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Physi ol ogy & Behavi or, Vol. 57, No. 4, pp. 791- 795, 1995
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Saccharin-Induced Increase in Dai l y Fluid Intake
as a Predictor of Voluntary Al cohol Intake in
Alcohol-Preferring Rats
AL E XE Y B. KAMP OV- P OL E VOY, ~ DAVI D H. OVE R S T R E E T , AMI R H. R E Z VANI
AND DAVI D S. J ANOWS KY
Ski pper Bowl es Cent er f or Al cohol Studies, Medi cal Research Bldg. A, CB# 7175, University of Nort h Carolina at
Chapel Hi l l School o f Medi ci ne, Chapel Hill, NC 27599-7175
Re c e i v e d 21 Ma r c h 1994
KAMPOV-POLEVOY, A. B., D. H. OVERSTREET, A. H. REZVANI AND D. S. JANOWSKY. Saccharin-induced increase
in daily fluid intake as a predictor of voluntary alcohol intake in alcohol-preferrring rats. PHYSIOL BEHAV 57(4) 791-795,
1995. --This study examined the relationship between saccharin intake and ethanol consumption in alcohol preferring (P) rats and
Fawn Hooded (FH) rats before and after exposure to forced ethanol (10%, v/v) solution. Both groups exhibited large increases
( >2X) in daily fluid intake (DFI) when saccharin (0.1%, w/v) was present and exhibited moderate levels of ethanol intake. Only
the P rats significantly increased their ethanol consumption after exposure to ethanol as the sole drinking fluid. Correlational
analyses revealed that the absolute intakes of saccharin and ethanol were not significantly correlated in either group, but the
increase in DFI in the presence of saccharin was highly correlated with ethanol intake after forced ethanol exposure (r > +0.8; p
< 0.05). Similarly, when correlations were conducted for these variables over both the P and FH groups, the correlation between
increase in DFI in the presence of saccharin and alcohol intake was significantly higher than that between saccharin and alcohol
intakes. Reexamination of previous data from 6 different rat strains also revealed a significant correlation between increase in DFI
in the presence of saccharin and ethanol intake. These findings suggest that the dramatic increase in of DFI in the presence of
saccharin may be an animal analog of the clinical phenomenon known as a loss of control.
Saccharin intake Alcohol intake Loss of control Alcohol preferring P rats Fawn-Hooded rats
A POSI TI VE associ at i on bet ween t he consumpt i on of the pal-
atable sol ut i ons and al cohol i nt ake has been demonst r at ed in a
number of ani mal studies. For exampl e, C57BL mi ce, wi t h a
genet i c pr edi sposi t i on to dri nk al cohol , also consumed l arger
amount s of a hi ghl y pal at abl e sacchari n sol ut i on than DBA mi ce,
wi t h a genet i c predi sposi t i on to avoi d al cohol (6,28). Si mi l ar re-
suits wer e f ound in popul at i on of Wi st ar (15) and r andoml y bred
rats (7). An even st r onger associ at i on bet ween sacchari n and al-
cohol intakes was demonst r at ed in rat strains ( AA & ANA, P &
NP, FH) wi t h di f f er ent propensi t i es to dri nk al cohol
(12, 14, 26, 31). The most r ecent study, whi ch exami ned sacchari n
and et hanol consumpt i on in 15 i nbred mous e trains, conf i r med
the hi gh posi t i ve associ at i on (r = +0. 77) bet ween t hese t wo vari -
abl es (4) across strains and suggest ed that genet i c factors l argel y
account ed for this correl at i on.
Our recent studies showed that in addi t i on to an associ at i on
bet ween sacchari n and al cohol intake, al cohol - pr ef er r i ng rats dra-
mat i cal l y i ncr eased t hei r dai l y fluid i nt ake (DFI) when sacchari n
sol ut i on was of f er ed al ong wi t h wat er. Thi s phenomenon was
first demonst r at ed in a popul at i on of r andoml y bred rats (15) and
t hen in NI H Het er ogeneous st ock (HS) rats (13). It was also
f ound that al cohol - pr ef er r i ng P and FH rats al most t ri pl ed t hei r
usual DFI when sacchari n sol ut i on was avai l abl e (14,26). On the
ot her hand, t hose rats wi t h a l ow intakes of al cohol usual l y drank
sacchari n sol ut i on wi t hi n the l i mi t s of t hei r DFI, al t hough t hei r
pr ef er ence f or sacchari n was as hi gh as t hose rats wi t h hi gh al-
cohol intakes (14,26,31). Such an i ncrease of DFI in ani mal s
exposed to sacchari n sol ut i on may be an ani mal model of the
cl i ni cal phenomenon known as " l os s of cont r ol . " Loss of con-
trol, when t he subst ance oft en is taken in l arger amount s or over
a l onger per i od than t he person i nt ended, is a c ommon phenom-
enon wi t hi n the eat i ng di sorders and subst ance abuse regardl ess
of the drug of choi ce (2,10). Taki ng i nt o consi derat i on the hi gh
l evel of comor bi di t y (up to 60%) bet ween eat i ng di sorders and
subst ance abuse (10) and the fact that el ement s of eat i ng di sor-
ders can be det ect ed l ong bef or e the devel opment of al cohol
abuse (11), we hypot hesi ze that t he loss of cont rol over the sac-
chari n i nt ake may refl ect a propensi t y to the devel opment of an
Portions of this paper were presented at meetings of Research Society of Alcoholism, San Antonio, Texas, June 19-24, 1993, 2nd International
Behavioral Neuroscience Society Conference, April 22-25, 1993, Clearwater, Florida.
To whom requests for reprints should be addressed.
791
792 KAMPOV-POLEVOY ET AL.
TABLE 1
PARAMETERS OF INITIAL DAILY FLUID INTAKE (DFI) AS WELL AS DFI IN PRESENCE OF SACCHARIN BEFORE
AND AFTER INITIATION PROCEDURE (EXPOSURE TO 10% ALCOHOL SOLUTION AS A SOLE SOURCE OF
FLUIDS FOR 5 DAYS) IN P AND FH RATS (M _+ SEM).
P Rats FH Rats F p
Initial DFI (ml/kg/day) 75.3 3.2 145.1 13.1 29.671 <0.0001
Saccharin consumption before initiation
(ml/kg/day) 182.3 29.8 308.2 _+ 11.0 14.397 0.0014
Saccharin preference before initiation
(%) 87.51 8.3 93.5 3.1 0.416 0.5274
DFI increase in the presence of
saccharin before initiation (% over
initial DFI) 159.8 31.6 136.8 25.2 0.315 0.5820
Saccharin consumption after initiation
(ml/kg/day) 194.9 28.3 333.1 227.1 12.300 0.0027
Saccharin preference after initiation
(%) 95.1 2.1 92.7 + 3.6 0.373 0.5494
DFI increase in the presence of
saccharin after initiation (% over
initial DF1) 179.3 45.6 165.91 + 32.0 0.055 0.8710
eating disorder and may indicate the individual risk for voluntary
alcohol consumption in rats.
The purpose of the present study was to determine if the DFI
increase at the presence of saccharin can be used as a predictor
of subsequent ethanol intake and compare its predictive value
with absolute saccharin intake and saccharin preference, two
other measures frequently associated with alcohol intake in ro-
dents (4,6,7). For this purpose we chose rat lines known for their
high voluntary intake, namely the P and FH rats. Alcohol-pre-
ferring P rats were selectively bred for the high voluntary alcohol
intake (19,20) and consume alcohol in quantities sufficient to
produce acute intoxication, tolerance and dependence (33,34).
FH rats has also been reported to voluntary consume similar high
amounts of alcohol (27), but they have a different levels of fluid
and saccharin intake (14,26).
METHODS
Animals
The animals used in these experiments were 10 male P rats
(obtained from the Indiana University Medical Center, Indian-
apolis) with a body weight of 364-468 g at the beginning of the
study and 9 FH rats (selected from viral-free colony of the FH
rats maintained in Skipper Bowles Center for Alcohol Studies,
The University of North Carolina at Chapel Hill) with a body
weight of 235-451 g at the beginning of the experiment. The P
rats have been selectively bred for high alcohol intake for more
than 30 generations and exhibited homozigosity for 13 of 17
markers tested at the 33rd generation (20). The FH rats obtained
to establish our breeding colony were provided by the New York
State Department of Health, where they had been brother-sister
mated for 19 generations (32). Therefore, both groups are highly
inbred. The rats were maintained under constant temperature
(22C) and humidity and a reversed 12:12 light:dark cycle (lights
on from 22:00-10.00 h).
Procedure
Animals were put in individual stainless-steel cages with free
access to food. Two 100-ml graduated Richter tubes were at-
tached to the front of each cage. Usually alcohol consumption in
P and FH rats has been studied after forced exposure to alcohol
solution to enhance their alcohol intake (19,27,33). In present
study we have evaluated the association between different mea-
sures of saccharin consumption (intake, preference, increase in
DFI) and alcohol intake both before and after forced exposure to
alcohol to provide more information about potential associations.
During the study animals were given following choices:
Day 1-5 (Estimation of DFI baseline)--tap water vs. tap water;
Days 6- 10 (Estimation of Saccharin intake and preference and
DFI increase in presence of Saccharin)--0.1% (w/v) saccharin
solution vs. tap water;
Days 11-20 (Estimation of spontaneous alcohol i nt ake)--10%
(v/v) ethanol solution vs. tap water;
Days 21-25 (Initiation)--10% (v/v) ethanol solution vs. 10%
(v/v) ethanol solution;
Days 26- 30 (Estimation of Saccharin intake and preference and
DFI increase in presence of Saccharin)--0.1% (w/v) saccharin
solution vs. tap water;
Days 31- 40 (Estimation of alcohol i nt ake)-- 10% (v/v) ethanol
solution vs. tap water.
The 0.1% (w/v) concentration of saccharin was selected on
the basis of previous studies (23) as a value which is highly
preferred (>80%) by all rats, regardless of propensity to drink
alcohol.
Positions of bottles were rotated daily to prevent place pref-
erence. Fluid intake from each bottle was measured each day and
corrected for the body weights of the rats. The increase in DFI
in the presence of saccharin was calculated as a percent differ-
ence between total fluid intake when saccharin was available and
the total fluid intake when only water was available.
Statistical Analyses
Comparisons of alcohol and saccharin intake between lines
were computed with the analysis of variance with Fisher LSD
posthoc comparisons. Pearsonian correlations between the vari-
ous measures of saccharin consumption (intake, preference and
increase in DFI) and alcohol intake were also performed.
SACCHARI N AND ALCOHOL INTAKE 793
TABLE 2
ETHANOL INTAKE (g/kg/day) BEFORE AND AFTER INITIATION PROCEDURE (EXPOSURE TO 10%
ALCOHOL SOLUTION AS A SOLE SOURCE OF FLUIDS FOR 5 DAYS)
BY P AND FH RATS (M _+ SEM)
P Rats FH Rats F p
Mean ethanol intake during days
1-5 before initiation
Mean ethanol, intake during
days 6-10 before initiation
Mean ethanol intake during days
1 - 5 after initiation
Mean ethanol intake during days
6-10 after initiation
3.8 _+0.4 3.0 _+0.6 I. 11 0.33071
3.9 _ 0.5 2.9 _+0.6 1.70 0.2095
5.1 _+0.5 3.9 _+0.6 1.907 0.1851
5.0 _+0.4 3.6 _+0.6 3.989 0.0621
RESULTS
The baseline DFI in the rats as well as their saccharin con-
sumption and preference and increase in DFI in the presence of
saccharin are summari zed in Table 1. The FH rats had signifi-
cantly higher baseline DFI and saccharin intake than the P rats.
However, neither saccharin preference nor increase in DFI in the
presence of saccharin were significantly different bet ween two
strains (Table 1). It is also apparent in the Table 1 that forced
exposure to alcohol did not significantly alter saccharin prefer-
ence, saccharin consumption, or the level of increase in DFI when
saccharin was available.
The alcohol intake of the FH and P rats, summari zed in 5-day
blocks, is shown in Table 2. The two groups drank comparable
amounts of alcohol prior to forced exposure, but the P rats drank
more after forced exposure. A paired t-test confirmed that the P
rats significantly increased their alcohol intake after forced ex-
posure to alcohol (t = 5.35; p = 0.0005). In contrast, the alcohol
intake of the FH rats was relatively constant (Table 2). The P rats
also had significantly higher ethanol preference than the FH rats
(73.6 _+ 5.3 vs. 37.9 _+ 6.1%; t = 3.65; p = 0.002 before forced
exposure; 84.8 _+_5.3 vs. 44.4 _ 5.3%; t = 5.40; p = 0.005 after
forced exposure).
The correlational analyses of the relation bet ween measure of
saccharin consumpt i on and alcohol intake are summari zed in Ta-
ble 3. It can be seen that the increase in DFI in the presence of
saccharin is the variable most consistently correlated with alcohol
intake. Saccharin preference, which was routinely high in all an-
imals, was second best predictor of alcohol intake, and saccharin
intake was significantly correlated on one occasion. Thus, the
best predictor of subsequent alcohol intake in alcohol-preferring
rats is the increase in DFI in the presence of saccharin. When
correlations were performed across both FH and P rats, then
only the correlation bet ween increase in DFI in the presence of
saccharin and alcohol intake was statistically significant; this
correlation was significantly higher than that bet ween saccharin
and alcohol intakes after forced exposure (t -- 2.73; p = 0.01;
Table 3).
DISCUSSION
Thi s study confi rmed that bot h FH and P rats consumed
large amount s of sacchari n sol ut i on (14,26,31), whi ch resul t s
TABLE 3
CORRELATION COEFFICIENTS BETWEEN SACCHARIN INTAKE AND PREFERENCE, DAILY FLUID
INTAKE (DFI) ELEVATION WHEN SACCHARIN WAS AVAIALBLE, AND SUBSEQUENT ETHANOL
INTAKE IN P AND FH RATS BEFORE AND AFTER FORCED EXPOSURE TO ALCOHOL
Variable Correlated With Ethanol Intake
Saccharin Intake Saccharin Ireference DFI Increase
P rats
Before forced exposure to alcohol
After forced exposure to alcohol
FH rats
Before forced exposure to alcohol
After forced exposure to alcohol
P and FH rats combined
Before forced exposure to alcohol
After forced exposure to alcohol
0.550 0.710 0.690
(p = 0.0995) (p = 0.0213) (p = 0.0273)
0.671 0.649 0.850
(p = 0.0335) (p = 0.0425) (p = 0.0085)
0.057 0.440 0.384
(p = 0.8832) (p = 0.2355) (p = 0.3070)
0.116 0.556 0.844
(p = 0.7656) (p = 0.1203) (p = 0.0042)
-0.048 0.400 0.480
(p = 0.845) (p = 0.090) (p = 0.035)
0.021 0.400 0.719
(p = 0.991) (p = 0.089) (p = 0.0005)
794 KAMP OV- P OL E VOY ET AL.
in a subst ant i al i ncr eas e in t hei r DFI when s acchar i n was pr es-
ent ( Tabl e 1). Thi s i ncr eas e is a l mos t 10 t i mes hi ghe r t han t hat
r epor t ed f or Wi s t a r rat s (15) and, unl i ke Wi s t ar rat s, t he i n-
cr eas e in DFI was de mons t r a t e d by al l FH and P rats. Thi s
i ncr eas e in DFI was al so s hown to be t he mos t r el i abl e pr e-
di ct or of s ubs equent a l c ohol c ons umpt i on in P and FH rat s
( Tabl e 3), as it was mos t cons i s t ent l y cor r el at ed wi t h a l c ohol
i nt ake and was s i gni f i cant l y mor e hi ghl y cor r el at ed t han sac-
char i n i nt ake on one occas i on. The r eas on f or t hi s out c ome
ma y be r el at ed to t he f act t hat t he i ncr eas e in DFI is t he var i -
abl e t hat is l east de pe nde nt upon t he bas el i ne DFI , whi ch di f -
f er ed s ubs t ant i al l y in t he P and FH rat s ( Tabl e 1).
Al c ohol i nt akes f or t he P and FH rats ar e mode s t ( Tabl e 2)
and s ubs t ant i al l y l owe r t han val ues whi c h ha ve been r epor t ed
in t he l i t er at ur e (16, 24). I n part , t hes e l owe r val ues ma y be
r el at ed to t he shor t dur at i on of expos ur e o f t he ani mal s to
et hanol (10 days be f or e and af t er f or c e d expos ur e) , si nce it is
t ypi cal to e xpos e t he rat s to at l east 21 days of c hoi c e condi -
t i ons af t er t he e xpos ur e to f or c e d a l c ohol ( 1, 19, 27, 33) . It is
al so pos s i bl e t hat t he r e duc e d a l c ohol i nt ake ma y be c ons e -
que nc e o f t he pr i or expos ur e t o s acchar i n (16, 17). I n any case,
t he i ncr eas e in a l c ohol i nt ake in t he P rat s, but not t he FH rats,
af t er f or c e d e xpos ur e t o a l c ohol ( Tabl e 2) r epl i cat es our pr e-
vi ous l y publ i s hed wor k (26).
The fact that i ncrease in DFI in t he pr esence of sacchari n was
the best predi ct or of al cohol i nt ake in t he present study l ed us to
r eexami ne dat a f r om a pr evi ous st udy (26). When correl at i ons
bet ween i ncrease in DFI and al cohol i nt ake wer e carri ed out for
pairs of al cohol preferri ng and nonpr ef er r i ng rat st rai ns/ l i nes, sig-
ni fi cant posi t i ve associ at i ons wer e f ound f or all pairs ( NP&P;
MR&MNRA; FH&FRL) . Thes e correl at i ons wer e at l east as
st rong as t hose f or sacchari n i nt ake and al cohol i nt ake (r > 0.6;
P < 0.05). However , t he sacchari n i nt ake can gi ve mi sl eadi ng
pi ct ure f or i nt erst rai n compar i sons, most l y because of t he de-
pendency of this measur e on t he basel i ne DFI, whi ch vari es f r om
strain to strain. Not e that in Tabl e 1, t he P rats have si gni fi cant l y
l ower basel i ne DFI and sacchari n i nt ake than the FH rats, but
t hei r scores f or i ncrease in DFI are similar. Over al l , the present
findings i ndi cat e that al t hough sacchari n i nt ake may i t sel f cor-
rel at e wi t h subsequent al cohol i nt ake under some ci r cumst ances,
as r epor t ed pr evi ousl y (4,26,31), t he i ncrease in DFI in the pres-
ence of sacchari n is a more rel i abl e predi ct or of subsequent al-
cohol i nt ake (Tabl e 3).
The dramat i c i ncrease in DFI in the pr esence of sacchari n
exhi bi t ed by the FH and P rats may be an ani mal anal og of the
cl i ni cal phenomenon known as " l os s of cont r ol . " Thi s phenom-
enon refers to situation wher e f ood or the drug of choi ce is t aken
in l arger amount s or over a l onger peri ods of t i me than the person
i nt ended. It has been descri bed f or eat i ng di sorders as wel l as for
the subst ance abuse (10) and may refl ect some basi c i nabi l i t y to
cont rol t he pl easurabl e stimuli. In this study, the loss of cont rol
may be easi l y seen when sacchari n is avai l abl e; the ani mal s al-
most triple t hei r DFI. However , it is not so obvi ous for al cohol
intake, as t hei r val ues wer e l ower than has been t ypi cal l y report ed
in t he literature. The possi bl e reasons for this l ow al cohol i nt ake
in the face of " o u t of cont r ol " dri nki ng of sacchari n have been
di scussed bri efl y above. One ot her fact or to consi der here is that
unl i ke t he pr ef er ence for sweet tastes that appears to be unl earned
and occurs as earl y as several hours after birth (See 18), the
pr ef er ence f or al cohol in ani mal s needs to be devel oped and, in
maj or i t y of cases, to be enhanced by speci al procedures, such as
pr ol onged and/ or f or ced exposur e to et hanol (1, 16, 27, 33) or fad-
i ng pr ocedur e (29).
One pot ent i al neur ochemi cal medi at or of this associ at i on be-
t ween i ncrease in DFI in the pr esence of sacchari n and al cohol
i nt ake coul d be serotonin. It has been hypot hesi zed that t he sero-
t oner gi c syst em modul at es appet i t i ve behavi or regardl ess of t ype
of r ei nf or cer (food, al cohol ) by faci l i t at i ng cessat i on/ sat i et y
mechani sms, rat her than by suppressi on of cr avi ng ( 23- 25) . The
fact that bot h FH and P rats, whi ch are known for dysfunct i on
of brai n serot onergi c syst ems (3, 5, 8, 9, 21, 30, 35) demonst rat e the
l ack of cont rol over sacchari n i nt ake and also cons ume large
amount s of al cohol is consi st ent wi t h this hypot hesi s. Furt her
support comes f r om studies demonst r at i ng that the intakes of
bot h al cohol and sweet pal at abl e sol ut i ons can be modi f i ed by
drugs i nt eract i ng wi t h the serot onergi c syst em (22,27,30).
ACKNOWLEDGEMENTS
The authors thank Dr. T.-K. Li and Indiana Alcohol Research Center
(P50-AA07611) for providing the P rats.
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