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Different doses of estradiol benzoate induce conditioned place preference
after paced mating
Rebeca Corona, Francisco J. Camacho, Patricia García-Horsman, Alfonso Guerrero,
Annette Ogando, Raúl G. Paredes⁎
Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, México
a b s t r a c ta r t i c l ei n f o
Received 11 February 2011
Revised 26 May 2011
Accepted 27 May 2011
Available online 25 June 2011
The ovarian hormones estrogen and progesterone are required for the complete display of sexual behavior in
female rats. Paced mating produces a reward state in intact cycling and ovariectomized (OVX), hormonally
primed females as evaluated by the conditioned place preference (CPP) paradigm. Most of the studies that
have evaluated CPP induced by paced mating in OVX females have used relatively high doses of estradiol
benzoate (EB). In the present study we determined if different doses of EB, combined with progesterone (P),
could induce CPP after paced mating. For this purpose OVX female rats were divided in five groups that
received one of different doses of estradiol benzoate (5, 2.5, 1.25 or 0.625 μg estradiol+0.5 mg of
progesterone) before being allowed to pace the sexual interaction and conditioned in a CPP paradigm. We
found that the lowest dose of EB used (0.625 μg) significantly reduced the lordosis quotient and the lordosis
coefficient. Even though these females paced the sexual interaction, they didn't change its original preference,
suggesting that sexual interaction did not induce a positive affective, reward state. Females allowed to pace
the sexual interaction with higher doses of EB developed CPP after paced mating. These results indicate that a
threshold of estradiol is required for paced mating to induce CPP.
© 2011 Elsevier Inc. All rights reserved.
Sexual behavior in the female rat is complex and characterized by
two phases: proceptivity and receptivity. The proceptive phase
includes stereotyped movements like hopping, darting, and ear-
wiggling that are displayed to attract the male. The receptivity phase
is recognized by the lordosis reflex, in which the female arches her
back and lifts her tail to allow the male to make an intromission. One
important aspect of proceptive behaviors that is most commonly
observed under semi-natural or natural conditions is the approach
and withdrawal behavior (pacing or paced mating) by which the
female regulates the frequency and timing for receiving a stimulus
(mount, intromission, or ejaculations). Pacing behavior is readily
observed in laboratory conditions if the mating chamber is divided by
a removable partition with a hole in the bottom of sufficient size to
allow only the female to go from one side to the other (Erskine, 1989).
The complete display of female sexual behavior depends on the
action of the ovarian hormones estrogen and progesterone. In intact
females, estradiol (E) and progesterone (P) are elevated when they
are sexually receptive. In experimental models where females are
ovariectomized (OVX), the exogenous administration of E and P
produces similar levels of receptivity and proceptivity, including
paced mating, as those seen in intact female rats (Zipse et al., 2000).
For example, it has been shown that a sexually receptive female rat
will exhibit paced mating behavior in response to a variety of
hormone priming regimens and that contact return latencies are not
affected by different doses of P (Brandling-Bennett et al., 1999; Fadem
et al., 1979; Gilman and Hitt, 1978). However, female rats exhibited
significantly longer contact return latencies when hormone treated
than when intact (Zipse et al., 2000). It has been argued that the
percent of exits after a stimulation received from the male appears to
be related to sensory discrimination, while contact return latencies to
the male are an index of sexual motivation (Erskine, 1992) this latter
factor could be modulated by different hormonal priming regimens.
Several groups (Agmo and Pfaff, 1999; Meerts and Clark, 2007;
Meerts and Clark, 2009a; Paredes, 2008; Paredes and Vazquez, 1999;
Pfaus et al., 2001) have extensively studied the appetitive aspect of
reproduction. Our group and others have demonstrated, using the
conditioned place preference paradigm (CPP), that this specific
pattern of controlling the sexual interaction is highly rewarding for
the female (Camacho et al., 2009; Coria-Avila et al., 2006; Garcia
Horsman and Paredes, 2004; Martinez and Paredes, 2001). In this
paradigm the positive rewarding components of the sexual interac-
tion are associated with a compartment that is not preferred at the
beginning of conditioning. When the females associate the positive
reward state produced by sexual behavior, they show a change of
Hormones and Behavior 60 (2011) 264–268
⁎ Corresponding author at: Instituto de Neurobiología, Apartado Postal 1–1141,
Querétaro, Qro. 76001, México. Fax: +52 442 234 0344.
E-mail address: email@example.com (R.G. Paredes).
0018-506X/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
Hormones and Behavior
journal homepage: www.elsevier.com/locate/yhbeh
Author's personal copy
preference; that is, they will now spend more time in the originally
non-preferred compartment. This reward state measured by CPP only
occurs when the female controls the sexual interaction (Camacho
et al., 2004; Martinez and Paredes, 2001; Paredes and Alonso, 1997).
Most of the studies in which we previously evaluated the reward
state induced by paced matingwere donein OVXfemales treated with
doses of estradiol that induced high levels of receptive and proceptive
behaviors. The aim of the present study was to evaluate different
doses of estradiol for the ability to modify pacing behavior, and
consequently, the reward state induced by this type of mating as
evaluated by CPP. Female rats were randomly divided in five groups
that received different doses of EB together with a constant dose of
P before being allowed to pace the sexual interaction and evaluated
Sixty sexually naive female Wistar rats (200–250 g) from the
breeding colony at the Instituto de Neurobiología, Universidad
Nacional Autónoma de México (Querétaro, México) were used in
the experiments. They were maintained under a reversed light/dark
cycle (12 h/12 h). Commercial rat pellets (LabDiet, Nutrition Interna-
tional, Brentwood, MO) and water were always available. Subjects
were housed four per cage, with animals of the same experimental
group living together. Sexually experienced males (Wistar, 320 g to
400 g) were used in tests of sexual behavior. All experiments were
carried out in accordance with the “Reglamento de la Ley General de
SaludenMateriadeInvestigación parala Salud”of theMexicanHealth
Ministry which follows NIH guidelines for care and use of animals in
research, and were approved by the local animal care committee.
The pacing chambers consists of an acrylic box (40 cm×60 cm×
40 cm) with wood shavings on the floor and is divided in two halves
by a partition with a small hole (4-cm diameter) near the bottom
through which only the female can move from one side to the other.
The hole is too small for the male to get through, allowing the females
to control the rate of sexual interaction.
Place preference cage
A three-compartment box made of acrylic was used. The middle
compartment consisted of a 22×24×32 cm area painted gray that
communicated with the lateral compartments through sliding doors
(10×10 cm). Lateral compartments (23×37×32 cm) offered distinct
stimuli in odor, color, and texture. One compartment was white and
had a wrinkled texture. The other lateral compartment was black, had
a smooth texture, and was moistened with a 2% solution of glacial
acetic acid. The front side of the middle compartment was made of
fine wire to allow observation of the animal inside the cage. The
place preference cages and the pacing cages were located in adjacent
rooms illuminated with dim white light.
Femaleswereanesthetized witha mixtureof ketamine(95 mg/kg)
and xylazine (12 mg/kg) before being bilaterally ovariectomized.
After a two-week recovery period, females were randomly assignedto
one of five groups with 12 rats each. Group 1 was treated with a dose
of EB (25 μg/rat) and P (1 mg/rat), which has been shown consistently
to prompt the development of CPP after paced mating (Garcia-
Horsman et al., 2008; Martinez and Paredes, 2001; Paredes and
Alonso, 1997). Since, as described in the Introduction, lower doses of
P don't alter pacing behavior, in the present experiment we decided
to use half the previous dose of P and different doses of EB in the other
4 groups to evaluate if lower doses of EB modify pacing behavior
and the reward state induced by this type of mating. The other 4 groups
receivedthefollowingtreatments:Group2)5 μg EB+0.5 mgP;Group3)
2.5 μg EB+0.5 mg P; Group 4) 1.25 μg EB+0.5 mg P; Group 5)
0.625 μg EB+0.5 mg P. The drugs were administered subcutaneously
48 h(EB)and4 h(P)beforetesting.Thesynthetichormoneswerebought
from Sigma Chemical (St. Louis, MO USA), dissolved in corn oil and
injected in a volume of 0.2 ml/rat.
Sexual behavior test
During mating tests in which females controlled the rate of sexual
interaction, the exits from the male chamber after a copulatory event
were determined and expressed as percentage of exits after mounts
(% EM) or intromissions (% EI). We also calculated the mount return
latency (MRL) for the female to re-enter the male's chamber after a
mount, the intromission return latency (IRL) for the female to return
to the male's chamber following an intromission; the lordosis
quotient [LQ: (number of lordosis/(number of mounts+number of
intromissions)×100]; the mean lordosis intensity (MLI: the sum of
lordosis points divided by the number of mounts plus intromissions
received) The lordosis degree was registered using a previously
described scale from 1 to 3 (Hardy and DeBold, 1972) depending on
the intensity of the dorsiflexion. The number of hops and darts (HD),
and ear-wiggling (EW) behaviors were registered. The number of
mounts and intromissions before ejaculation and the mount and
intromission latencies (time from introduction of male until the first
mount with pelvic thrusting or until the first vaginal penetration)
Conditioned place preference paradigm (CPP)
The procedure that we have used successfully and repeatedly to
evaluate CPP after mating has been described in detail before
(Camacho et al., 2004; Camacho et al., 2009; Garcia-Horsman et al.,
2008; Martinez and Paredes, 2001; Paredes and Alonso, 1997). The
original preference was determined in a 10 min pre-test in which
the subjects were placed in the middle compartment, and the time
spent in each of the lateral compartments was recorded. In the non-
reinforced session, the animals were placed in the preferred compart-
ment for 30 min. On alternate days, females were allowed to pace the
sexual interaction and after receiving 15 intromissions (including
ejaculations), they were gently transferred to the non-preferred
(rewarded) compartment for 30 min. The test was ended after at
least 10 intromissions if the female did not return to the male side in a
period of 30 min. After six alternating sessions three non-reinforced
and three reinforced, the preference for each compartment was tested
again (test) in exactly the same way as before conditioning (pre-test).
An interval of 24–72 between sessions was used. Both pre-test and
test were videotaped using Ethovision 3.0 (Noldus), a behavioral data
acquisition computer program.
To evaluate CCP, we compare the time spent in the reinforced
compartment before and after conditioning and the preference score
(time in reinforced compartment divided by the time in reinforced
compartment plus the time in non-reinforced compartment). A CPP is
established only if both parameters increase significantly after condi-
tioning. The time in the reinforced compartment and the preference
score before and after conditioning were compared by paired t-tests.
The sexual behavior parameters of the 3 conditioning sessions were
R. Corona et al. / Hormones and Behavior 60 (2011) 264–268
Author's personal copy
averaged and evaluated by a completely randomized ANOVA. In case
of a significant effect a Scheffé post hoc test was done.
When the parameters of the sexual behavior were analyzed, sig-
nificant differences were observed in the number of intromissions
(F(4,55)=8.85, pb0.001) between the group treated with 0.625 μg EB
and the other groups (pb0.01). Significant differences were also
found in LQ (F(4,55)=9.97, pb0.0001) and MLI (F(4,55)=4.69, pb0.01).
With respect to LQ, posthoc tests revealed that females treated with
0.625 μg EBshowedalowerLQthanthefemalesthatreceived25,5,and
2.5 μg EB (pb0.01). Also, the groups of females treated with the lower
dose of EB (0.625 μg) showed a reduced MLI with respect to the groups
treated with 25 and 5 μg of EB (pb0.05; Table 1). Females with
1.25 μg EB displayed a higher percent of exits after intromissions in
comparison to the females that received 5 and 2.5 μg EB (F(4,55)=4.64,
pb0.05). No significant differences were found in the number of
mounts (F(4,55)=1.08, p=0.37), or in mount (F(4,55)=1.32, p=0.28)
were found in mount (F(4,55)=0.19, p=0.94), intromission (F(4,55)=
p=0.36) or hops and darts (F(4,55)=1.82, p=0.13).
Conditioned place preference
The analysis of the CPP measures revealed a clear change of
preference in all groups except in the females injected with the lowest
dose of EB (0.625 μg). The time in the reinforced compartment
significantly increased after conditioning in the groups treated with
25 (t(11)=−2.23, pb0.05) 5 (t(11)=−2.44, pb0.05) 2.5 (t(11)=
−2.68, pb0.05) and 1.25 (t(11)=−2.72, pb0.05) μg of EB. No
significant increase was observed in the group of females treated with
0.625 μg (t(11)=−1.95, p=0.08) (see Fig. 1-A). Finally, the preference
score increased significantly in all groups 25 (t(11)=−3.79, pb0.01); 5
(t(11)=−3.05,pb0.01); 2.5(t(11)=−5.78, pb0.01)and 1.25 μg(t(11)=
−3.43, pb0.01) except in the group treated with the lowest dose of EB
0.625 μg (t(11)=−1.82, p=0.09); see Fig. 1-B.
Sexual behavior parameters in females that paced the sexual interaction with different treatments of estradiol benzoate (EB) plus progesterone (P), N=12.
25 μg EB+1.0 mg P5 μg EB+0.5 mg P2.5 μg EB+0.5 mg P1.25 μg+0.5 mg P0.625 μg+0.5 mg P
The data (mean±SEM) represent the average of the 3 conditioning sessions. NM = number of mounts, IN = number of intromissions, ML = mount latency, IL = intromission
latency, LQ = lordosis quotient, MLI = mean lordosis intensity, % EM = percent of exits following mount, % EI = percent of exits following intromission, MRL = return latency
following mount, IRL = return latency following intromission, E = ear wiggling, and D = darting.
NI different from all the other groups.
LQ different from 25, 5, and 2.5 μg EB groups.
MLI different from 25 and 5 μg EB groups.
% EI different from 5 and 2.5 μg EB groups.
25µg E5µg E 2.5µg E1.25µg E0.625µg E
25µg E5µg E2.5µg E1.25µg E0.625µg E
TIME IN REINFORCEMENT
Fig. 1. Time spent in the reinforced compartment (A) and preference score (B) between
pre-test and test in the conditioned place paradigm after paced mating of females in
different hormonal treatments. (A) The time spent in the reinforced compartment, and
(B) the preference score during the pre-test (white bars) and the test (black bars) were
compared in all the hormonal treatments. The group with 25 μg of estradiol (EB)
received 1 mg of progesterone (P), and the other 4 groups received the indicated dose
of EB plus 0.5 mg of P. Data are expressed as mean±SEM. (N=12 for each group).
*Different from the pre-test, pb0.05; ** pb0.01.
R. Corona et al. / Hormones and Behavior 60 (2011) 264–268
Author's personal copy
The results of the present study indicate that EB over a wide range
of doses produce similar levels of paced mating behavior which, in
turn, induce a reliable CPP indicative of a positive affective, reward
state after mating. Although females of all groups showed receptive
behavior, the LQ and the MLI values presented by the females that
received 0.625 μg of EB were significantly lower than those displayed
by the groups receiving higher doses of EB. This group also received
fewer intromissions than the other groups treated with higher doses
of EB (25, 5 and 2.5 μg).
It is well established that adequate levels of E and P are essential for
the display of a complete proceptive and receptive behavior in females
(Blaustein and Mani, 2006; Brandling-Bennett et al., 1999; Erskine,
1989; Erskine, 1992). Paced mating induces a positive affective state
that develops CPP in females (Camacho et al., 2009; Gonzalez-Flores
et al., 2004; Meerts and Clark, 2009b; Paredes and Alonso, 1997). In the
present experiment the groups of females that received 25, 5, 2.5,
or 1.25 μg of EB change their original preference after conditioning,
these females. The group that received the lowest concentration of
EB (0.625 μg) and as a consequence was also the less receptive and
received fewer intromissions, didn't develop CPP. It is unlikely that the
failure to develop CPP in this group could be attributed to the fact that
they received fewer intromissions (12.2±0.7), because in previous
studies we showed that females that received at least 10 paced
intromissions developed CPP (Paredes and Vazquez, 1999). Although
received could have been aversive. A more plausible explanation is
mating to induce a positive affective state. In addition, we have shown
that P is required to induce CPP after paced mating. Progesterone or its
ring A reduced metabolites [megestrol acetate (13 μg), 5ß-pregnan-20
dione(3 μg),5ß-pregnan-3a-ol-20-one(3 μg)]reliably induce a change
of preference when females are allowed to pace the sexual interact-
ion (Gonzalez-Flores et al., 2004). In another study it was shown that
females treated with 3a, 5a-THP before paced mating develop CPP
without significantly modifying pacing behavior (Frye et al., 1998).
It could also be argued that E and/or P itself could contribute to the
CPP observed after paced mating. Some studies have evaluated the
It is clear that E and P modulate CPP induced by different drugs, but
upon CPP (see Paredes (2010) for a discussion). For example, daily
administration of estradiol (10 μg in sesame oil) to intact adult females
during CPP training (approximately eight days) associated with food
reward disrupts the acquisition of CPP, suggesting that an over-dose of
estradiol impairs the formation of appetitive conditioning CPP (Galea
et al., 2001). On the other hand, administration of E (at the same
CPP formation (Frye and Rhodes, 2006). In previous studies, we have
shown that females treated with EB (25 μg) only, do not change their
preference after paced mating (Gonzalez-Flores et al., 2004; Paredes
and Alonso, 1997; Paredes and Vazquez, 1999). Also in the study by
Gonzalez-Flores et al. (2004) the administration of the different P
metobolites did not induce CPP when administered alone. The results
obtained in the present study could not be attributed to a accumulative
effect of the hormonal treatments because all groups received the same
sequence of hormone replacement and previous studies have shown
that even higher doses of EB and P, administered in the same sequence
and Alonso, 1997).
Aside from the minimum levels of E and P that are required for
paced mating to be rewarding as evaluated by CPP, there are other
factors that contribute to the reward state induced by sexual behavior
in females. During copulation the females receive complex social and
sensory stimuli like visual, olfactory, auditory, vaginocervical—VCS-
and clitoral—CLS-stimulation Meerts and Clark (2009a); Parada et al.,
2010; Pfaus et al., 2000). Estrogen and progesterone are important
for the display of behaviors (proceptive and receptive) that the
females display trying to ensure that the male is going to start and
maintain the sexual interaction displaying mounts, intromissions and
ejaculations. Once the male displays mounts and/or intromissions the
female receives VCS and CLS that are capable of inducing CPP. For
example, vaginal lavage immediately before the conditioning session
induces CPP (Walker et al., 2002). As well, female rats given artificial
VCS with the rubber tipped end of the plunger from a syringe
developed CPP suggesting that VCS itself can produce a reinforcing
state in the rats that makes them change its original preference
Meerts and Clark (2009a). On the other hand Parada et al. (2010)
demonstrated that artificial and distributed clitoral stimulation given
with a paintbrush induced CPP. Taken together, these observations
and the results of the present experiment indicate that minimum
levels of E and P plus adequate vaginocervical and clitoral stimulation
that the females receive by pacing the sexual interaction are crucial
for the development of a positive affective, reward state.
In previous experiments we have shown that OVX hormonally
primed (Martinez and Paredes, 2001; Paredes and Vazquez, 1999) as
well as intact (Camacho et al., 2009) females developed CPP after
paced mating. In the experiments in which we have used OVX
females,theyreceivedrelativelyhighdosesofEB(25 μg)andP(1 mg).
These doses induce high levels of receptive, proceptive, and paced
mating behavior. In the present experiment we used the dose of 25 μg
of EB and 1 mg of P as a control to compare with the other 4 groups
that received: 5, 2.5, 1.25 and 0.625 μg of EB (plus 0.5 mg of P). The
results clearly demonstrate that there are no differences between
the control dose and the doses of 5, 2.5 and 1.25 μg of EB plus 0.5 mg
of P in the display of pacing behavior and in the induction of CPP,
suggesting that in that range of EB doses the positive affective
(reward) state induced by paced mating is similar.
Paced mating behavior in OVX females is observed in response to
different hormonal treatments. In fact, long term daily treatment with
EB alone induces high levels of receptivity and paced mating behavior
that are not different from injections of EB+P (Brandling-Bennett
et al., 1999). On the other hand, there are reports indicating that in
OVX females doses of P (range 50 to 200 μg) shorten the contact
return latency after an intromission (Fadem et al., 1979; Gilman and
Hitt, 1978) but there is also evidence indicating that different doses of
P (range 1 to 8 mg/kg) have no effect on contact return latencies
(Brandling-Bennett et al., 1999). In the present study no differences
were observed in contact return latencies even at the lowest dose of
EB (0.625 μg) which induces lower levels of receptive behavior.
Furthermore, no differences were found between the control group
and the other groups that received half the dose of P. Further studies
will need to address if long term EB treatment or lower doses of P
induce CPP after paced mating.
To summarize, the results of the present experiment indicate that
a wide range of EB doses induce similar levels of pacing behavior
which, in turn, induce CPP. They also indicate that minimum levels of
E and P are required for and adequate stimulation (vaginocervical
and clitoral, for example) during paced mating to induce a positive
affective, reward state.
This research is supported by grants DGAPA IN213609 and
CONACyT 53547. The authors would like to thank Martín García,
Leonor Casanova, Lourdes Lara, Javier Valles, Ramón Martínez, Omar
Gonzalez, Rafael Silva and Dorothy Pless for their technical assistance.
R. Corona et al. / Hormones and Behavior 60 (2011) 264–268
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