Neuroscience Letters 436 (2008) 278–282

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Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Effects of environmental enrichment and social isolation on sucrose

consumption and preference: Associations with depressive-like
behavior and ventral striatum dopamine
Juan C. Brenes a,∗ , Jaime Fornaguera a,b
a
Neuroscience Research Program, University of Costa Rica, Costa Rica
b
Biochemistry Department, School of Medicine, University of Costa Rica, Costa Rica

a r t i c l e i n f o a b s t r a c t

Article history: Little attention has been directed towards environmental control of sensitivity to natural reward and its
Received 28 November 2007 possible relationship with other motivated behaviors, besides the well-known effects of environmental
Received in revised form 18 February 2008
enrichment and social isolation on drug self-administration and locomotor sensitization to psychostimu-
Accepted 18 March 2008
lants. Here, we investigate the effects of these rearing conditions on sucrose consumption and preference,
and tissue levels of striatal dopamine. The possible relationship among sucrose intake, immobility behav-
Keywords:
ior in the forced swimming test, and dopamine concentration was explored through correlation and
Reward
regression analyses. Even though all animals preferred sucrose over water, we found, that during post-
Sucrose
Dopamine natal period, isolated rats consumed more sucrose than control or enriched littermates. In isolated rats
Striatum sucrose intake correlated positively with ventral but not with dorsal striatum dopamine, even when
Addiction striatal dopamine did not differ among groups. Especially in isolated animals immobility behavior was
Depression positively predicted by differences in sucrose intake. The dopamine concentration did not correlate with
immobility behavior. Taken together, the present data support previous findings regarding the effects
of early life events upon reward-sensitivity and depressive-like behavior, and also provide further evi-
dence about the relationship between these motivated behaviors and the likely role of ventral striatum
dopamine in regulating them.
© 2008 Elsevier Ireland Ltd. All rights reserved.

Rearing rats under social isolation or environmental enrichment
produces long-term effects on brain development and subsequent
adult behavior [3,8,9,19]. It is known that the sensitivity to per-
ceive the aversive or reward properties of stimuli as well as the
response threshold to them, are differentially affected by envi-
ronmental enrichment and social isolation [22]. Opposite trends
between these rearing conditions have been found upon anticipa-
tory behavior to reward [28,30], drug self-administration [3,25] and
locomotor sensitization to amphetamine [2,6,20] and morphine [4].
The ventral striatum (VS), which includes the nucleus accum-
bens (NAcc), is the main target of the mesolimbic dopamine (DA)
system which arises in the ventral tegmental area (VTA) of the
midbrain [1,5]. The VS mediates the reinforcing effects of natural
and artificial rewards [1,5,14,31], as well as the altered reward-
sensitivity following differential rearing or stress [6,20,29].
∗ Corresponding author at: Post-Office Box, San Pedro, ZIP Code 2060, Programa
de Investigación en Neurociencias, Universidad de Costa Rica, San Pedro, Cost Rica.
Tel.: +506 2207 49 03; fax: +506 2207 58 27.
E-mail address: brenesaenz@gmail.com (J.C. Brenes).
It might be thought that the heightened reward-sensitivity
observed in isolated rats could be a consequence of enhanced DA
function in the VS [17,19,20]. However, the relationship between
DA levels and natural rewards (i.e., sucrose) has been poorly inves-
tigated in both the enriched or isolated rats, contrary to the
well-known rewarding effects of psychostimulants on locomotor
activity [2,4,6]. Although social isolation has been found to increase
sucrose consumption [15,27], data were not always consistent and
may be due to variations in sucrose paradigms and strains [16].
Surprisingly, in those studies aimed at investigating the social
isolation effect on natural reward-sensitivity the striatal DA con-
centrations were not concurrently analyzed. Thus far, it has not
been established how isolation rearing would affect the relation-
ship between striatal DA concentration and sucrose intake. On the
other hand, the evidence that environmental enrichment modi-
fies reward-sensitivity and dopamine concentration in striatum
came from studies where rats have been trained to earn food or
sucrose [28,30] or sensitized with dopaminergic agonists [2,4,25];
but in our knowledge, neither free-choice sucrose consumption nor
basal DA levels in VS have concomitantly been assessed in enriched
rats. To determine whether rearing conditions exhibit dissimilar
sensitivity to natural reward, which could be differentially associ-

0304-3940/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.neulet.2008.03.045
 J.C. Brenes, J. Fornaguera / Neuroscience Letters 436 (2008) 278–282 279

ated with the DA concentration in VS, rats reared in environmental The neurochemical analysis was performed without any mod-
enrichment standard housing, and social isolation were submitted ification as we previously reported [9]. At PND 114 rats were
to a two-bottles sucrose consumption test (32% sucrose solution vs. decapitated and brains were quickly dissected on ice to obtain
tap water), and afterward the tissue levels of DA in VS and dorsal the dorsal (DS) and ventral (VS) bilateral regions of striatum.
striatum (DS) and the accumulative sucrose consumption obtained Thereafter, each pooled sample was analyzed for their content of
from two different measures were analyzed through Pearson cor- dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) using high-
relation analysis. performance liquid chromatography coupled with electrochemical
Individual differences on sucrose intake have been used to detection (HPLC-EC). The substance concentration was expressed
predict positive-reward related behavior, such as drug self- as nanograms per milligram of wet tissue weight.
administration or sucrose pellets earning [7,11–13], but little Statistical comparisons were carried out using the unpaired
attention has been directed upon the relationship between sucrose or paired one-way multivariate variance analysis (MANOVA) test,
intake and negatively motivated behaviors. There is evidence sug- when appropriate. Tukey’s HSD and Bonferroni post hoc tests
gesting that individual differences in sucrose intake predicted were used for between groups or repeated measures comparisons,
anxiety/fear-motivated avoidance behavior [12], but it is not clear respectively. Linear regression analysis (R) between sucrose intake
if they would predict behavior in depression models under highly and immobility behavior was used. Pearson correlation coefficients
stressful and uncontrollable conditions. Therefore, in the current (r) were calculated between DA concentration (in DS and VS) and
experiment the forced swimming test (FST), a widely accepted pre- sucrose intake, and between DA and immobility behavior. The
dictive model of the efficacy of antidepressant drugs [10], was used sucrose consumption corresponding to the PNDs 65–66 and 93–94
to evaluate whether depressive-like behavior could be differentially was summed to be included into the regression and correlation
predicted by the differences in sucrose intake among rearing condi- analyses. The last SPT (PNDs 108–109) was excluded due to the pos-
tions. The final objective of the present study was to assess whether sible effect of FST (PNDs 106–107) on sucrose intake. In all statistical
striatal DA is associated with immobility behavior. Here we con- analyses significance was set at P < 0.05.
trast the hypothesis that immobility is not especially associated Regardless of housing conditions, all animals preferred sucrose
with striatal DA. solution over water (Fig. 1A) during all PNDs tested (P < 0.0001 in
Briefly, at postnatal day (PND) 30 (after 1-week habituation all tests). In respect to sucrose preference, the EE rats showed the
to our colony room) 45 male Sprague–Dawley rats were ran- lowest percentages in PNDs 66 and 94 (Fig. 1B), but significance
domly distributed into three experimental groups (n = 15 each). was only reached at PND 94 (P < 0.04). The preference did not dif-
Two groups were kept in standard cages (top 26.5 cm × 42 cm, fer significantly between SC and SI animals, although in PND 66 SI
lower 22 cm × 37.5 cm, height 18 cm and bottom 825 cm2 ) under showed the highest values. The repeated measures analysis showed
either isolation (SI) or group housing (three rats by cage) (SC). The that sucrose preference in EE animals increased significantly at each
other group was housed in an enriched environment (EE) in a spe- PND measured (P < 0.0001). In contrast, in SC (P < 0.0001) and SI
cially designed box (120 cm length × 70 cm width × 100 cm height) groups (P < 0.02) the significant differences appeared only when
containing non-chewable plastic objects, two PVC tubes, five food
dispensers and two water bottles [8], which were rearranged after
1 or 2 days. Rats were maintained until PND 114 under 12:12 h
light–dark schedule (light on at 06:00–18:00 h), room tempera-
ture at 20.5 ± 1.20 ◦ C, 78–87% of relative humidity, 10 air cycles per
hour, and free access to water and food. All animals included in the
current experiment were the same which were used in a previous
study [9]. Experimental procedures were done in accordance to the
guidelines of the Costa Rican Ministry of Science and Technology
for the Care and Use of Laboratory Animals, and were approved by
the Institutional Committee for Animal Care and Use of the Univer-
sity of Costa Rica. Particular care was taken in order to minimize
the number of animals used and to reduce their suffering.
At PNDs 65–66, 93–94 and 108–109 our version of sucrose
preference test (SPT) was carried out [8]. Briefly, rats were indi-
vidually housed in standard cages during 48 h where one bottle
with 200 ml of 32% sucrose solution (w/v), another with 200 ml
of tap water and food ad libitum were available. After this period,
sucrose (ml), water (ml), and food consumption (g), were measured
and animals were returned to their previous housing conditions.
Preference was calculated as follows: preference % = [(sucrose con-
sumption/sucrose + water consumption) × 100].
At PNDs 106–107, the forced swimming test was performed
during the dark phase (19:00–24:00 h) under infrared light, as we
previously described [9]. Rats were individually placed into Plex-
iglas cylinders (35 cm height, 30 cm diameter) containing water
(25 ± 0.5 ◦ C) to a depth of 21.5 ± 1.5 cm (the animals’ hind-paws
did not touch the cylinder’s bottom). Two swimming sessions were
Fig. 1. Sucrose and water consumption (A) and sucrose preference percentage (B)
conducted: a 15 min pre-test followed 24 h later by a 5 min test. measured along postnatal days (mean ± S.E.M., n = 15 each). Each test lasted 48 h, but
The time spent on immobility (floating posture including small figures only indicate the day when consumption was measured. During postnatal
movements necessary to keep the animal’s head above the water) days 106 and 107 the forced swimming test was carried out. (*) Enriched differed
from standard and isolated, P = 0.04. (# ) Isolated differed from enriched, P = 0.007. (+)
was manually scored from the video of the 5-min session (day 2),
Isolated differed from enriched, P = 0.002. (×) Isolated differed from standard and
and was expressed as percent values: immobility % = [(seconds of enriched, P = 0.001. All P values correspond to MANOVAs followed by HSD post hoc
immobility/300 s) × 100]. test.
280 J.C. Brenes, J. Fornaguera / Neuroscience Letters 436 (2008) 278–282

values at PND 66 were compared with PNDs 94 and 109, but not
when these latter PNDs were compared to each other. Prior to FST,
the sucrose consumption was higher in SI rats and lower in EE rats,
which never differed from SC group (Fig. 1A). At PND 66 the SI rats
drank between 14.5% and 22.3% more sucrose than SC and EE ani-
mals, respectively. The differences were only significant between
SI and EE groups (P < 0.002). At PND 94 the consumption difference
between SI and SC animals remained almost the same (14.04%),
while between SI and EE rats it diminished (19%). Here, the con-
sumption in SI rats was significantly higher than the other groups
(P < 0.001). In PND 109, after the FST (Fig. 1A), the between-group
differences diminished until significance disappeared. Neverthe-
less, EE animals still showed the lowest and SI littermates the
highest values. The within groups comparison of sucrose consump-
tion did not reveal any significant trends over PNDs in EE and SC
rats, contrary to SI animals, which drank significantly more sucrose
at PND 66 (Fig. 1A) compared with the following PNDs (P < 0.0001).
In respect to the water consumption, this was only affected by
housing conditions at PND 109 (after the FST) (P < 0.007), where SI
animals drank significantly more water than EE rats (Fig. 1A). The
repeated measures analysis showed that water intake in EE rats
was decreasing significantly at each time point (P < 0.0001). The
same significant tendency was observed in SC (P < 0.0001) and SI
(P < 0.0001) groups when PND 66 was compared with PNDs 94 and
109, but not when these latter PNDs were compared to each other.
Regarding food intake during SPTs, neither between-group differ-
ences nor suggestive tendencies were observed (data not shown).
Finally, adjusting sucrose intake to body weight did not change the
Fig. 2. Linear regression analysis between sucrose intake and immobility behav-
between-groups differences (data not shown). Nor did initial neo- ior (A), and Pearson correlation analysis between ventral striatum dopamine and
phobia explain the differences among groups since consumption sucrose intake (B). Symbols indicate the rearing conditions (n = 15 each). Sucrose
tendencies during the first 12 h did not differ from consumption at intake corresponding to postnatal days 65–66 and 93–94 were summed to be
included in the analyses. Sucrose intake and immobility time were expressed as
24 or 48 h (data not shown).
percentages (%) and dopamine concentration as nanograms per milligram (ng/mg)
A detailed analysis of FST behavior was already reported [9]. of wet tissue weight.
Briefly, the time spent immobile was significantly different among
the three housing conditions (P < 0.0001), showing EE the low-
est (51.1 ± 3.64%, mean ± S.E.M.), SC the mid-range (68.1 ± 3.64%) [15,27] SI rats consumed more sucrose than SC or EE littermates.
and SI the highest (80.1 ± 3.64%) values. Furthermore, the linear In addition, we showed that EE rats consumed slightly less sucrose
regression analysis computed over all subjects (Fig. 2A) revealed than SC congeners. This effect was already noted 36 days after the
that sucrose intake significantly predicted immobility behavior onset of rearing conditions (PND 66), and was maintained until
(R2 = 0.46, P < 0.0001). Within each group, this prediction pattern PND 94. After the FST stress (PND 109), the sucrose intake slightly
was observed in SI animals (R2 = 0.30, P < 0.02), but not in SC increased in SC and EE animals to a level in which the signifi-
(R2 = 0.10, P > 0.12) nor in EE (R2 = −0.006, P > 0.49) groups (Fig. 2A). cant between-group differences previously detected disappeared.
The DA and DOPAC concentrations did not differ among groups In SI animals the FST did not increase the sucrose consumption
neither in DS (DA: EE = 6.64 ± 0.82, SC = 7.16 ± 0.82, SI = 6.38 ± 0.82; compared with their preceding values. However, SI rats continued
DOPAC: EE = 1.03 ± 0.21, SC = 1.09 ± 0.21, SI = 1.47 ± 0.22) nor in showing the highest intake. In respect to sucrose preference, it did
VS (DA: EE = 6.73 ± 0.74, SC = 7.66 ± 0.74, SI = 7.23 ± 0.74; DOPAC: not appear consistently affected along PNDs, but EE rats showed the
EE = 1.54 ± 0.21, SC = 1.70 ± 0.21, SI = 1.55 ± 0.22). Also, the DA lowest ratios at PNDs 66 and 94, and SI animals the highest at PND
turnover (DOPAC/DA) did not vary among rearing conditions (data 66. Regardless of rearing conditions, sucrose preference increased
not shown). from PND 66 to 94. After FST only EE rats maintained this tendency.
In addition, no correlation was detected over all subjects In all groups water and sucrose intake decreased from PND 66 to
between sucrose intake and DA concentration neither in DS 94, but this reduction was much higher in water than in sucrose
(r = −0.19, P > 0.11) nor in VS (r = −0.005, P > 0.49). Within each intake. The differences in sucrose preference between PND 66 and
group, a positive and moderate correlation between DA concentra- 94 seem to be related to a decrease in water intake rather than to
tion in VS and sucrose intake was only obtained in SI rats (r = 0.55, a net increase in sucrose consumption. Even though several phys-
P < 0.03) (Fig. 2B). In EE rats (Fig. 2B) a negative and nonsignifi- iological factors could underlie the age-dependent differences in
cant tendency appeared (r = −0.33, P > 0.23), whereas in SC group water intake, a clear effect of rearing on this measure was not evi-
(Fig. 2B) no suggestive pattern was observed (r = −0.03, P > 0.91). dent. At PND 109 (after the FST) the water intake only increased in
Between DA in DS and sucrose intake no significant correlations SI animals, suggesting a particular effect of FST stress in this group.
were detected within each group (EE: r = −0.28, P > 0.31; SC: r = 0.01, In contrast, a previous study did find that SI rats drank not only
P > 0.72; SI: r = 0.14, P > 0.67). There were not significant correlations more sucrose but also more water throughout testing periods [15].
between immobility behavior and DA concentration neither in DS On the other hand, immobility behavior was significantly
(r = −0.16, P > 0.30) nor VS (r = −0.08, P > 0.60). affected by rearing conditions in a way that seems to depend on
The results of the present study demonstrated that rearing con- the extent of social and physical stimulation provided by differen-
ditions affected sucrose intake over postnatal days, supporting the tial housing, as it has been discussed elsewhere [9]. Furthermore,
evidences that differential rearing is sufficient to modify reward- we showed that sucrose intake was a good predictor, principally
sensitivity [3,22,25,28,30]. In agreement with previous studies in SI rats, of an altered coping response to an uncontrollable and
 J.C. Brenes, J. Fornaguera / Neuroscience Letters 436 (2008) 278–282
unavoidable stress situation, as it is in the FST. Even though EE rats
showed the lowest sucrose intake and immobility time, a signifi-
cant association between these behaviors was not detected. In SC
group the moderate levels in both behaviors led to a low regres-
sion coefficient which failed to reach the significance. Overall, the
predictive capacity of sucrose intake seems to follow a trend that
varied accordingly with the social and physical activity allowed by
each rearing condition. Especially in SI rats, the positive relationship
between sucrose consumption and immobility suggests that these
behaviors could be different traits of a general motivational state
altered by the isolation stress, which represent the outcome of dis-
rupted neural circuitries involved in regulating reward-sensitivity
and coping-stress responses, as it has been suggested elsewhere
[8,17,19,20]. The fact that negatively motivated behaviors can be
predicted by the differences in sucrose intake supports previous
findings obtained with anxiety models [12]. Moreover, our results
provide new information regarding the predictive capacity of a
reward-sensitivity parameter over a depressive-like behavior, and
how early postnatal experiences could modify this relationship as
well.
Similar to previous studies, we did not find differences in stri-
atal DA concentration between SI and non-SI rats [17,19]. However,
especially in SI rats an increased sucrose intake was strongly asso-
ciated with higher DA levels in VS, but not in DS. Although within
SI group there were individual differences on DA levels and sucrose
intake, the animals with high sucrose consumption also showed
high DA concentration (Fig. 2B). Interestingly, within EE group the
rats with high DA concentrations tended to consume less sucrose
(Fig. 2B), suggesting that physical and social stimulation somehow
inverted the association between sucrose intake and DA content
in VS observed in SI animals. However, further experiments are
required to corroborate this observation.
In agreement with our results, there is evidence indicating that
sucrose intake is related with mesolimbic DA activity. Sucrose
intake increases DA release in NAcc [1,14]. Whether DA agonists and
antagonists are administered in NAcc or systemically, they increase
or decrease the sucrose intake, respectively [1,18,26,31]. Moreover,
studies conducted with rats selected by their high or low sucrose
consumption support the relationship between DA and sucrose
intake obtained in the current study with the SI animals. First, high
sucrose consumer rats showed exaggerated responses to DA ago-
nists, similar has been found in SI animals [2,6,20]. High consumers
self-administrated more amphetamine [11], met the acquisition
criteria for cocaine infusion sooner than low consumers [13], and
also develop greater locomotor sensitization to amphetamine [23].
Second, high consumers earned more rewards than low ones, and
this effect is potentiated under conditions of DA facilitation by a
non-anorectic dose of amphetamine [7]. Third, the elevated sucrose
intake observed in these animals has been addressed to a high DA
tone in NAcc [11,24]. Altogether these findings not only support
the fact that high sucrose intake is closely associated with high
mesolimbic DA activity, but also suggest that isolation rearing could
augment sucrose consumption through increasing the endogenous
DA tone selectively in VS.
As we expected, either over all subjects or within groups, stri-
atal DA did not correlate with immobility behavior. It is known that
antidepressants could act indirectly through the mesolimbic DA
system mediating in part some of their behavioral and neurochemi-
cal effects in animal models of depression including the FST [21], but
up till now, there is not evidence indicating that immobility behav-
ior depends on endogenous DA tone in VS. In these animals we
have already found a negative association between immobility and
tissue levels of prefrontal cortex serotonin and VS norepinephrine
[9]. Both, current and previous findings suggest that immobility
behavior and sucrose intake might not be controlled by the same
neurochemical mechanism, at least in the VS.
281
In summary, rearing conditions affected differentially sucrose
intake and immobility behavior without modifying the tissue lev-
els of striatal DA. Especially in SI animals, immobility behavior was
positively predicted by differences in sucrose intake. Moreover,
VS, but not DS DA was associated with social isolation-induced
changes in sucrose consumption but not with those observed in
immobility behavior. These results not only support the fact that
postnatal manipulations affect concomitantly reward-sensitivity
and depressive-like parameters but also provide further evidence
about the relationship between these motivated behaviors and the
likely role of VS DA in regulating them.
Acknowledgements
We are grateful to Odir Rodrı́guez and Elvira Salas for helpful
scientific and technical assistance. This work was supported by
Universidad de Costa Rica: Project No. 422-A6-609.
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