Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative
emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid
to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio
control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-
in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and
compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked
Alcoholism is a complex psychiatric condition characterized by
compulsive alcohol seeking and ingestion, loss of control over
intake, and the emergence of a negative emotional state during
withdrawal (Koob and Volkow, 2010). Similar to stress, alcohol
intake activates the hypothalamic-pituitary-adrenal (HPA) axis
corticosterone in rodents) from the adrenal gland (Ellis, 1966;
to the reinforcing effects of drugs (Fahlke et al., 1995, 1996;
Goeders, 1997; Piazza and Le Moal, 1998; Mantsch et al., 1998;
Uhart and Wand, 2009). Upon release, CORT binds to two types
of brain receptors: mineralocorticoid receptors (MRs or type I,
(GRs or type II, which have a lower affinity for CORT and are
activated predominantly at high circulating CORT levels; McE-
wen et al., 1968, McEwen, 2007). A consequence of high CORT
levels is the dysregulation of gene transcription, including
corticotropin-releasing factor (CRF), a critical factor in alcohol
dependence-related neuroadaptations (Heilig and Koob, 2007).
In alcohol dependence, the neuroendocrine stress system is
dysregulated in both humans (Adinoff et al., 1990; 2003; Lovallo
et al., 2000; Uhart and Wand, 2009; Sinha et al., 2011) and ro-
dents (Rasmussen et al., 2000; Zorrilla et al., 2001; Richardson et
al., 2008), but the consequences of this dysregulation for the es-
calation of alcohol intake, compulsive use, and relapse remain
unclear. Following a prolonged history of alcohol dependence,
negative reinforcement becomes a dominant motivational factor
for continued alcohol use (i.e., alcohol is used to alleviate or
prevent negative emotional symptoms, such as anxiety, dyspho-
ria, and hypohedonia that emerge in the absence of the drug;
Edwards and Koob, 2010). The transition from positive rein-
forcement in nondependent individuals to negative reinforce-
from National Institute of General Medicine, Grants AA006420, AA017371, AA012602, and AA013191 from
for author M.L.L. by NIAAA Grant F32AA018914. We thank Michael Arends for proofreading the manuscript, Dr. Scott
TheJournalofNeuroscience,May30,2012 • 32(22):7563–7571 • 7563
ment in alcohol dependence may therefore be driven by
dysregulated HPA axis function, yet the role of MRs and GRs in
the transition to alcohol dependence remains to be investigated.
the escalated and compulsive alcohol intake that results when
alcohol dependence is induced by alcohol vapor exposure. Com-
pulsive drinking was assessed by a progressive-ratio (PR) test, in
reinforcement increases progressively (Hodos, 1961), and by a
quinine adulteration test that measures persistent alcohol con-
alcohol solution; Wolffgramm and Heyne, 1995). We found that
associated with changes in glucocorticoid receptor (GR) expres-
sion levels in several stress/reward-related brain areas. Chronic
GR antagonism prevented the development of escalated and
compulsive alcohol drinking produced by alcohol vapor expo-
escalated drinking in alcohol dependence.
Subjects. Adult male Wistar rats (Charles River), weighing 225–275 g at
the beginning of the experiments, were housed in groups of 2–3 per cage
in a temperature-controlled (22°C) vivarium on a 12 h/12 h light/dark
behavioral tests were conducted during the dark phase of the light/dark
cycle. All procedures adhered to the National Institutes of Health Guide
for the Care and Use of Laboratory Animals and were approved by the
Institutional Animal Care and Use Committee of the Scripps Research
Operant self-administration. Self-administration sessions were con-
ducted in standard operant conditioning chambers (Med Associates).
The rats were first trained to self-administer alcohol using a modified
(Walker and Koob, 2007) sucrose-fading procedure (Samson, 1986), in
which 10% (w/v) alcohol was added to a sweet solution and then sweet-
eners were gradually removed from the experimental solution. Upon
completion of this procedure, the animals were allowed to self-
administer a 10% (w/v) alcohol solution and water on a fixed-ratio 1
(FR1) schedule of reinforcement (i.e., each operant response was rein-
forced with 0.1 ml of the solution). For the pharmacological tests with
mifepristone, rats were trained to self-administer alcohol according to
ing but with less testing in preliminary studies. First, the rats were given
free-choice access to alcohol (10% w/v) and water for 1 d in their home
cages to habituate them to the taste of alcohol. Second, the rats were
subjected to an overnight session in the operant chambers with access to
one lever (right lever) that delivered water (FR1). Food was available ad
a 2 h session (FR1) for 1 d and a 1 h session (FR1) the next day, with one
30 min, and two levers were available (left lever: water; right lever: alco-
this procedure is equivalent to the sucrose-fading procedure (Samson,
1986; Walker and Koob, 2007). Upon completion of this procedure, the
animals were allowed to self-administer a 10% (w/v) alcohol solution
and water on an FR1 schedule of reinforcement.
Alcohol vapor chambers. The rats were made dependent by chronic,
intermittent exposure to alcohol vapors as previously described (O’Dell
et al., 2004; Gilpin et al., 2008). They underwent cycles of 14 h on (blood
and 10 h off, during which behavioral testing for acute withdrawal oc-
curred (i.e., 6–8 h after vapor was turned off when brain and blood
al., 1995; Roberts et al., 2000; Valdez et al., 2002; Rimondini et al., 2003;
O’Dell et al., 2004; Zhao et al., 2007; Sommer et al., 2008; Edwards et al.,
2012). Nondependent rats were not exposed to alcohol vapor. For pro-
for acute withdrawal but 3–6 weeks after the vapor was turned off.
Operant self-administration during alcohol vapor exposure. Behavioral
testing occurred 2–4 times per week. The rats were tested for alcohol
13 30-min sessions. Operant self-administration on an FR1 schedule
on a PR schedule, under which the number of lever presses necessary to
obtain the next reinforcer progressively increased according to the fol-
lowing progression: 1, 1, 2, 2, 3, 3, 4, 4, 5, 5, 7, 7, 9, 9, 11, 11, 13, 13, etc.
the rat obtaining a reinforcer. In this test, the workload (“price”) for the
next alcohol reinforcer increases progressively until the rat reaches a
it no longer responds for alcohol.
adulterated with increasing concentrations of quinine (0.0005, 0.001,
0.0025, and 0.005 g/L) presented between-sessions (one concentration
per session). This test measures the persistence of animals to consume
alcohol despite the aversive bitter taste of quinine that was added to the
alcohol solution and was considered herein a measure of compulsive
Finally, the rats were tested for saccharin (0.004%, w/v) self-
administration under an FR1 schedule for five 30 min sessions to deter-
types of reward. A submaximal rewarding saccharin concentration was
chosen based on previous studies (Vendruscolo et al., 2010) to prevent
reaching a “ceiling effect” in any group and maintain similar response
rates as alcohol.
Brain collection. Brains from dependent and nondependent rats were
collected and snap-frozen with isopentane for measurements of GR and
MR mRNA levels during acute alcohol withdrawal (24 h after the vapor
effects caused by earlier withdrawal. Importantly, the escalation of alco-
hol consumption has been demonstrated in rats at 2–8 h and 24 h of
withdrawal and 2–7 weeks post-vapor (Valdez et al., 2002; Rimondini et
al., 2003; O’Dell et al., 2004; Gilpin et al., 2008; Sommer et al., 2008).
vapor was turned off to investigate whether changes in GR mRNA levels
could be detected during protracted alcohol abstinence. The brains were
sliced on a cryostat, and bilateral punches (300 ?m thickness, 2 mm
diameter) were collected from the prefrontal cortex (PFC), nucleus ac-
cumbens (NAc), bed nucleus of the stria terminalis (BNST), amygdala,
and hippocampus. Because we expected that smaller gene expression
changes might occur during protracted alcohol abstinence, we dissected
300 ?m cryostat-cut slices (Cuello and Carson, 1983).
Quantitative nuclease protection array. The expression of GR and MR
clease protection assays (qNPA, High Throughput Genomics). This assay
was used because it allowed us to quantitatively measure several stress/
reward-related genes at the same time. The primer sequences were the fol-
GAGACAGAAACAAAAGTGATGGGGAATGACTTGG; position 1474,
GATTGCAGCAGTGAAATGGC), MR (position 346, CCTCTCCATCCT
ACC CCACGG; position 3380, CTGGGAATGCCAAACCCCTTTACTTT
7564 • J.Neurosci.,May30,2012 • 32(22):7563–7571 Vendruscoloetal.•CorticosteroidReceptorsandAlcoholDependence
was extracted and purified from brain tissue using the PureLinkTM RNA
to a 96-well plate. The plate was then heated at 95°C for 15 min (denatur-
by S1-nuclease digestion for 90 min at 50°C. The enzymatic reaction was
terminated by adding 10 ?l of S1 stop solution, followed by incubation at
heteroduplexes and degrade the RNA, leaving the sample with the selected
probe only. The samples were then transferred for RNA quantification to a
probe, had been printed into each well, and incubated at 50°C for 24 h to
allow for probe hybridization to the plate. After several washes, 40 ?l of
detection linker solution was added to each well, and the ArrayPlate was
30 min after the addition of the detection enzyme (40 ?l). This step was
luminescent substrate. The chemiluminescent signal from each well of the
Reverse transcription and quantitative PCR. Given that GR mRNA levels
and not MR mRNA levels were differentially expressed in dependent and
DNase I (Qiagen). Concentrations were determined using the Quant-iT
RiboGreen RNA Assay Kit (Invitrogen). cDNA was reverse-transcribed
and random primers according to the manufacturer’s instructions. Gene
expression levels were determined by quantitative PCR (qPCR) using a
SYBR Green-based detection system (iQ SYBR Green Supermix, Bio-Rad
to detect changes in fluorescence in real time, and cDNA concentrations of
GR were calculated according to the relative quantification (ddCt)
method, corrected for differences in PCR efficiency, and normalized to
glyceraldehyde-3-phosphate dehydrogenase (Gapdh), cyclophilin A (Ppia),
or ?-actin (Actb). The following primers were used: GR primer pair 1 (for-
ward, 5? TACAAAGATTGCAGGTATCCTATGA 3?; reverse, 5? ACTCTT
GGCTCTTCAGACCTTC 3?), primer pair 2 (forward, 5? GCACCAGCTA
TCAGAAGACC 3?; reverse, 5? GCTCTACACCAGTTAGGACG 3?), Ppia
GCTGGTCTTGCCATTCC 3?), Actb (forward, 5? AGATTACTGCCCT
Mifepristone (RU38486) treatment. To investigate the functional role
of GRs in the escalation of alcohol self-administration during alcohol
vapor exposure, the rats were trained to self-administer alcohol as de-
GR/progesterone receptor antagonist; 150 mg; Innovative Research of
America) or placebo pellets for chronic release (21 d). The mifepristone
dose was chosen based on previous studies (Schneider et al., 2003;
Nephew et al., 2008) and adjusted for bodyweight. Twenty-four hours
protracted alcohol abstinence, additional groups of dependent and non-
cebo pellets 1 week after the vapor was turned off. Behavioral testing
began 1 week after pellet implantation. Three animals from this experi-
ment were excluded: one mifepristone-treated dependent rat and one
one placebo-treated dependent rat outlier.
Statistical analysis. The data are expressed as mean and SEM. The data
were analyzed using ANOVA with or without repeated measures, with
factors. When appropriate, post hoc comparisons were performed using
Fisher’s Least Significant Difference (LSD) test. Glucocorticoid receptor
level of significance for all tests was p ? 0.05.
Pre-vapor operant responding for alcohol is shown in Figure
1a. Subsequent testing began after 1 month of intermittent
alcohol vapor exposure (“dependence induction” for the de-
pendent group) and was performed during acute withdrawal
(6–8 h after the vapor was turned off). Vapor-exposed depen-
dent rats showed increased lever press responding for alcohol
(group effect: F(1,32)?7.6,p?0.01)comparedwithnondepen-
dent rats (Fig. 1a). Similar results were obtained for alcohol in-
take (in g/kg). With the exception of session 10, dependent rats
dent rats (0.3 ? 0.02 g/kg/30 min) in all self-administration ses-
post hoc test: p ? 0.05). Dependent rats also showed increased
responding compared with nondependent rats (group effect:
F(1,32)? 17.1, p ? 0.0005) in the PR test (Fig. 1b).
For the quinine-adulteration test (Fig. 1c), the analyses re-
vealed a significant group ? concentration interaction (F(3,96)?
5.6, p ? 0.001) for the percentage change from baseline con-
taste of quinine, with significantly greater intake by dependent
rats than nondependent rats of solutions adulterated with 0.01
quinine may be appetitive at low concentrations (Da Silva et al.,
2005), and a trend toward increased drinking was observed in
tionally performed a statistical analysis that excluded the lowest
exposed rats during acute alcohol withdrawal. a, Number of lever presses for alcohol before
the alcohol solution). The data represent the percentage change from baseline (i.e., lever
presses for alcohol alone before adulteration with quinine). d, Number of lever presses for a
Specific increase in alcohol intake and compulsive drinking in alcohol vapor-
Vendruscoloetal.•CorticosteroidReceptorsandAlcoholDependenceJ.Neurosci.,May30,2012 • 32(22):7563–7571 • 7565
quinine concentration. The results again
revealed a significant group ? concentra-
tion interaction (F(2,64)? 5.0, p ? 0.01),
thus confirming the robustness of the ob-
To control for taste differences between
solution (0.025 g/L) without alcohol. A
36.6% versus 32.9% reduction in respond-
ing was observed in vapor-exposed versus
control rats (p ? 0.8), respectively, com-
pared with baseline responding for alcohol.
When 10% alcohol was added to the qui-
nine solution, vapor-exposed animals in-
alcohol self-administration, whereas con-
trol animals showed even lower levels of al-
cohol/quinine intake (group effect: p ?
0.01). Thus, dependent and nondependent
for alcohol consumption, and compulsive
drinking exhibited by dependent rats was
specific for alcohol because dependent and
administration of saccharin-sweetened wa-
We next determined GR and MR mRNA
expression levels in several stress/reward-
related brain regions. Acute alcohol with-
drawal (24 h after the alcohol vapor was turned off) was associated
Fig. 2c) but not amygdala (Fig. 2d) or hippocampus (Fig. 2e). No
group differences were found for MR mRNA levels in any brain
For protracted alcohol abstinence (3 weeks after the alcohol
higher in dependent rats than in nondependent rats in the NAc
core (t12? 3.6, p ? 0.005), ventral BNST (t10? 2.6, p ? 0.05),
and central nucleus of the amygdala (CeA; t11? 4.4, p ? 0.005)
of the amygdala (BLA; Fig. 3).
Before vapor exposure, the groups selected as dependent and
nondependent did not differ significantly with regard to baseline
alcohol intake. Chronic mifepristone treatment selectively
blocked the escalation of alcohol intake in vapor-exposed rats
(group ? treatment ? day interaction: F(4,136)? 2.8, p ? 0.05).
Placebo-treated, vapor-exposed rats exhibited a significant in-
crease in lever pressing for alcohol compared with placebo-
treated nondependent rats on day 10 (p ? 0.05), day 13 (p ?
0.005), and day 17 (p ? 0.05) of vapor exposure and compared
with mifepristone-treated vapor-exposed rats on day 6 (p ?
0.05), day 10 (p ? 0.005), day 13 (p ? 0.001), and day 17 (p ?
0.001) of vapor exposure. Mifepristone-treated, vapor-exposed
not affect lever pressing for alcohol in nondependent rats (Fig.
4b). Although a marginal, nonsignificant effect was detected for
by group revealed an overall treatment effect in dependent rats
only (F(5,85)? 3.3, p ? 0.01), with mifepristone-treated depen-
reward-related brain areas. Dependent rats showed lower GR mRNA levels in the (a) PFC, (b) NAc, and (c) BNST but not (d)
companied by GR upregulation in stress/reward-related brain areas. Dependent rats showed
Protracted alcohol abstinence (3 weeks after the vapor was turned off) was ac-
7566 • J.Neurosci.,May30,2012 • 32(22):7563–7571 Vendruscoloetal.•CorticosteroidReceptorsandAlcoholDependence
0.98 ? 0.08 g/kg/30 min for mifepristone- and placebo-treated
dependent rats, respectively.
p ? 0.05) was detected. Mifepristone blocked the increased re-
vapor exposure (p ? 0.005), without al-
tering responding to obtain alcohol in
nondependent controls (Fig. 4c).
ing alcohol vapor exposure, dependent rats
displayed higher alcohol self-administration
compared with nondependent rats (F(1,18)?
6.6, p ? 0.05). Placebo-treated rats with a
calated alcohol intake during protracted
abstinence, and mifepristone treatment
blocked this effect. The treatment did not
affect alcohol intake in nondependent rats.
all of the other groups (group vs treatment
For the PR test, a group ? treatment
interaction (F(1,18)? 5.7, p ? 0.05) was
detected. Placebo-treated dependent rats
displayed increased responding for alco-
hol compared with mifepristone-treated
dependent rats and placebo-treated non-
dependent rats (p ? 0.05; Fig. 5c).
alcohol intake and compulsive alcohol
drinking compared with nondependent
rats, traits that are thought to be hallmarks
of alcohol dependence. Compared with
nondependent rats, dependent rats showed
GR mRNA downregulation in several
stress/reward-related brain areas during
ing protracted alcohol abstinence. A func-
tional role for GRs in alcohol dependence
was demonstrated by showing that chronic
GR blockade during the course of alcohol
vapor exposure prevented the escalation of
alcohol intake and blocked the increase in
PR responding. Chronic GR antagonism
hol drinking during protracted abstinence
the development and maintenance of alco-
downregulated in the PFC, NAc, and BNST during acute alcohol
withdrawal, an effect also observed with chronic stress (de Kloet
et al., 2005; Noguchi et al., 2010). The lack of effect in the
amygdala and hippocampus does not exclude the possibility of
Vendruscoloetal.•CorticosteroidReceptorsandAlcoholDependence J.Neurosci.,May30,2012 • 32(22):7563–7571 • 7567
alterations in GR levels in these brain regions because the mea-
surements included the whole structures rather than discrete
CeA, and ventral BNST during protracted alcohol abstinence,
suggesting receptor adaptation when alcohol exposure ceased.
alcohol-dependent and postdependent brain. Evidence shows
that both increased GR activity and decreased GR activity are
associated with increased anxiety (Wei et al., 2004; Ridder et al.,
2005; Jakovcevski et al., 2008), but escalated alcohol intake dur-
in GR levels during acute alcohol withdrawal and protracted ab-
stinence may play a role in sensitivity to stress/reward and esca-
lated alcohol intake during these distinct phases of alcohol
al., 2004; Zhao et al., 2007; Gilpin et al., 2008; Sommer et al.,
2008). Corticosterone levels have been shown to be blunted dur-
ing acute withdrawal and protracted abstinence in our models of
but directly relating CORT levels to GR changes during these
ent findings suggest the occurrence of allostatic-like changes in
the extrahypothalamic GR system in alcohol dependence.
Chronic mifepristone treatment during alcohol vapor exposure
completely prevented the escalation of alcohol intake in vapor-
exposed rats, indicating that functional GRs are required for the
escalation of alcohol intake that is associated with the develop-
ment of alcohol dependence. Mifepristone did not affect alcohol
consumption in nondependent rats, as previously reported
(Fahlke et al., 1995; 1996; O’Callaghan et al., 2005; Yang et al.,
2008; Lowery et al., 2010). This result suggests that mifepristone
prevents neuroplasticity involved in escalated alcohol drinking
but does not influence the positive reinforcing properties of al-
ing in nondependent rats. Mifepristone also blocked the
Progressive-ratio responding can be linked to the construct of
compulsivity, in which responding to alcohol is persistent in the
face of adverse consequences (i.e., increased cost for each subse-
quent reward) (Koob, 2012). Mifepristone has also been shown
to attenuate behavioral sensitization produced by repeated stress
or alcohol injections (Roberts et al., 1995), decrease alcohol
drinking in limited-access conditions (Koenig and Olive, 2004),
and reduce the stress-induced reinstatement of alcohol seeking
(Simms et al., 2012) in nondependent rats, suggesting that mife-
ditions. Additionally, placebo-treated rats with a history of
nence compared with nondependent rats, as previously reported
(Valdez et al., 2002; Rimondini et al., 2003; Gilpin et al., 2008;
Sommer et al., 2008). In the present study, chronic mifepristone
treatment also decreased alcohol intake during protracted absti-
nondependent rats. This effect was selective for alcohol depen-
dence (i.e., nondependent alcohol drinking was unaffected by
mifepristone). Possibly, low doses of mifepristone block the re-
support a functional role for GRs in escalated drinking during
Although peak HPA axis activation is blunted during pro-
tracted abstinence in alcohol dependence (Adinoff et al., 1990;
Zorrilla et al., 2001), alcohol dependence-mediated GR dysregu-
drive escalated and compulsive drug intake (Makino et al., 2002) via negative reinforcement (Edwards and Koob, 2010). Right, During protracted abstinence, GR levels are upregulated in
7568 • J.Neurosci.,May30,2012 • 32(22):7563–7571Vendruscoloetal.•CorticosteroidReceptorsandAlcoholDependence
lation remains. A sensitized GR system would be expected to
increase the “gain” for a neuronal response to CORT, sustaining
the escalation of alcohol intake even in the absence of peak levels
several levels. One possibility is that there is a greater overall
number of cytosolic GRs that facilitate ligand-dependent recep-
tor dimerization and translocation to the nucleus. Alternatively,
there may be altered phosphorylation of the GR (e.g., Sr203,
Ser211, Ser226), thus modulating its transcriptional activity and
Cidlowski, 2001; Itoh et al., 2002; Miller et al., 2005; Chen et al.,
2008; Avenant et al., 2010). Another possibility is that GR disso-
ciation with cytosolic binding partners (HSPs, FKBPs) and nu-
clear translocation may be sensitized following repeated
activation of these pathways. Additionally, the nuclear interac-
tions between GR and other cofactors or transcriptional regula-
tors (e.g., AP-1, NFKB) may remain altered during protracted
abstinence and sensitize the GR system indirectly. Ligand-
independent GR function (Eickelberg et al., 1999; Verhoog et al.,
sensitized. Each of these molecular processes may work to sensi-
tize the GR system and maintain escalation despite blunted
CORT release. However, given the several steps between GR
1998; Davies et al., 2008), pinpointing a single molecular mech-
anism that underlies escalated alcohol intake is difficult. Under-
standing this process will clearly require further research.
Mifepristone also inhibits the progesterone receptor (Peeters
et al., 2004), which may participate in alcohol-related behaviors
(Janis et al., 1998). However, the effects of mifepristone during
alcohol withdrawal appear to be GR-specific (Jacquot et al.,
2008). Moreover, one question is whether mifepristone can pen-
etrate the blood–brain barrier. Mifepristone has somewhat lim-
ited blood–brain barrier permeability, but the concentrations
attained in the brain are still significant (almost one-third those
of serum; Heikinheimo and Kekkonen, 1993). Accordingly, sys-
temic mifepristone administration produces behavioral changes
inhibits neurogenesis (Oomen et al., 2007), and, most directly,
competes with dexamethasone for binding sites in the rat CNS
reaches central GRs at concentrations sufficient for receptor
amplitude of release during the active period (i.e., the dark in
rodents), thus reflecting the circadian pattern of release (Young
et al., 2004). Because of the relatively low affinity of CORT for
GRs, these receptors are only activated during stressful condi-
tions or during the circadian peaks of CORT release. Thus,
chronic blockade of GRs by mifepristone in hypothalamic and
extrahypothalamic structures may prevent GR activation and
intoxication/withdrawal, but chronic blockade may also influ-
stress-related behaviors (Young et al., 2004; Sarabdjitsingh et al.,
Previous work has shown that CORT facilitates the reinforcing
effects of alcohol in nondependent subjects (Fahlke et al., 1995,
1996). However, high circulating levels of CORT during alcohol
intoxication/withdrawal can feed back to shut off the HPA axis,
and compulsive drug intake (Makino et al., 2002). Therefore,
although activation of the HPA axis may contribute to the rein-
forcing effects of alcohol during initial drug use, its excessive
activation may lead to the sensitization of brain stress systems
that mediate negative reinforcement in the transition to alcohol
tion in extrahypothalamic stress systems, possibly via a hypothe-
sized initial excessive activation of GRs, are involved in alcohol
dependence (Fig. 6). Normalizing GR signaling early in the tran-
sition to dependence may block the sensitization of the brain
stress systems, and the normalization of GR function after alco-
hol detoxification may reset the reward system to result in a shift
or block the well documented sensitization of reward associated
with protracted abstinence. Importantly, altered GR levels have
been found in the superior frontal cortex of alcoholics (Liu et al.,
ise for treating dysregulated mood (Flores et al., 2006; Nihalani
and Schwartz, 2007; Blasey et al., 2009). The present results indi-
cate that the GR system may be an attractive potential pharma-
cological target for the treatment of alcohol dependence.
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