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The Journal of Neuroscience, March 15, 2003, 23(6):2488
Striatal Cell Type-Specific Overexpression of  FosB Enhances
Incentive for Cocaine
Christina R.
Colby1,
Kim
Whisler2,
Cathy
Steffen2,
Eric J.
Nestler2, and
David W.
Self2
1 Division of Molecular Psychiatry, Yale University
School of Medicine and Connecticut Mental Health Center, New Haven,
Connecticut 06508, and 2 Department of Psychiatry, The Seay
Center for Basic and Applied Research in Psychiatric Illness, The
University of Texas Southwestern Medical Center, Dallas, Texas
75390-9070
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ABSTRACT |
The transcription factor  FosB accumulates in substance
P-dynorphin-containing striatal neurons with repeated cocaine use. Here, we show that inducible transgenic FosB overexpression in this
same striatal cell type facilitates acquisition of cocaine self-administration at low-threshold doses, consistent with increased sensitivity to the pharmacological effects of the drug. Importantly, FosB also enhances the degree of effort mice will exert to maintain self-administration of higher doses on a progressive ratio schedule of
reinforcement, whereas levels of cocaine intake are not altered on less
demanding fixed-ratio schedules. Acquisition and extinction of behavior
reinforced by food pellets is not altered in FosB-overexpressing mice, indicating that FosB does not alter the capacity to learn an
instrumental response or cause response perseveration in the absence of
reinforcement. These data suggest that accumulation of FosB
contributes to drug addiction by increasing the incentive properties of
cocaine, an effect that could increase the risk for relapse long after
cocaine use ceases.
Key words:
cocaine; reinforcement; reward; addiction; nucleus
accumbens; craving
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Introduction |
Neuroadaptations to repeated drug
use are thought to underlie many addiction-related changes in behavior
(Self and Nestler, 1998 ; Koob and Le Moal, 2001; Nestler, 2001). One
such neuroadaptation involves accumulation of the transcription factor
FosB, a highly stable product of the fosB gene
(Hope et al., 1994; Chen et al., 1997). Unlike other Fos-related
proteins induced by acute drug treatment, FosB accumulates only in
striatal neurons after repeated exposure to cocaine and other drugs of
abuse (Nye et al., 1995; Nye and Nestler, 1996; Chen et al., 1997; Pich
et al., 1997), primarily because of its slow rate of degradation (Chen
et al., 1997). FosB is induced selectively in the substance
P-dynorphin-containing neurons of the striatum (Nye et al., 1995;
Moratalla et al., 1996), which coexpress primarily
D1 dopamine receptors and project to midbrain
structures, including the ventral tegmental area (Lu et al., 1998;
Steiner and Gerfen, 1998; Aubert et al., 2000; Canales and Graybiel,
2000). Drug-induced accumulation of FosB in nucleus accumbens, a
ventral striatal brain region highly implicated in regulation of
motivated behaviors, suggests that FosB could contribute to certain
transitional changes underlying the addiction process, such as
escalating drug intake and increased drug craving.
Using a tetracycline-inducible, cell-specific transgenic system, we
found previously that FosB overexpression in substance P-dynorphin-containing striatal neurons increases sensitivity to the
pharmacological properties of low doses of cocaine, suggesting that
FosB accumulation contributes to pharmacological sensitization (Kelz
et al., 1999). However, the addicted phenotype modeled in self-administration studies is not related directly to leftward shifts
in dose sensitivity but rather to vertical shifts in dose-intake function and to enhanced motivation to seek cocaine in the absence of
reinforcement (Ahmed and Koob, 1998; Mendrek et al., 1998; Lorrain et
al., 2000; Piazza et al., 2000; Sutton et al., 2000). The latter
reflects sensitization to the incentive properties of cocaine, an
effect thought to underlie craving and relapse during withdrawal
(Robinson and Berridge, 2001). In this study, we tested whether
accumulation of FosB in striatum contributes to such
addiction-related changes in cocaine self-administration using
procedures designed to measure discrete aspects of cocaine-taking and
-seeking behaviors.
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Materials and Methods |
Mice. Male bigenic mice were derived from a cross
between transgenic homozygotes with neuron-specific enolase (NSE)-tTA
(tetracycline transactivator protein) (line A) and tetOp
(tetracycline-responsive promoter)-fosB (line
11d), with both parental lines maintained on a mixed outbred background
(50% ICR, 50% C57BL/6 × SJL) as described previously (Kelz et
al., 1999). All mice were conceived and raised on 100 µg/ml
doxycycline (Sigma, St. Louis, MO) in the drinking water.
At weaning, mice destined for the FosB group were switched to water
for 8-11 weeks before behavioral testing commenced, whereas controls
remained on doxycycline. Mice weighing 25-40 gm were housed
individually in accordance with the National Institutes of Health
Guide for the Care and Use of Laboratory Animals. A serial
testing procedure was implemented involving acquisition-extinction of
food pellet self-administration, surgical catheter implantation,
acquisition of cocaine self-administration, and self-administration
dose-response testing on both fixed and progressive ratio schedules of
cocaine reinforcement.
Acquisition-extinction of food pellet self-administration.
Mice were food deprived for 16 hr and placed in operant test chambers (Med Associates, St. Albans, VT) for an initial 1 hr period to measure spontaneous lever press behavior in the absence of
reinforcement. On subsequent test days, mice were allowed to lever
press for food pellets consisting of standard laboratory chow (25 mg)
by performing three responses at one lever (FR3) designated as active and signaled by a cue light above the lever. After each test session, mice were allowed to consume enough chow to maintain initial body weight but were food deprived for 16 hr before the subsequent test.
Testing continued until mice achieved acquisition criteria ( 25
pellets per session) and continued lever-press training for an
additional two test sessions. After the acquisition criterion was met,
mice were fed ad libitum and were allowed to extinguish responding in daily 2 hr tests until mice extinction criteria were
achieved ( 10 responses per lever at food-paired and inactive levers).
Mice that failed to reach extinction criteria after 15 d were
given an extinction latency of 15 test sessions and were not used in
subsequent testing (3 of 12 control and 5 of 15 FosB mice). Data
from the first 27 mice were analyzed and showed no significant
differences. All other mice were subjected to this procedure, and only
mice that met extinction criteria were used in subsequent cocaine
self-administration experiments.
Acquisition of cocaine self-administration. After
achievement of extinction criteria, animals were surgically implanted
with a chronic indwelling jugular catheter composed of SILASTIC tubing (0.012 inch inner diameter; 0.025 inch outer diameter) passing subcutaneously to exit the back through 23 gauge stainless steel tubing
embedded in cranioplastic cement and secured with Marlex surgical mesh.
Animals were allowed at least 4 d to recover before cocaine
self-administration testing. Catheters were flushed daily with 0.05 ml
of heparinized (20 IU/ml) bacteriostatic saline containing gentamycin
sulfate (0.33 mg/ml); this antibiotic does not interact with tTA.
Each mouse was tested for acquisition of cocaine self-administration in
daily 1 hr sessions in the same chamber used for food pellet
self-administration. Catheters were connected to a 10 ml syringe pump
(Razel Scientific Instruments, Stamford, CT) through a fluid swivel
(Stoelting, Kiel, WI). During acquisition of cocaine self-administration, a single lever-press response on the active lever
(FR1) delivered an intravenous cocaine injection in 50 µl of saline
over 2.5 sec. A cue stimulus consisting of a cue light above the lever,
house light off, and injection pump sound was concurrent with each
injection, followed by an additional 8 sec time-out when responding had
no programmed consequences. Acquisition of cocaine self-administration
was conducted over 10 d, with access to a low-threshold dose for
the first 5 d (125 or 250 µg/kg per injection), followed by a
higher dose (500 µg/kg per injection) for days 6-10. This procedure
ensured acquisition of cocaine self-administration in most mice after
10 test sessions. Catheter patency was verified after each test phase
(acquisition, fixed-ratio dose-response, and progressive ratio
dose-response) with sodium methohexital (0.5 mg/ml).
Cocaine self-administration dose-response on fixed and
progressive ratio schedules. After acquisition testing, mice
continued to self-administer cocaine at 500 µg/kg per injection in
daily 1 hr sessions, and the response requirement was increased
incrementally to a fixed ratio of five responses per injection (FR5)
and until daily cocaine intake stabilized to within 15% of the mean of
three consecutive sessions. Mice were subsequently allowed to
self-administer descending injection doses of cocaine, each for two
consecutive daily 1 hr sessions, beginning with 1000 µg/kg per
injection and ending with saline; the number of cocaine injections per
session and the total amount of cocaine intake per session from the
second test were used for the analysis. Thirty-one of 41 mice entering fixed-ratio dose-response testing maintained catheter patency and were
used in the analysis.
After fixed-ratio dose-response testing, animals were restabilized at
500 µg/kg per injection for at least 3 d and subsequently allowed to self-administer cocaine on a progressive ratio schedule, with the response requirement for each successive injection increasing by progressive increments according to the following series: 1, 2, 4, 6, 9, 12, 16, 20, 25, 30, 36, 42, 49, 56, 64, 72, 81, 90, 100, and 110. Three intermediate to high injection doses were chosen on the basis of
their ability to maintain equivalent levels of cocaine
self-administration on fixed-ratio schedules (250, 500, and 1000 µg/kg per injection). Each dose was tested in two consecutive daily
sessions in counterbalanced order. The highest ratio of responses per
injection achieved before a 30 min period when no additional injections
were earned was analyzed for the second test day at each dose.
Twenty-eight of 31 mice entering progressive ratio testing maintained
catheter patency and were used in the analysis.
Data analysis. Data were analyzed by two-factor ANOVA
on group with repeated measures on either dose or time. Post
hoc comparisons between controls and FosB mice used tests for
simple effects at each time point or cocaine dose. Unitary measures
(e.g., latency) were compared with unpaired t tests.
Separate within-group ANOVAs were conducted on self-administration
dose-response (fixed ratio), and post hoc analysis compared
the number of injections at each cocaine dose with saline by Dunnett's
test; significant effects are shown for the 63 µg/kg per injection
dose only.
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Results |
In male bigenic mice (NSE-tTA × tetOp-fosB),
removal of doxycycline from the drinking water at weaning induces a
7.5-fold increase in FosB immunoreactivity at adulthood that is
restricted to substance P-dynorphin-containing striatal neurons, and
no appreciable expression is seen in other brain regions (Chen et al.,
1998; Kelz et al., 1999). We first tested these mice for possible
differences in instrumental behavior using 25 mg food pellets as a
reinforcer while they were maintained on a food-restricted diet. Figure
1B shows that mice
overexpressing FosB and their bigenic littermate controls
(maintained on doxycycline) sample the levers at equivalent rates in
the absence of reinforcement during an initial test for spontaneous
lever-press behavior. When food reinforcement is made available on a
FR3 schedule (three responses per pellet), both FosB mice and
controls acquire lever-press responding at similar rates (Fig.
1A), averaging approximately five to six test
sessions to achieve acquisition criteria (first session in which 25
pellets are earned). Acquisition latencies range from 1 to 13 d in
controls and 1 to 9 d in FosB-overexpressing mice.
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Figure 1.
Striatal cell-specific overexpression of FosB
(n = 15; filled circles and
bars) fails to alter acquisition and extinction of
lever-press responding reinforced by food pellets compared with bigenic
littermate controls maintained on doxycycline (n = 12; open circles and bars).
A, The percentage of mice achieving acquisition criteria
(for criteria, see Results) in daily 1 hr tests and the mean ± SEM number of test sessions to acquire self-administration of food
pellets on an FR3 reinforcement schedule are shown. B,
Spontaneous lever-press responding in naive mice before acquisition
testing is similar between groups (left), and FosB
overexpression also fails to alter lever discrimination on the day
acquisition criteria are met (middle) or the latency to
consume 30 food pellets after 2 additional training days
(right). C, The percentage of FosB
mice achieving extinction criteria (10 responses in 2 hr at both
levers) and the number of test sessions to achieve extinction criteria
in the absence of reinforcement are similar in FosB and control
mice.
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Both FosB and control mice showed a similar preference for the
active lever on achieving acquisition criteria and consumed the
30-pellet allotment in similar times after 2 additional training days
(Fig. 1B). After food pellet self-administration,
both FosB and control mice extinguished responding at similar rates
in the absence of reinforcement (Fig. 1C), requiring an
average of eight sessions to achieve extinction criteria (10
responses in 2 hr at both levers). These data indicate that
FosB-over-expressing mice and doxycycline controls are equally
capable of acquiring and discriminating instrumental responses and
equally capable of extinction learning when reinforcement is not available.
Acquisition of cocaine self-administration was tested in daily 1 hr
sessions over 10 d on a FR1 reinforcement schedule, with an 8 sec
time-out period after each cocaine injection. Figure 2A shows that
FosB-overexpressing mice avidly learn to self-administer a
low-threshold dose of cocaine (125 µg/kg per injection), taking significantly more cocaine injections than doxycycline controls after
4 d of acquisition testing
(F(1,22) = 5.806; p = 0.025). Total active lever responses increase progressively only in
FosB mice at this low dose during acquisition (lever × test
day; F(4,40) = 2.823;
p = 0.037), although both FosB
(F(1,10) = 16.505; p = 0.002) and control (F(1,12) = 6.087;
p = 0.030) mice respond more at the active than the
inactive lever. FosB mice achieve acquisition criteria for cocaine
self-administration faster than doxycycline controls, as indicated by
the number of test sessions required to achieve >15 cocaine injections
for 3 consecutive days, each with a 3:1 ratio of active-inactive lever
presses. Both groups show similar self-administration rates when the
injection dose is raised to 500 µg/kg per injection over days 6-10
of acquisition testing, indicating that increased self-administration
at the lower dose does not reflect a generalized rate-enhancing effect in FosB mice that self-administer cocaine. Indeed, when mice are
allowed to initiate cocaine self-administration at a higher injection
dose for the first 5 test days (250 µg/kg per injection), there is no
difference in response rates or the latency to acquire self-administration (Fig. 2B). These data indicate
that FosB increases sensitivity to the reinforcing effects of very
low doses of cocaine, consistent with increased sensitivity to cocaine
in locomotor and place preference tests reported previously (Kelz et
al., 1999). However, 7 of 25 FosB mice completing acquisition testing with patent catheters (5 of 16 at 125 µg/kg; 2 of 9 at 250 µg/kg) failed to achieve acquisition criteria compared with only 1 of
24 controls (1 of 14 at 125 µg/kg), and analysis of acquisition rates
is limited to animals that demonstrate a capacity to acquire cocaine
self-administration. These latter differences are not statistically
significant but could suggest that FosB mice that fail to acquire
cocaine self-administration at low doses are more refractory than
controls to subsequent acquisition at higher doses.
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Figure 2.
Striatal cell-specific overexpression of FosB
(filled circles and bars)
facilitates acquisition of cocaine self-administration (FR1) at a
low-threshold dose of cocaine (125 µg/kg per injection)
(A) but not at a higher suprathreshold dose (250 µg/kg per injection) (B) compared with
littermate bigenic controls maintained on doxycycline (open
circles and bars). The numbers of cocaine
injections (solid lines) and inactive lever presses
(dashed lines) are shown at left, and the number
of test sessions (latency) to achieve criteria for acquisition of
cocaine self-administration are shown at right (for
criteria, see Results). Each dose is tested for 5 d,
followed by a higher training dose (500 µg/kg per injection) for days
6-10 to demonstrate a capacity for acquisition in all mice used in the
analysis. Asterisks indicate that FosB mice
(n = 11, 7) differ from littermate controls
(n = 13, 10) for threshold-dose cocaine
self-administration by tests for simple effects
(p < 0.05).
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After 10 d of acquisition testing, mice that met acquisition
criteria (41 of 49) were trained to self-administer cocaine at 500 µg/kg per injection in daily 1 hr sessions, and the response requirement was gradually increased to five lever presses per injection
until self-administration rates stabilized to within 15%. Mice were
subsequently tested with descending injection doses, each available for
2 consecutive days over 12 d of testing; 31 of 41 mice maintained
catheter patency throughout this procedure. Cocaine self-administration
produces an inverted U-shaped dose-response curve on fixed-ratio
schedules, spanning dose thresholds for maintaining self-administration, and a descending limb in which increasing the
injection dose prolongs the duration of cocaine reward, resulting in fewer self-injections. Figure
3A shows that both
FosB-over-expressing mice and doxycycline controls show typical
inverted U-shaped self-administration dose-response curves. However,
the lowest cocaine dose (63 µg/kg per injection) maintains
self-administration rates above saline injections only in FosB mice
but not in controls, consistent with enhanced sensitivity to cocaine
reinforcement at low doses in acquisition testing. At higher doses that
maintain self-administration in both groups, FosB fails to alter
self-administration rates on the descending limb of the curve, and
overall cocaine intake is similar for both groups across these
injection doses (Fig. 3B), indicating that FosB
overexpression does not alter the duration of reward produced by the
cocaine injections.
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Figure 3.
Striatal cell-specific overexpression of FosB
increases sensitivity to a low threshold dose of cocaine after
acquisition and stabilization of self-administration on an FR5 schedule
(n = 16; filled circles) but does
not alter self-administration rates at higher doses that are
reinforcing in littermate controls (n = 17;
open circles) (A) or overall
cocaine intake across all doses (B). Black
dots indicate that the 63 µg/kg per injection dose differs
from saline by Dunnett's test (p < 0.001).
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After dose-response testing on a fixed-ratio schedule, mice returned
to the training dose and were stabilized for at least 3 d before
subsequent testing on a progressive ratio schedule of cocaine
reinforcement. In progressive ratio testing, each successive cocaine
injection requires a progressively greater number of lever-press responses; the highest ratio of lever presses per cocaine injection achieved before self-administration ceases represents the degree of
effort animals will exert to maintain cocaine self-administration and
is thought to reflect the incentive strength of cocaine. Figure 4A shows representative
cumulative response records from individual control and
FosB-overexpressing mice self-administering cocaine (250 µg/kg per
injection) on the progressive ratio schedule. The FosB mouse
achieves a higher ratio of responses per injection before
self-administration ceases, performing 56 responses for the final
cocaine injection, as indicated by the vertical difference between the
last two injections (dotted lines), relative to 30 responses
per injection in the control mouse. FosB mice complete higher
response ratios at 250 and 500 µg/kg per injection
(F(1,26) = 4.620; p = 0.041), indicating greater effort to maintain self-administration (Fig.
4B). A main effect of dose indicates that the highest
ratio of responses per injection completed increases in a
dose-dependent manner (F(2,52) = 5.984; p = 0.005), although convergence at the highest
dose probably reflects a performance ceiling in both groups. Moreover,
the fact that the final ratio completed converges at this high dose
indicates that increased response ratios at lower doses in FosB mice
are not related to a generalized enhancement of performance capacity
but rather to greater motivation to obtain cocaine reinforcement.
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Figure 4.
Striatal cell-specific overexpression of FosB
facilitates cocaine self-administration on a progressive ratio schedule
of reinforcement. A, Cumulative active lever response
records for representative mice show that FosB increases the number
of cocaine injections (arrows) earned relative to a
bigenic littermate control (250 µg/kg per injection). dox,
Doxycycline. B, FosB mice (n = 11; filled circles) exert greater effort to maintain
cocaine self-administration, as reflected by completing a higher ratio
of responses per injection (distance between dotted
lines in A) immediately before cessation of
self-administration. Convergence of the final ratio completed at the
highest injection dose indicates that littermate control mice
(n = 17; open circles) are capable
of performing at levels found in FosB mice. Asterisk
indicates main effect of group on ratio completed by ANOVA across the
250 and 500 µg/kg per injection dose (p < 0.05).
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Discussion |
Striatal cell-specific overexpression of FosB in inducible
transgenic mice produces two major effects on cocaine
self-administration behavior. The first enhances sensitivity to the
reinforcing effects of very low injection doses of cocaine. Thus,
FosB-overexpressing mice will learn to self-administer
cocaine at doses lower than controls and will maintain
self-administration of even lower doses after cocaine
self-administration is acquired. These results are entirely consistent
with a role for FosB in substance P-dynorphin-containing striatal
neurons in regulating pharmacological sensitivity to cocaine (Kelz et
al., 1999) and show that enhanced sensitivity translates into a
propensity to acquire cocaine self-administration at these low doses.
Such increased sensitivity to cocaine is not caused by altered
pharmacokinetics by FosB or doxycycline because (1) we reported
previously that FosB overexpression in these mice fails to alter
serum cocaine levels (Kelz et al., 1999), (2) the NSE promoter
restricts transgenic expression to neural tissue, and (3) doxycycline
treatment fails to alter serum cocaine levels and locomotor responses
to acute and repeated cocaine administration in monogenic NSE-tTA or
tetOp-FosB mice (data not shown). Moreover, both groups
self-administer similar amounts of cocaine at higher doses. Increased
acquisition at a low cocaine dose in FosB mice also is unrelated to
facilitation of instrumental learning or response perseveration,
because both FosB mice and controls acquire responding at similar
rates when reinforced by higher cocaine doses or by food pellets and
extinguish at similar rates in the absence of reinforcement.
Importantly, cell-specific overexpression of FosB also raises the
amount of effort mice will exert to maintain cocaine
self-administration. Given that FosB and control mice reach similar
asymptotic response ratios in progressive ratio testing, these
differences cannot be ascribed to a generalized performance-enhancing
effect. Instead, these results suggest that FosB sensitizes animals
to the incentive properties of cocaine, thereby increasing the
motivation to seek cocaine when reinforcement is withheld.
Sensitization to the incentive properties of cocaine differs markedly
from an increase in pharmacological sensitivity discussed above,
because FosB mice work harder to maintain self-administration of
doses that also are effective reinforcers in control mice. Thus, both
groups readily acquire and take similar amounts of cocaine at the 250 and 500 µg/kg injection doses when self-administered on less
demanding fixed-ratio schedules of reinforcement, but FosB mice work
harder to self-administer these same doses on a progressive ratio schedule.
Sensitization to the incentive properties of cocaine can be dissociated
from pharmacological sensitivity and regulation of drug intake in
self-administration studies (Richardson and Roberts, 1996; Green et
al., 2002), suggesting that these phenomena are independently regulated
by separate neural substrates. For example, rats raised in isolated
environmental conditions have lower dose thresholds for amphetamine
self-administration than rats raised in enriched conditions, but they
exert equal effort to maintain self-administration of suprathreshold
doses (Green et al., 2002). In contrast, increased motivation for
suprathreshold doses of drug is arguably more relevant to craving in
humans than pharmacological sensitivity. In this regard, it is notable
that attempts to model the addicted phenotype in animals, whether by
inherent differences or by transitional changes in drug
self-administration, have not found overall leftward shifts in dose
sensitivity but instead are related to higher levels of drug intake and
drug-seeking behavior (Ahmed and Koob, 1998; Mendrek et al., 1998;
Deroche et al., 1999; Ahmed et al., 2000; Lorrain et al., 2000; Piazza
et al., 2000; Sutton et al., 2000).
FosB accumulates in both dorsal and ventral striatum with repeated
cocaine exposure, and this regional pattern of expression is reproduced
in the inducible FosB mice used in these studies. However, the
effects of FosB on cocaine self-administration may result from
FosB accumulation in ventral striatal regions, including the nucleus
accumbens, because cocaine self-administration is modulated by
dopaminergic lesions of the nucleus accumbens and not the
caudate-putamen (Koob and Goeders, 1989). An important advantage in
our studies is that the transcription factor is expressed only in
substance P-dynorphin containing striatal neurons, precisely the same
cell type in which endogenous FosB accumulates with repeated cocaine
exposure (Nye et al., 1995; Moratalla et al., 1996). In nucleus
accumbens, these neurons project primarily to the ventral tegmental
area and constitute a major output pathway from the basal ganglia (Lu
et al., 1998; Steiner and Gerfen, 1998; Aubert et al., 2000; Canales
and Graybiel, 2000).
FosB is induced by a cascade of events thought to involve
cocaine-induced elevations in nucleus accumbens dopamine levels and
activation of D1 dopamine receptor-cAMP-mediated
signaling pathways (Nye et al., 1995). Accumulation of FosB in these
neurons would be expected to alter expression of multiple genes that
contain activator protein 1 (AP-1) binding sites in their
promoter regions. One of these AP-1 targets is the cyclin-dependent
kinase CDK-5 that is induced by both FosB overexpression and chronic
cocaine (Bibb et al., 2001). FosB-induced expression of CDK-5 may
represent a negative feedback signaling pathway, because CDK-5 converts DARPP-32 (dopamine-regulated phosphoprotein 32) into a cAMP-dependent protein kinase inhibitor. Thus, CDK-5 expression may counteract the
acute effects of cocaine mediated by D1 receptors
and cAMP and upregulation of cAMP signaling proteins in nucleus
accumbens produced by chronic cocaine (Terwilliger et al., 1991;
Freeman et al., 2001). In another sense, FosB induction of CDK-5
expression and the subsequent inhibition of cAMP signaling could
contribute to enhanced motivation for cocaine by FosB, because we
found previously that inhibition of cAMP-dependent protein kinase in nucleus accumbens promotes cocaine-seeking behavior (Self et al., 1998), an effect entirely consistent with FosB action in progressive ratio testing.
Chronic cocaine use produces numerous neuroadaptations in the brain,
but very few have been shown, as FosB is shown here, to cause
addiction-related changes in drug self-administration. Our previous
studies suggest that drug-induced upregulation of nucleus
accumbens cAMP signaling could contribute to escalating cocaine
intake as initial recreational use leads to cocaine addiction, consistent with an intracellular mechanism of tolerance to cocaine reward (Self et al., 1998). The fact that FosB accumulation does not
affect overall cocaine intake suggests that other cAMP-mediated cellular events contribute to this escalation. In contrast,
striatal accumulation of FosB could enhance incentive for cocaine as
the addiction process advances, thereby sensitizing mechanisms that regulate drug craving and relapse. Moreover, these results emphasize the notion that drug-taking and -seeking behaviors are regulated by
different neuronal processes and illustrate the importance of studying
each drug-induced neuroadaptation in the context of discrete aspects of
drug self-administration behavior.
Another consideration is that most neuroadaptations to chronic drug
use, including FosB, inevitably return to normal after withdrawal
from self-administration. However, neuroadaptations that directly
increase the incentive properties of drugs could inevitably lead to
long-term, even permanent, influences by facilitating the motivational
salience of drug-related memories. Thus, by directly increasing the
incentive value of cocaine during drug use, FosB could indirectly
facilitate drug craving triggered by environmental stimuli associated
with cocaine use, even after FosB levels return to normal in
prolonged abstinence. Similar incentive learning during early heroin
withdrawal can subsequently influence the motivation to seek heroin
long after withdrawal symptoms subside (Hutcheson et al., 2001) and
could also outlast certain neuroadaptations to repeated drug use.
Alternatively, relatively transient neuroadaptations in transcription
factors like FosB could instigate a cascade of neuronal events
leading to relatively permanent changes in synaptic organization
(Robinson et al., 2001) that sensitize subsequent neural and
motivational responses to cocaine or cocaine-related environmental
stimuli. Additional investigation on how FosB and other
neuroadaptations contribute to the long-term consequences of drug
addiction ultimately will provide new opportunities to reverse or
prevent neurobehavioral processes that underlie persistent addictive behavior.
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FOOTNOTES |
Received Oct. 31, 2002; revised Dec. 26, 2002; accepted Dec. 31, 2002.
This work was supported by United States Public Health Service Grants
DA-10460 and DA-08227 and by the Lydia Bryant Test Professorship (University of Texas Southwestern Medical Center).
Correspondence should be addressed to David W. Self, Department of
Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX
75390-9070. E-mail: david.self{at}utsouthwestern.edu.
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TOP
ABSTRACT
Introduction
