving and relapse after prolonged abstinence.
| |
FOOTNOTES |
Received Sept. 9, 2002; revised Oct. 25, 2002; accepted Nov. 13, 2002.
*
J.W.G., L.L., and T.H. contributed equally to this work.
This work was supported by the National Institute on Drug Abuse,
Intramural Research Program. We thank Drs. Roy Wise, Barry Hoffer, and
Yun Wang for helpful suggestions and Kelly Badger and Polly Robarts for
technical assistance.
Correspondence should be addressed to Dr. Yavin Shaham, Behavioral
Neuroscience Branch, Intramural Research Program/National Institute on
Drug Abuse/National Institutes of Health, 5500 Nathan Shock Drive,
Baltimore, MD 21224. E-mail: yshaham{at}intra.nida.nih.gov.
J. W. Grimm's present address: Department of Psychology, Western
Washington University, 516 High Street, Bellingham, WA 98225-9089.
| |
References |
-
Childress AR,
Mozley PD,
McElgin W,
Fitzgerald J,
Reivich M,
O'Brien CP
(1999)
Limbic activation during cue-induced cocaine craving.
Am J Psychiatry
156:11-18[Abstract/Free Full Text].
-
Everitt BJ,
Parkinson JA,
Olmstead MC,
Arroyo M,
Robledo P,
Robbins TW
(1999)
Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems.
Ann NY Acad Sci
877:412-438[Web of Science][Medline].
-
Gawin FH,
Kleber HD
(1986)
Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations.
Arch Gen Psychiatry
43:107-113[Abstract/Free Full Text].
-
Grimm JW,
Hope BT,
Wise RA,
Shaham Y
(2001)
Incubation of cocaine craving after withdrawal.
Nature
412:141-142[Medline].
-
Grimm JW,
Shaham Y,
Hope BT
(2002)
Effect of the cocaine and sucrose withdrawal period on extinction behavior, cue-induced reinstatement and protein levels of the dopamine transporter and tyrosine hydroxylase in limbic and cortical areas in rats.
Behav Pharmacol
13:379-388[Web of Science][Medline].
-
Hall J,
Thomas KL,
Everitt BJ
(2000)
Rapid and selective induction of BDNF expression in the hippocampus during contextual learning.
Nat Neurosci
3:533-535[Web of Science][Medline].
-
Henry DJ,
White FJ
(1995)
The persistence of behavioral sensitization to cocaine parallels enhanced inhibition of nucleus accumbens neurons.
J Neurosci
15:6287-6299[Abstract].
-
Horger BA,
Iyasere CA,
Berhow MT,
Messer CJ,
Nestler EJ,
Taylor JR
(1999)
Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor.
J Neurosci
19:4110-4122[Abstract/Free Full Text].
-
Houston FP,
Stevenson GD,
McNaughton BL,
Barnes CA
(1999)
Effects of age on the generalization and incubation of memory in the F344 rat.
Learn Mem
6:111-119[Abstract/Free Full Text].
-
Hyman SE,
Malenka RC
(2001)
Addiction and the brain: the neurobiology of compulsion and its persistence.
Nat Rev Neurosci
2:695-703[Web of Science][Medline].
-
Kalivas PW,
Stewart J
(1991)
Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity.
Brain Res Brain Res Rev
16:223-244[Medline].
-
McFarlane S
(2000)
Dendritic morphogenesis: building an arbor.
Mol Neurobiol
22:1-9[Web of Science][Medline].
-
Nestler EJ
(2001)
Molecular basis of long-term plasticity underlying addiction.
Nat Rev Neurosci
2:119-128[Web of Science][Medline].
-
Nestler EJ,
Aghajanian GK
(1997)
Molecular and cellular basis of addiction.
Science
278:58-63[Abstract/Free Full Text].
-
O'Brien CP
(1997)
A range of research-based pharmacotherapies for addiction.
Science
278:66-70[Abstract/Free Full Text].
-
Paxinos G,
Watson C
(1998)
In: The rat brain in stereotaxic coordinates, Ed 4. San Diego: Academic.
-
Piazza PV,
Le Moal M
(1997)
Glucocorticoids as a biological substrate of reward: physiological and pathophysiological implications.
Brain Res Brain Res Rev
25:359-372[Medline].
-
Pierce RC,
Bari AA
(2001)
The role of neurotrophic factors in psychostimulant-induced behavioral and neuronal plasticity.
Rev Neurosci
12:95-110[Web of Science][Medline].
-
Robbins TW,
Cador M,
Taylor JR,
Everitt BJ
(1989)
Limbic-striatal interactions in reward related processes.
Neurosci Biobehav Rev
13:155-162[Web of Science][Medline].
-
Robinson TE,
Berridge KC
(1993)
The neural basis of drug craving: an incentive-sensitization theory of addiction.
Brain Res Brain Res Rev
18:247-291[Medline].
-
Robinson TE,
Berridge KC
(2003)
Addiction.
Annu Rev Psychol
54:25-53[Web of Science][Medline].
-
Robinson TE,
Kolb B
(1999)
Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine.
Eur J Neurosci
11:1598-1604[Web of Science][Medline].
-
Robinson TE,
Gorny G,
Mitton E,
Kolb B
(2001)
Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex.
Synapse
39:257-266[Web of Science][Medline].
-
Seroogy KB,
Lundgren KH,
Tran TM,
Guthrie KM,
Isackson PJ,
Gall CM
(1994)
Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs.
J Comp Neurol
342:321-334[Web of Science][Medline].
-
Shalev U,
Morales M,
Hope BT,
Yap J,
Shaham Y
(2001)
Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats.
Psychopharmacology
156:98-107[Medline].
-
Shalev U,
Grimm JW,
Shaham Y
(2002)
Neurobiology of relapse to heroin and cocaine: a review.
Pharmacol Rev
54:1-42[Abstract/Free Full Text].
-
Stewart J
(2000)
Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking.
J Psychiatry Neurosci
25:125-136[Web of Science][Medline].
-
Taylor JR,
Horger BA
(1999)
Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization.
Psychopharmacology
142:31-40[Medline].
-
Thoenen H
(1995)
Neurotrophins and neuronal plasticity.
Science
270:593-598[Abstract/Free Full Text].
-
Thomas MJ,
Beurrier C,
Bonci A,
Malenka RC
(2001)
Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine.
Nat Neurosci
4:1217-1223[Web of Science][Medline].
-
Ungless MA,
Whistler JL,
Malenka RC,
Bonci A
(2001)
Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons.
Nature
411:583-587[Medline].
-
Wang Y,
Chiang YH,
Su TP,
Hayashi T,
Morales M,
Hoffer BJ,
Lin SZ
(2000)
Vitamin D(3) attenuates cortical infarction induced by middle cerebral arterial ligation in rats.
Neuropharmacology
39:873-880[Web of Science][Medline].
-
White FJ,
Kalivas PW
(1998)
Neuroadaptations involved in amphetamine and cocaine addiction.
Drug Alcohol Depend
51:141-153[Web of Science][Medline].
-
Yamada K,
Mizuno M,
Nabeshima T
(2002)
Role for brain-derived neurotrophic factor in learning and memory.
Life Sci
70:735-744[Web of Science][Medline].
Copyright © 2003 Society for Neuroscience 0270-6474/03/233742-06$05.00/0
This article has been cited by other articles:
|
|
|
|
 
R. Goldstein, P. Woicik, S. Moeller, F. Telang, M. Jayne, C. Wong, G. Wang, J. Fowler, and N. Volkow
Liking and wanting of drug and non-drug rewards in active cocaine users: the STRAP-R questionnaire
J Psychopharmacol,
February 1, 2010;
24(2):
257 - 266.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. Jeanblanc, D.-Y. He, S. Carnicella, V. Kharazia, P. H. Janak, and D. Ron
Endogenous BDNF in the Dorsolateral Striatum Gates Alcohol Drinking
J. Neurosci.,
October 28, 2009;
29(43):
13494 - 13502.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Vargas-Perez, R. Ting-A-Kee, C. H. Walton, D. M. Hansen, R. Razavi, L. Clarke, M. R. Bufalino, D. W. Allison, S. C. Steffensen, and D. van der Kooy
Ventral Tegmental Area BDNF Induces an Opiate-Dependent-Like Reward State in Naive Rats
Science,
June 26, 2009;
324(5935):
1732 - 1734.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Russo, M. B. Wilkinson, M. S. Mazei-Robison, D. M. Dietz, I. Maze, V. Krishnan, W. Renthal, A. Graham, S. G. Birnbaum, T. A. Green, et al.
Nuclear Factor {kappa}B Signaling Regulates Neuronal Morphology and Cocaine Reward
J. Neurosci.,
March 18, 2009;
29(11):
3529 - 3537.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-Q. Li, F.-Q. Li, X.-Y. Wang, P. Wu, M. Zhao, C.-M. Xu, Y. Shaham, and L. Lu
Central Amygdala Extracellular Signal-Regulated Kinase Signaling Pathway Is Critical to Incubation of Opiate Craving
J. Neurosci.,
December 3, 2008;
28(49):
13248 - 13257.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Stewart
Psychological and neural mechanisms of relapse
Phil Trans R Soc B,
October 12, 2008;
363(1507):
3147 - 3158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Logrip, P. H. Janak, and D. Ron
Dynorphin is a downstream effector of striatal BDNF regulation of ethanol intake
FASEB J,
July 1, 2008;
22(7):
2393 - 2404.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-Y. Wang, M. Zhao, U. E. Ghitza, Y.-Q. Li, and L. Lu
Stress Impairs Reconsolidation of Drug Memory via Glucocorticoid Receptors in the Basolateral Amygdala
J. Neurosci.,
May 21, 2008;
28(21):
5602 - 5610.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-C. Huang, C.-H. Chen, C.-H. Chen, S.-C. Liu, C.-J. Ho, W. W Shen, and S.-J. Leu
Alterations of Serum Brain-Derived Neurotrophic Factor Levels in Early Alcohol Withdrawal
Alcohol Alcohol.,
March 7, 2008;
(2008)
agm172v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Noonan, K. H. Choi, D. W. Self, and A. J. Eisch
Withdrawal from Cocaine Self-Administration Normalizes Deficits in Proliferation and Enhances Maturity of Adult-Generated Hippocampal Neurons
J. Neurosci.,
March 5, 2008;
28(10):
2516 - 2526.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Angelucci, V. Ricci, M. Pomponi, G. Conte, A. A. Mathe, P. Attilio Tonali, and P. Bria
Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor
J Psychopharmacol,
November 1, 2007;
21(8):
820 - 825.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. A. Hollander and R. M. Carelli
Cocaine-Associated Stimuli Increase Cocaine Seeking and Activate Accumbens Core Neurons after Abstinence
J. Neurosci.,
March 28, 2007;
27(13):
3535 - 3539.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Taylor, W. J. Lynch, H. Sanchez, P. Olausson, E. J. Nestler, and J. A. Bibb
Inhibition of Cdk5 in the nucleus accumbens enhances the locomotor-activating and incentive-motivational effects of cocaine
PNAS,
March 6, 2007;
104(10):
4147 - 4152.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. Kalivas and N. D. Volkow
The Neural Basis of Addiction: A Pathology of Motivation and Choice
Focus,
January 1, 2007;
5(2):
208 - 219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Shen, G. E. Meredith, and T. C. Napier
Amphetamine-Induced Place Preference and Conditioned Motor Sensitization Requires Activation of Tyrosine Kinase Receptors in the Hippocampus
J. Neurosci.,
October 25, 2006;
26(43):
11041 - 11051.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Olausson, J. D. Jentsch, N. Tronson, R. L. Neve, E. J. Nestler, and J. R. Taylor
{Delta}FosB in the Nucleus Accumbens Regulates Food-Reinforced Instrumental Behavior and Motivation
J. Neurosci.,
September 6, 2006;
26(36):
9196 - 9204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Berton, C. A. McClung, R. J. DiLeone, V. Krishnan, W. Renthal, S. J. Russo, D. Graham, N. M. Tsankova, C. A. Bolanos, M. Rios, et al.
Essential Role of BDNF in the Mesolimbic Dopamine Pathway in Social Defeat Stress
Science,
February 10, 2006;
311(5762):
864 - 868.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Colvis, J. D. Pollock, R. H. Goodman, S. Impey, J. Dunn, G. Mandel, F. A. Champagne, M. Mayford, E. Korzus, A. Kumar, et al.
Epigenetic Mechanisms and Gene Networks in the Nervous System
J. Neurosci.,
November 9, 2005;
25(45):
10379 - 10389.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. Kalivas and N. D. Volkow
The Neural Basis of Addiction: A Pathology of Motivation and Choice
Am J Psychiatry,
August 1, 2005;
162(8):
1403 - 1413.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Lu, J. Dempsey, S. Y. Liu, J. M. Bossert, and Y. Shaham
A Single Infusion of Brain-Derived Neurotrophic Factor into the Ventral Tegmental Area Induces Long-Lasting Potentiation of Cocaine Seeking after Withdrawal
J. Neurosci.,
February 18, 2004;
24(7):
1604 - 1611.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
Introduction
