GABRA2 Alleles Moderate the Subjective Effects of Alcohol,
Which are Attenuated by Finasteride
Amira Pierucci-Lagha1, Jonathan Covault1, Richard Feinn1, Maggie Nellissery1, Carlos Hernandez-Avila1,
Cheryl Oncken2, A Leslie Morrow3and Henry R Kranzler*,1
1Department of Psychiatry, Alcohol Research Center, University of Connecticut School of Medicine, Farmington, CT, USA;2Department of
Medicine, University of Connecticut School of Medicine, Farmington, CT, USA;3Departments of Psychiatry and Pharmacology, Bowles Center for
Alcohol Studies, University of North Carolina, Chapel Hill, NC, USA
GABAAreceptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABAAreceptors to
mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding
the GABAAreceptor a-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to
alcohol. We also examined whether finasteride (a 5-a steroid reductase inhibitor), which blocks the synthesis of some neuroactive
steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind,
placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks.
Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic
variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis.
Subjects homozygous for the more common A-allele (n¼7) showed more subjective effects of alcohol than did individuals with one or
two copies of the alcohol dependence-associated G-allele (n¼20, including two homozygotes). Among the A-allele homozygotes, there
was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings
provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective
response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the
subjective effects of alcohol.
Neuropsychopharmacology (2005) 30, 1193–1203, advance online publication, 9 February 2005; doi:10.1038/sj.npp.1300688
Keywords: GABA; alcohol; GABRA2; finasteride; allopregnanolone
Two genome-wide scans in humans provided evidence of
linkage of alcohol dependence to a region of chromosome
4p that includes a cluster of four genes encoding GABAA
receptor subunits (Reich et al, 1998; Long et al, 1998).
Edenberg et al (2004), by fine mapping this region, found
that numerous single-nucleotide polymorphisms (SNPs) in
the gene encoding the GABAAa-2 subunit (GABRA2), but
not in other members of the gene cluster, were associated
with alcohol dependence. In addition, all 3-SNP haplotypes
examined in the 30region of GABRA2 were significantly
associated with alcohol dependence (Edenberg et al, 2004).
Covault et al (2004) replicated this haplotypic association in
a region of the gene that overlaps the region identified by
Edenberg et al (2004). These findings, together with
evidence that GABAAreceptors mediate several behavioral
effects of alcohol (Grobin et al, 1998; Davies, 2003),
underscore the potential contribution of variation at
GABRA2 to the risk for alcohol dependence.
As alcohol elevates plasma and brain concentrations of
GABAergic neuroactive steroids, including 3a–5a-THP
(allopregnanolone or ALLO), and 3a–5a-THDOC (allote-
trahydrodeoxycorticosterone), it has been hypothesized that
these compounds may contribute to specific behavioral
actions of ethanol by modulating GABAAreceptor function
(Morrow et al, 1999; Barbaccia et al, 1999; VanDoren et al,
2000). Two recent reports in humans suggest that acute
alcohol exposure stimulates neuroactive steroid production
(Torres and Ortega, 2003, 2004). Compared to adolescents
seen for nonalcohol-related reasons, plasma levels of ALLO
and progesterone were elevated in both male and female
adolescents presenting to the emergency department with
acute alcohol intoxication. The effects were seen among
Online publication: 1 July 2005 at http://www.acnp.org/citations/
Received 6 May 2004; revised 10 December 2004; accepted 15
*Correspondence: Dr HR Kranzler, Department of Psychiatry,
MC2103, Health Center, University of Connecticut School of Medicine,
263 Farmington Ave., Farmington, CT 06030, USA, Tel: þ1 860 679
4151; Fax: þ1 860 679 1316, E-mail: email@example.com
Neuropsychopharmacology (2005) 30, 1193–1203
& 2005 Nature Publishing GroupAll rights reserved 0893-133X/05 $30.00
females during both the luteal and follicular phases of the
ovarian cycle. Studies in chronic drinkers have shown 40–
50% lower plasma concentrations of ALLO and THDOC in
the first week of abstinence, with normalization during the
subsequent 3 weeks (Romeo et al, 1996, 2000). These studies
suggest a direct link between increased neuroactive steroid
levels and acute alcohol intoxication in humans, with
chronic intoxication producing the opposite effect, findings
that parallel those described in the animal literature
(Barbaccia et al, 1999; VanDoren et al, 2000; Khisti et al,
2003; Finn et al, 2004).
The present study examined the moderating effects of
GABRA2 alleles and high-dose finasteride on subjective and
physiological effects of a standardized dose of alcohol in
healthy social drinkers. Finasteride, a 5-a steroid reductase
(5AR) inhibitor that limits the conversion of testosterone to
dihydrotestosterone, is FDA approved for the treatment of
benign prostatic hypertrophy. Finasteride also reduces the
metabolism of progesterone to the 5a-reduced neuroactive
steroids ALLO and THDOC. Based on these considerations,
we hypothesized that GABRA2 alleles would moderate the
subjective effects of alcohol measured during the ascending
limb of the breath alcohol concentration (BrAC) curve and
that finasteride would attenuate the subjective response to
alcohol. We focused on the ascending limb of the BrAC
curve, since it is commonly associated with the stimulating
effects of alcohol (de Wit et al, 1987), which are in turn
associated with alcohol preference (de Wit et al, 1987;
Chutuape and de Wit, 1994) and heavy drinking (Holdstock
et al, 2000).
In all, 27 subjects (15 men) were recruited from the greater
Hartford, CT area by advertisement and were paid for
their participation. After an initial telephone interview, a
psychiatric history was obtained using the Structured
Clinical Interview for DSM-IV (First et al, 1995). A 90-day
timeline follow-back interview (Sobell and Sobell, 1992) was
used to quantify recent alcohol and drug use. Subjects
underwent a medical history and physical examination and
routine laboratory tests (including complete blood count,
liver and renal function tests, blood glucose and electrolyte
concentration, and among female subjects, a serum
pregnancy test). All subjects gave written informed consent
to participate in the protocol, as approved by the University
of Connecticut Health Center Institutional Review Board.
Subjects were included in the study if they reported
moderate social drinking (ie a minimum of three drinks per
week and at least three drinks on one occasion in the past
month) and had a body mass index of 18.5–30kg/m2. They
were excluded if they ever met the criteria for DSM-IV
(American Psychiatric Association, 1994) substance abuse
or dependence or another major psychiatric disorder, had
evidence of liver dysfunction, were using benzodiazepines
or other psychotropic medications, were smokers, or were
pregnant or nursing. Women were included only if they
reported having regular menstrual cycles and were not
using oral contraceptives or other hormones and had no
history of endocrine or reproductive abnormalities.
The study involved a balanced design, in which each subject
served as his or her own control, with two experimental
sessions, separated by 1 month. At 24h prior to each
laboratory session, and 2h before the first drink, subjects
were pretreated with high-dose finasteride or matching
placebo, under double-blind conditions. The order of the
sessions was randomized. Among women, the experimental
sessions were held during the follicular phase of two
consecutive menstrual cycles (based on a 28-day menstrual
cycle). The sessions were scheduled 5–9 days following the
onset of menstruation, with the menstrual cycle phase
determined by counting the days from the onset of
menstruation. To ensure comparability, the laboratory
sessions were separated by 1 month for men also.
Subjective effects were measured using the following
Alcohol Sensation Scale (SS; Maisto et al, 1980) consists of
26 items that are divided into six subscales measuring
somatic sensations produced by alcohol, particularly on the
ascending limb of the blood alcohol concentration curve:
the Central-Stimulant Subscale measures sensations asso-
ciated with effects on the brain (four items), the Dynamic-
Peripheral Subscale measures sensations associated with
excitation, including increased breathing and heart rate
(three items), the Warmth-Glow Subscale measures blush-
ing sensations (three items), the Anesthetic Subscale
measures sensations associated with loss of feeling or
decreased sensitivity to feeling (nine items), the Gastro-
intestinal Subscale measures sensations felt in the stomach
(four items), and the Impaired-Function Subscale measures
perceived changes in psychomotor performance (three
Biphasic Alcohol Effects Scale (BAES; Martin et al, 1993) is
a 14-item unipolar adjective rating scale designed to
measure both the stimulant and sedative effects of alcohol.
Subjects rated the adjectives on a scale of 0 (not at all) to 10
(extremely). We used the items from the Stimulation
Subscale (seven items), which has been experimentally
associated with increasing BrAC (de Wit et al, 1987; Martin
et al, 1993).
Drug Effects Questionnaire (DEQ; Holdstock and de Wit,
1998) consists of four items that measure current drug
effects that were adapted to measure alcohol effects: ‘feel
alcohol’, ‘feel high’, ‘like alcohol’, and ‘want more alcohol’.
Subjects indicated on a 100-mm line the extent to which
they endorsed each statement, with anchors from ‘not at all’
on the left end of the scale to ‘extremely’ on the right end of
We also measured BrAC, blood pressure, and heart rate
To maximize the antagonism of 5AR activity (Ohtawa et al,
1991), subjects received either finasteride 100mg or placebo
in identical capsules 24h prior to each laboratory session
(see Figure 1) and were instructed to avoid alcohol,
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