Alcool Gaba Sacarose

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Alcohol 30 (2003) 1–7

High-priority communication✩

Comparison of the effects of allopregnanolone with directGABAergic agonists on ethanol self-administration with

and without concurrently available sucrose

Patricia H. Janak*, T. Michael Gill Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, 5858 Horton Street,

Suite 200, Emeryville, CA 94608, USA

Received 6 February 2003; received in revised form 14 April 2003; accepted 18 April 2003

Abstract

Behavioral effects of ethanol are mediated by actions at multiple neurotransmitter receptors and signaling systems; prominent among

these isthe typeA γ -aminobutyric acid (GABAA) receptor.Previous work has shown that the GABAergic neuroactive steroid allopregnanolone

enhances ethanol-reinforced instrumental responding in rat. In the current study, we compared the effects of allopregnanolone with the direct

GABAA agonist muscimol and the direct type B GABA (GABAB) agonist baclofen in male Long–Evans rats lever pressing for a 10%

ethanol solution in a limited-access procedure. The effects of concurrently available sucrose were also tested to determine the selectivity

of these drugs for altering ethanol self-administration when an alternate reinforcer was available. In Experiment 1, we found that presession

systemic administration of both muscimol (0.3 and 1 mg/kg) and baclofen (1 and 3 mg/kg) reduced responding for ethanol. In contrast,

allopregnanolone (3 and 5.6 mg/kg) enhanced responding for ethanol. In Experiment 2, we found that a 1-mg/kg dose of baclofen reduced

responding for ethanol, but not for sucrose, whereas both baclofen and muscimol, administered at a higher dose of 3 mg/kg, decreased both

ethanol- and sucrose-reinforced responding. Allopregnanolone, at a dose of 5.6 mg/kg, but not of 3 mg/kg, selectively increased ethanol-

reinforced responding, indicating a less robust effect of allopregnanolone on responding within the concurrent reinforcement procedure

than that observed when ethanol alone was available. The results support the suggestion that direct agonist action at either the GABAAor the GABAB receptor decreases ethanol self-administration. Muscimol produces a nonselective decrease in instrumental responding,

whereas baclofen may selectively reduce ethanol intake at lower doses, but not higher ones, possibly limiting its potential use for treatmentof alcohol abuse in human beings. In contrast, allopregnanolone can selectively enhance ethanol self-administration in the presence of a

concurrently available alternate reinforcer, indicating that the direct GABAA agonist muscimol and the allosteric GABAA modulator

allopregnanolone do not produce similar behavioral effects on instrumental responding for ethanol reinforcement. 2003 Elsevier Inc.All rights reserved.

Keywords: Neurosteroid; Allopregnanolone; Muscimol; Baclofen; Operant self-administration; Alcohol

1. Introduction

The endogenous neuroactive steroid allopregnanolone

(3α-hydroxy-5α-pregnan-20-one) increases ethanol-reinforcedresponding (Janak et al., 1998). Allopregnanolone is a po-

sitive modulator of type A γ -aminobutyric acid (GABAA)

receptors; that is, allopregnanolone enhances GABAAreceptor function, as measured with chloride-flux assays

✩A paper published as a high-priority communication is onethat review-

ers have identified as being of high scientific significance and have recom-

mended that the study findings should be communicated to the scientific

community as soon as possible.

* Corresponding author. Tel.:1-510-985-3880; fax:1-510-985-3101.

E-mail address: [email protected] (P.H. Janak).

Editor: T.R. Jerrells

0741-8329/03/$ – see front matter 2003 Elsevier Inc. All rights reserved.

doi: 10.1016/S0741-8329(03)00068-5

(Harrison et al., 1987; Majewska et al., 1986), and pro-

longs GABAA-mediated inhibitory postsynaptic potentials

in hippocampal culture (Harrison et al., 1987). GABAergic

neuroactive steroids, including allopregnanolone, are re-ported to potentiate the neurochemical (Majewska, 1988)

and electrophysiological (Criswell et al., 1999) effects of

ethanol on GABAA-mediated function [see Morrow et al.

(2001) for review]. These effects are thought to result from

interaction with a putative neurosteroid-binding site on the

GABAA receptor (Lambert et al., 1995, 2001; Paul & Purdy,

1992; Purdy et al., 1990). Therefore, the mechanism for

allopregnanolone’s effects on ethanol intake likely involves

actions at the GABAA receptor. Recent reports indicate that

GABAergic neuroactive steroids produce stimulus effects

that do not generalize to those of direct GABAA receptor

mailto:[email protected]:[email protected]


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P.H. Janak, T.M. Gill / Alcohol 30 (2003) 1–7 2

agonists such as muscimol (Engel et al., 2001). In addition,

allopregnanolone, but not the GABAA agonist muscimol nor

the type B γ -aminobutyric acid (GABAB) agonist baclofen,

substitutes for ethanol in subjects trained to discriminate a

1-g/kg dose of ethanol from vehicle (Bowen et al., 1999;

Shelton & Balster, 1994). These findings support the sugges-

tion that other behavioral effects of neuroactive steroids anddirect GABA receptor agonists will differ, especially with

regard to possible interactions with ethanol. In the current

study, we compared the effects of allopregnanolone, musci-

mol, and baclofen on instrumental responding for ethanol

alone or for concurrently available ethanol and sucrose.

2. Materials and methods

2.1. Subjects

Male Long–Evans rats (Harlan, Indianapolis, IN), each

weighing between 250 and 335 g at the start of the behavioralprocedures, were singly housed in polycarbonate cages with

food and water available ad libitum (with exceptions during

training as noted below), under a 12-h:12-h light:dark cycle

(lights on at 6:00 a.m.). All procedures with animals in

this report were approved by the Gallo Center Institutional

Animal Care and Use Committee and are in agreement with

recommendations in the Guide for the Care and Use of

Laboratory Animals (Institute of Laboratory Animal Re-

sources, Commission on Life Sciences, National Research

Council, 1996).

2.2. Ethanol-reinforced operant responding

Training was conducted as previously described (Nadal

et al., 2002) in a standard conditioning chamber (Med Asso-

ciates, St. Albans, VT) equipped with two levers and two

liquid-delivery ports, all located on one wall of the chamber,

such that each liquid-delivery port was located 8 cm to the

right of its respective lever (center to center). In brief,

water-restricted subjects (1 h of home cage accessdaily) were

placed in the operant chambers overnight for 1–3 nights to

allow acquisition of a lever-press response for a 10% sucrose

(10S) solution in water. The behavioral schedule during this

procedure (and subsequent procedures) was as follows. After

completion of a lever press, a variable delay of 0.5–1.5 s

was followed by presentation of a 0.5-s tone, followed 0.5

slaterbydeliveryof 0.1mlofreinforcerbymeansofasyringe

pump (PHM100, Med Associates, St. Albans, VT) into a

cup receptacle housed within the liquid-delivery port. Addi-

tional lever presses made during the delay between the first

press and the reinforcer did not have any scheduled conse-

quences. After lever-press acquisition, 30-min operant ses-

sions were conducted 5 or 6 days a week. During the first

week, daily 1-h water access was gradually increased until

ad libitum conditions were achieved. The reinforcer solution

was changed every 2 or 3 days, such that the percentage of

ethanol in the solution was progressively increased and then

the percentage of sucrose in the solution was progressively

decreased [sucrose-fading procedure; Samson et al. (1988)].

The solutions used during the sucrose fade, in order of

presentation, were 10S, 10S/2% ethanol (10S/2E), 10S/5%

ethanol (10S/5E), 10S/10% ethanol (10S/10E), 5% sucrose/

10E (5S/10E), 2% sucrose/10E (2S/10E), and 10E.

For nine subjects in Experiment 1, the right lever deliv-ered 10E; presses on the left lever were counted but had no

consequence. Drug injections began after 72 sessions of

responding for 10E. For eight subjects in Experiment 2, both

levers were active during the sucrose-fading procedure, and

responses on both delivered the same reinforcer. After 23

sessions of responding for 10E on both levers, this group

was divided into two, counterbalanced for lever bias, with

half the subjects receiving 10E after presses on the right

lever and 2S after presses on the left lever, and vice versa.

After an additional 8 sessions, the concentration of sucrose

was lowered to 1% to assess drug effects on non-ethanol-

reinforced responding while maintaining adequate levels of

10E-reinforced responding and, hence, intake. Drug injec-tions began after 30 sessions of training with both 10E and

1S available.

2.3. Dose-effect determinations

All rats in both experiments were habituated to the injec-

tion procedure by the administration of two or three vehicle

injections before the first drug injection. For Experiment 1,

the effects of baclofen, muscimol, and allopregnanolone on

responding for ethanol were determined in that randomly

chosen order, with a random order of doses for each test

compound. Each subject received every dose of each com-pound. Subjects received one or two injections per week,

on Tuesday, Thursday, or both days, depending on the

reestablishment of baseline responding after each injec-

tion. Procedures were identical for Experiment 2, except

that the order of drugs was randomized from Experiment

1 with muscimol tested first, followed by baclofen and

allopregnanolone.

2.4. Drugs

Allopregnanolone (3α-hydroxy-5α-pregnan-20-one), mus-

cimol, and baclofen were obtained from Sigma (St. Louis,

MO). Allopregnanolone was suspended in a 25% solution

of (2-hydroxypropyl)-b-cyclodextrin (Sigma, St. Louis, MO)

by means of sonication for 2–4 h and administered subcuta-

neously. Muscimol and baclofen were dissolved in saline

and administered intraperitoneally. Injection volumes were 1

ml/kg, and all treatments were administered 20 min before

the start of the session.

2.5. Data analysis

Data obtained from one subject after muscimol and baclo-

fen administration were not included in the analysis for


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Experiment 2 because of experimenter error (the lever as-

signment for ethanol and sucrose reinforcers was inadver-

tently switched for some sessions). The remainder of data

obtained from vehicle or drug injection sessions was an-

alyzed by using repeated-measures analysis of variance

(ANOVA) for the number of responses on each of the two

levers and for the amount of ethanol consumed. Significantmain effects or interactions were followed by planned com-

parisons. All data were analyzed with Statistica (StatSoft,

Tulsa, OK).

3. Results

3.1. Experiment 1: ethanol reinforcement

Fig. 1 shows the results of presession administration of

muscimol, baclofen, and allopregnanolone to subjects

responding for 10E in daily, limited-access (30-min) ses-

sions. As can be seen in Fig. 1A, administration of the

GABAA agonist muscimol reduced responding for 10E

[F (2,16) 6.40, P .01]. A dose× lever interaction [F (2,16)

5.07, P .02] indicated a differential effect of muscimol

on active versus inactive lever responding. Planned compari-

sons confirmed that both the 0.3- and 1-mg/kg doses of

muscimol significantly reduced responding on the active

ethanol lever (P .045 and P .022, respectively), but did

not alter responding on the inactive lever. The mean number

of lever presses for 10E was not different between the 0.3-

and 1-mg/kg doses of muscimol.

The GABAB agonist baclofen likewise reduced re-

sponding for ethanol [main effect of dose: F (3,24) 46.58,

Fig. 1. Mean lever-press responding ( S.E.M.) for ethanol after presession administration of (A) muscimol, (B) baclofen, and (C) allopregnanolone. The

top row of panels with the header “10E” presents mean responding on the 10% ethanol–reinforced lever; the bottom row of panels with the header “Inactive”

presents mean responding on the inactive, nonreinforced lever. *P .05, **P .003, relative to vehicle (V) treatment (n 9 for each drug condition).

P .0001] on the active lever only [dose × lever interaction:

F (3,24) 38.77, P .0001]. Planned comparisons revealed

that both the 1- and 3-mg/kg doses of baclofen reduced re-

sponding for ethanol (P .008 and P .00002, respec-

tively), but did not significantly affect inactive lever presses

(Fig. 1B).

In contrast with the effects of muscimol and baclofen,the neuroactive steroid allopregnanolone increased re-

sponding f or ethanol at the doses tested [F (2,16) 9.04,

P .003] (Fig. 1C). A significant dose × lever interaction

indicated a differential effect of allopregnanolone on the

active and inactive levers [F (2,16) 8.65, P .003].

Planned comparisons indicated that both the 3- and 5.6-mg/

kg doses of allopregnanolone significantly enhanced lever-

press responding for ethanol (P .019 and P .0025, re-

spectively), but did not alter responding on the inactive lever.

As expected, analysis of the estimated grams of ethanol

per kilogram of body weight (g/kg) consumed after treatment

with muscimol, baclofen, and allopregnanolone revealed the

same pattern of results as the analysis of lever-pressresponding. These data are presented in Table 1.

3.2. Experiment 2: concurrent ethanol and sucrose

reinforcement

The effects of presession administration of muscimol,

baclofen, and allopregnanolone on subjects responding

under independent, concurrent fixed ratio 1 (FR1) schedules

for 10E on one lever and 1S on the other lever are shown

in Fig. 2. The presession administration of the GABAAagonist muscimol significantly and dose-dependently de-

creased lever-press responding [F (3,18) 8.84, P .0001].


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Table 1

Estimated amount [grams per kilogram of body weight (g/kg)] of ethanol consumed after experimental treatment with muscimol, baclofen, and

allopregnanolone

Dose (mg/kg)

Vehicle 0.3 1.0 3.0 5.6

Experiment 1

Muscimol 0.63 0.07 0.54 0.07* 0.39 0.07*

Baclofen 0.63 0.08 0.58 0.04 0.50 0.07** 0.08 0.03**

Allopregnanolone 0.54 0.05 0.65 0.05* 0.73 0.08**

Experiment 2

Muscimol 0.41 0.09 0.43 0.07 0.40 0.06 0.10 0.05*

Baclofen 0.42 0.07 0.43 0.12 0.32 0.08# 0.08 0.04**

Allopregnanolone 0.46 0.07 0.49 0.08 0.57 0.08*

Values are expressed as mean S.E.M. #P .057, *P .05, **P .01, compared with vehicle treatment.

The lack of a dose × lever interaction [F (3,18) .31,

P .82] indicates that the effects of muscimol on ethanol

and sucrose responding were not different. Further analysis

revealed that only the 3-mg/kg dose of muscimol signifi-cantly decreased responding for 10E (P .017), but that

same dose also decreased responding for 1S (P .045,

Fig. 2A).

The GABAB agonist baclofen also dose-dependently re-

duced responding within the concurrent 10E/1S procedure

[F (3,18) 10.61, P .0004]. The dose × lever interaction

[F (3,18) 1.87, P .17] was not significant, supporting

the suggestion that baclofen reduced responding in a similar

manner for both 10E and 1S (Fig. 2B). Planned comparisons

revealed that the 1-mg/kg dose reduced responding for etha-

nol (P .04), but not for sucrose, whereas administration

of a 3-mg/kg dose of baclofen significantly reduced re-

sponding for both ethanol (P .0013) and sucrose

(P .045).

Analysis of the effects of allopregnanolone on concurrent

responding for ethanol and sucrose revealed no significant

Fig. 2. Mean lever-press responding ( S.E.M.) for ethanol and sucrose after presession administration of (A) muscimol, (B) baclofen, and (C) allopregnano-

lone. Rats were trained to lever press for both 10% ethanol and 1% sucrose, available concurrently within the same 30-min session. For each figure,

the left striped or solid black bar in a pair of bars represents ethanol-reinforced responding; the right white bar represents sucrose-reinforced responding.

*P .05, **P .002, relative to ethanol-reinforced responding after vehicle treatment. #P .05 relative to sucrose-reinforced responding after vehicle

treatment (n 7 for muscimol and baclofen conditions and n 8 for the allopregnanolone condition).

main effect of dose [F (2,14) 2.56, P .11], but a signifi-

cant dose × lever interaction [F (2,14) 4.54, P .04], in-

dicating that allopregnanolone produced a differential effect

on ethanol and sucrose responding. Planned comparisonsrevealed that a 5.6-mg/kg dose of allopregnanolone in-

creased responding for ethanol (P .04), but not for sucrose

(Fig. 2C).

The pattern of effects for the estimated grams of ethanol

per kilogram of body weight consumed after the various

treatments for Experiment 2 wassimilar to that observed after

analysis of the number of lever presses and is presented in

Table 1.

4. Discussion

In this article, we report that the neuroactive steroid allo-

pregnanolone enhances ethanol-reinforced responding, but

that the GABAA agonist muscimol and the GABAB ago-

nist baclofen decrease responding for ethanol. Hence, the


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effects of allopregnanolone do not resemble the effects of

direct agonist action at either GABAA or GABAB receptors.

Previous work has shown that allopregnanolone enhances

ethanol-reinforced responding by rats (Janak et al., 1998).

Results of the current study extend those findings by demon-

strating that the increases in lever-press responding for etha-

nol are not due to nonspecific increases in motor activity,because allopregnanolone did not alter responding at a

second “inactive” lever. Further, allopregnanolone selec-

tively increased responding for ethanol within a concurrent

ethanol–sucrose paradigm, indicating that allopregnanolone

does not produce a nonselective increase in reward-seeking

behavior. Although the availability of concurrent reinforcers

within Experiment 2 did not result in equivalent respond-

ing, these results still strongly support the suggestion that

the effects of allopregnanolone are selective for ethanol-

reinforced responding under these conditions.

The modulation of ethanol intake by allopregnanolone

was modest (increased by approximately 25%–35%).

Results of the previous study (Janak et al., 1998) showed

that a lower dose of allopregnanolone (1 mg/kg) had no

effect, whereas the effect of a higher dose (10 mg/kg)

produced behavioral disruption. Thus, the modest enhance-

ment observed in the 3–5.6 mg/kg dose range may be maxi-

mal for this neuroactive steroid when administered to rats

tested within operant ethanol self-administration protocols.

Our findings are in agreement with those of another inves-

tigation of the effects of repeated allopregnanolone admin-

istration on limited-access home cage intake in mice. Sinnott

et al. (2002b) found that allopregnanolone increased ethanol

intake by male mice 1 h, but not 2 h, after allopregnanolone

administration. Interestingly, these investigators also report

that allopregnanolone enhanced intake of a saccharin solu-

tion under conditions of free choice between saccharin and

water. There were a number of differences between the

current study and that of Sinnott et al. (2002b), including

different species (rat vs. mouse), behavioral procedures (op-

erant vs. home cage; simultaneous vs. separate availability

of ethanol and sweet solutions), and drug delivery (one vs.

three daily injections of allopregnanolone). Further work

is needed to determine whether allopregnanolone can alter

intake of sweet solutions in rats under conditions different

from those reported in this article.

In contrast with allopregnanolone, muscimol decreasedresponding for ethanol in Experiment 1 and decreased re-

sponding for both ethanol and sucrose in Experiment 2,

although a higher dose of muscimol was required to decrease

responding when ethanol and sucrose were available concur-

rently. It is possible that the lack of specificity of musci-

mol reflects a general reduction in motor activity. However,

inactive lever-press responding was unaffected by muscimol.

Levels of responding at the inactive lever were quite low,

however, possibly precluding the ability to observe further

decreases. These findings indicate that direct activation of

the GABAA receptor by the prototypical GABA agonist

muscimol produces opposite effects on ethanol self-adminis-

tration from the actions of the neuroactive steroid allopregna-

nolone. These findings are in agreement with those obtained

in drug-discrimination studies in rats in which allopregnano-

lone and related GABAergic neuroactive steroids, but not

muscimol, substituted for the ethanol-discriminative stimu-

lus cue (Engel et al., 2001; Kostowski & Bienkowski, 1999;Shelton & Balster, 1994). The opposing behavioral actions

of muscimol and allopregnanolone could result from the

different means by which these two compounds interact with

the GABAA receptor complex. Specifically, muscimol and

allopregnanolone are thought to bind to distinct sites on the

GABAA receptor complex (Korpi et al., 2002). In addition,

distinct effects of allopregnanolone and muscimol on ethanol

self-administration may also be related to differential sensi-

tivity of functionally diverse GABAA receptor populations

resulting from heterogeneous subunit composition.

Baclofen, like muscimol, also reduced responding for

ethanol in Experiments 1 and2. As with allopregnanolone and

muscimol, no significant effect of baclofen on inactive leverresponding was found, supporting the suggestion that the

decreases in responding were not due to motor incapacita-

tion. However, similar to the effects of muscimol, the low

level of inactive lever responding may prevent a complete

estimation of the effect of baclofen on overall motor

responding. A 1-mg/kg dose of baclofen reduced ethanol,

but not sucrose, responding in Experiment 2, but at the

higher dose of 3 mg/kg, it suppressed both ethanol and

sucrose responding. This narrow window of selectivity sup-

ports the suggestion that baclofen has limited utility for

selectively reducing ethanol intake. These findings are simi-

lar to those observed by Colombo et al. (2000) in which 14-day repeated administration of baclofen decreased home

cage ethanol and food intake, although the decreases in food

intake recovered whereas the decreases in ethanol intake

did not (Colombo et al., 2000).

Results of the current study provide further evidence that

the behavioral effects of positive modulators of the GABAAreceptor differ from those of direct GABA agonists. Other

positive modulators of the GABAA receptor, such as benzo-

diazepines and barbiturates, might therefore also be pre-

dicted to enhance the operant self-administration of ethanol.

However, the barbiturate pentobarbital is reported to

decrease both saccharin and ethanol intake in a two-

lever-alternating multiple schedule of reinforcer delivery

(Shelton & Balster, 1997). Studies of the effects of benzodi-

azepines on ethanol self-administration have produced con-

flicting results. Some investigators have found that low doses

of benzodiazepines increase operant (Petry, 1997) or home

cage (Soderpalm & Hansen, 1998) ethanol self-administra-

tion, whereas other investigators report no ef fect of chlordi-

azepoxide on operant (Rassnick et al., 1993) or home cage

(Beaman et al., 1984) ethanol self-administration. In addi-

tion, the benzodiazepine diazepam does not affect operant

ethanol self-administration when administered at nonse-

dating doses (Janak et al., 1998; Rimondini et al., 2002).


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The findings collectively do not support a general enhance-

ment of ethanol self-administration by positive modulators

of the GABAA receptor. Although further studies are needed

to draw reliable conclusions, it seems that allopregnanolone

may increase ethanol intake in a manner not commonly seen

with other classes of GABAA modulators.

Activity at the GABAA receptor, especially benzodiaze-pine-mediated activity, has been implicated in taste reactivity

and palatability (Berridge, 1996; Petry & Heyman, 1997).

For example, the benzodiazepine midazolam is reported to

enhance the palatability of ethanol, as indicated by hedonic

orofacial responses (Soderpalm & Hansen, 1998). These

findings support the suggestion that a possible contribution

of taste factors to the enhancement of ethanol intake by

allopregnanolone should be considered. Because the effects

of allopregnanolone were selective for ethanol in an ethanol–

sucrose concurrent-reinforcement procedure, it is unlikely

that general effects on palatability account for the effects of

allopregnanolone reported in this article. In agreement with

this statement, investigators have found that allopregnano-lone increased intake of a saccharin, but not quinine, solution

(Sinnott et al., 2002b), supporting the suggestion that overall

alterations in taste reactivity and palatability cannot account

for the effects of allopregnanolone on ethanol intake.

If allopregnanolone is not affecting ethanol intake by

enhancing motor activity or palatability, how might it alter

ethanol-reinforced responding? It is not clear if the increase

in responding after allopregnanolone reflects an attenuation

or enhancement of the reinforcing effects of ethanol. Finn et

al. (1997) found that allopregnanolone induces a conditioned

place preference in mice, a finding supported by results of

a study in rats [Franklin et al. (2002), but see Beauchampet al. (2000)]. In addition, it has been demonstrated that

rats will orally self-administer allopregnanolone (Sinnott

et al., 2002a). These findings indicate that allopregnanolone

has inherent reinforcing properties, leading to the sugges-

tion that the reinforcing effects of allopregnanolone and

ethanol may summate to produce a greater total reinforce-

ment (Sinnott et al., 2002b), resulting in the expression of

greater reward-seeking behavior.

The finding that the neuroactive steroid allopregnanolone

increases responding for ethanol supports the suggestion

that further study of this neuroactive steroid (and related

neuroactive steroids) may provide a novel means of modulat-

ing GABAA receptor function and ethanol self-administra-

tion. Central nervous system levels of allopregnanolone are

increased by stress (Purdy et al., 1991); depend on changing

endocrine states, including estrus (Genazzani et al., 1995)

and pregnancy (Concas et al., 1998); and are reported to

increase after systemic ethanol injections (Barbaccia et al.,

1999; VanDoren et al., 2000). Therefore, additional studies

are needed to determine whether alterations in endoge-

nous allopregnanolone levels significantly alter ethanol-

seeking behavior.

In conclusion, results of the current study do not provide

strong support for a selective suppressive effect of muscimol

or baclofen on ethanol-reinforced responding. The findings

indicate that the enhancement of ethanol-reinforced re-

sponding after pretreatment with the neuroactive steroid allo-

pregnanolone is selective for ethanol-reinforced responding.

These studies add further impetus to the study of the role

of endogenous allopregnanolone and the GABAA receptor

neurosteroid–binding site in the reinforcing effects of ethanol.

Acknowledgments

This work was supported by award # DAMD17-01-1-

0801 to PHJ awarded and administered by the U.S. Army

Medical Research Acquisition Activity, 820 Chandler St.,

Fort Detrick, MD 21702, USA. We thank Dan Tram Nguyen

for technical assistance.

Disclaimer

The content of information herein does not reflect the

position or policy of the government and no official en-

dorsement should be inferred.

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