Advances in Bioscience and Biotechnology, 2011, 2, 75-84 ABB
doi:10.4236/abb.2011.22012 Published Online April 2011 (http://www.SciRP.org/journal/abb/).
Published Online April 2011 in SciRes. http://www.scirp.org/journal/ABB
Increased serotonin concentration and tryptophan
hydroxylase activity in reproductive organs of copulator males:
a case of adaptive plasticity
Ana Ingrid Pichardo1, José L.Tlachi-L ó pe z 2, Francisco Jiménez-Trejo3, Alma L. Fuentes-Farías4,
Armida Báez-Saldaña1, María L. Molina-Cerón1, Gabriel Manjarréz-Gutiérrez5,
Gabriel Gutiérrez-Ospina1*, Rosa Angélica Lucio2*
1Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de
México, Ciudad Universitaria 04510, México, D.F., México;
2Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Carretera Tlaxcala-Puebla km 1.5 s/n, Loma
Xicotencatl, 90062, Tlaxcala, México;
3Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria 04510,
México, D.F., México;
4Laboratorio de Invertebrados y Ecofisiología, Facultad de Biología, Universidad Michoacana de San Nicolás de Hidalgo, Ciudad
Universitaria 58030, Michoacán, México;
5Unidad de Investigación Biomolecular, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro
Social 06720, México, D.F., México.
Received 27 December 2010; revised 19 February 2011; accepted 27 February 2011.
ABSTRACT
Individual male rats may systematically display or
not copulatory behavior when paired with receptive
females. Although these phenotypes are associated
with differences in brain organization and function,
they might also do so at the level of the reproductive
organs. We then used high performance liquid chro-
matography to quantify serotonin concentration and
the activity of tryptophan hydroxylase in the repro-
ductive organs of copulator and non-copulator males.
Sexual behavior display was compared between
groups and parameters of fertility and reproductive
fitness were determined for copulator males. Copu-
lator males had higher concentrations of serotonin in
the epididymis, testicle and ventral prostate than
their non-copulator counterparts, as it was found for
epididymal and testicular tryptophan hydroxylase
activity. However, preliminary data shows that sero-
tonin elevation occurs in copulator males only until
they have accumulated several sexual encounters, so
it might be a response to genital gratification or sex-
ual rewarding. Interestingly, only epididymal sero-
tonin concentration correlated with reproductive fit-
ness, offspring number, mating success and seminal
plug volume in copulator males. Our results support
that copulator and non-copulator male rats feature a
phenotype-specific serotoninergic tone in the epidi-
dymis, testicle and ventral prostate gland. The ob-
servation documenting that epididymal serotonin
concentration correlated with parameters that moni-
tor male fertility and reproductive fitness in copula-
tor males predicts that epididymal factors increase
their chances of parenting offspring.
Keywords: Sexual Accessory Glands; Copulation;
Indolamines; Seminal Fluid; Seminal Plug; Successful
Mating; Reproductive Fitness
1. INTRODUCTION
Copulatory or consummatory behavior in male rats is
displayed as a stereotyped motor pattern that comprises
mounts, intromissions and ejaculation [1]. Although this
pattern suits well the majority of male rats, a small per-
centage of them exhibit either none or incomplete copu-
latory behavior when repeatedly paired with sexually
receptive females [2]. Even though the origin of the rat’s
copulator and non-copulator phenotypes is unclear, evi-
dence showing differences in motivational and precopu-
latory behaviors, detection of sexually significant odors,
number of hypothalamic and amygdaline neurons con-
taining androgen or estrogen receptors and levels of hy-
pothalamic aromatase activity between both rat groups
[3-6] suggests that these are innate phenotypes.
The display of successful sexual behavioral responses
,These authors contributed equally to the present work.

A. I. Pichardo et al. / Advances in Bioscience and Biotechnology 2 (2011) 75-84 76
depends upon the ability of each male to accurately as-
sess his internal physiological state and precisely match
it with his sexual/reproductive expectations/output under
a given context [1]. It is then likely that copulator and
non-copulator rat males also feature distinct traits in
their genital organs. Accordingly, the present work
evaluated possible differences of the serotoninergic tone
in reproductive organs of males displaying or not normal
copulatory behavior. Studying the serotoninergic tone
seems an adequate election because this parameter shifts
across genital/reproductive organs as sexual maturation
progresses, with reproductive status or photoperiod
length and along the breeding season in various different
species [7-9]. Also genital serotonin modulates, among
other important reproductive processes, ejaculation, se-
miniferous tubule fluid transit, production and clea-
rance, sexual accessory glands contraction, epididymal
fluid composition, testicular steroidogenesis and sper-
matogenesis [10-15].
2. MATERIALS AND METHODS
2.1. Animals
Sexually inexperienced adult male Wistar rats (Rattus
norvegicus; 90 days of age/300 grams of body weight; n
 22) were chosen randomly from the regular stock of
the colony raised at the animal facility of the Instituto de
Investigaciones Biomédicas, Universidad Nacional
Autónoma de México. Males were screened for their
copulatory abilities and grouped as copulators or non-
copulators (see below). Male rats were then caged in
clusters of three or four individuals of the same class.
The animals were kept in rooms with constant tempera-
ture (22°C ± 1°C) and humidity under an inverted light
cycle (12:12 hours, lights off at 7:00 hrs). Food (2018S
Pellets, Harlan) and water were available ad libitum.
Animal handling and experimentation followed the
Guidelines for the Care and Use of Laboratory Animals
published by the National Institutes of Health. Local
Animal Right’s Committees approved all of the animal
protocols described in this work.
2.2. Male Selection
Male rats were classified as copulators (n  10) or
non-copulators (n  13) after analyzing their sexual per-
formance along four consecutive copulatory encounters
with receptive, ovariectomized female rats [16]. Copu-
lator males displayed fully the copulatory pattern in
every encounter within a 15 minute period of having
being initiated the testing session. In contrast, non-copu-
lator males executed incomplete copulatory behavior in
every encounter within a 45 minute period of having
being started the testing trial. Mounting, intromission
and ejaculation latencies and the number of mounts and
intromissions associated with pelvic thrusting were re-
corded for each male during each encounter. The hit rate,
an index taken to reflect erectile potential, was also es-
timated [17].
2.3. Semen and Seminal Plug Evaluation in
Copulator Males
Semen and seminal plug quality was evaluated only in
copulator males (n  7) because non-copulators never
reached the ejaculatory threshold. These analyses were
carried out in ejaculates withdrawn from the uterine
horns and in seminal plugs released from the vagina of
the inseminated females used during the third and fourth
copulatory encounters, as described elsewhere [16]. The
parameters obtained for copulator males were compara-
ble to those reported previously for sexually experienced
rat males of the same strain (see Tables 1 and 2 and ref-
erence [16]).
2.4. Fertility and Reproductive Fitness in
Copulator Males
To evaluate individual reproductive fitness in copulator
males (n  7), each male was paired in a regular enclo-
sure with a naturally receptive, intact female during 48
hours, fifteen days after the last copulatory encounter.
Reproductive encounters were repeated four times for
each copulator male every 15 days. By the end of each
reproductive encounter, the couple was separated and the
dam caged individually and visually inspected every day
first to corroborate pregnancy and then to assure normal
pregnancy progression. After delivery, the offspring re-
mained with the mother until weaning by postnatal day 28
when living pups were counted. Individual reproductive
fitness was then estimated by calculating what we called
the reproductive fitness index. This parameter resulted
from summing up the number of opportunities to mate,
the number of pregnancies achieved and the number of
living pups by the end of weaning divided by 47. The
constant in the divisor represents the sum of the total
number of mating opportunities, pregnancies and living
pups of the male with the greatest reproductive efficacy.
This constant then defines the conditions that each male
would have must achieved to assure maximal reproduc-
tive outcome under the experimental paradigm tested.
2.5. Serotonin Concentration and Tryptophan
Hydroxylase Activity in Copulator Males
Copulator (n  7) and non-copulator males (n  7) were
sacrificed immediately after the last reproductive or
copulatory encounter, respectively. The rats were sacri-
ficed by overdosing pentobarbital administered intrap-
eritoneally (26 mg/Kg of body weight). Then, the right
reproductive organs (testicle and epididymis) and ac-
cessory sexual glands (ventral prostate, seminal vesicle,

A. I. Pichardo et al. / Advances in Bioscience and Biotechnology 2 (2011) 75-84 77
Table 1. Copulatory parameters of copulator (C) and non-copulator males (NC).
Mounting
Latency
(seconds)
Intromission
Latency
(seconds)
Ejaculation
Latency
(seconds)
Mounts
Number Intromission Number
Hit Rate
Male
C NC C NC C NC C NC C NC C NC
1 18 16
26 - 902 - 26 36 24 - 0.48 -
2 15 32
115 183 1271 - 79 56 24 8 0.23 0.21
3 16 22
92 - 532 - 13 39 16 - 0.55 -
4 37 12
58 - 1190 - 29 28 22 - 0.43 -
5 21 14
23 480 558 - 13 42 19 9 0.59 0.17
6 21 21
101 - 928 - 52 16 27 - 0.34 -
7 10 18
87 - 1762 - 81 10 22 - 0.21 -
Table 2. Parameter of the seminal fluid in copulator males*.
Macroscopic Seminal Fluid
Parameters
Microscopic Seminal Fluid Parameters
Male color viscosity
(mm) pH sperm motility (%) sperm viability (%) sperm morphology (%) sperm concentration (millions/milliliter)
1 white 2.5 7.5
20.0 46 97 15.5
2 white 1 8
43.2 69 100 4.0
3 white 0.5 8
57.5 62 98 16.0
4 white 1.5 8
47.0 51 99 7.2
5 white 2 7.5
72.5 54 100 17.2
6 white 1.5 8
37.7 55 98 7.2
7 white 1.5 8
63.0 63 100 24.2
*Values of the third and fourth copulatory encounters were averaged.
coagulating gland and bulbourethral gland) of copulator
and non-copulator males were excised and processed to
determine serotonin concentrations (least detectable
dose 5 pg/l) following the protocol published by [7].
The left reproductive organs and accessory sexual
glands were used to determine the activity of tryptophan
hydroxylase (TPH) according to the protocol described
by [7]. Results for serotonin concentration are expressed
in pg/ mg of tissue and for TPH activity in nMol of
5-hydroxytryptophan produced/milligram of protein/
hour.
2.6. Statistical Analysis
Differences of serotonin concentration and TPH activity
among various reproductive organs of copulator and
non-copulator males were evaluated by using the
Mann-Whitney U tests (Statistica 7.0) setting the sig-
nificance level at p < 0.05. Correlations among fertility
parameters, reproductive fitness and serotonin concen-
tration in different organs were evaluated by using Pear-
son’s Coefficient analyses (Statistica 7.0).
3. RESULTS
3.1. Copulatory Behavior in Copulator and
Non-Copulator Males
Copulator males showed the complete repertoire of
copulatory movements, right from the first copulatory
encounter. In sharp contrast, non-copulator males dis-
played incomplete copulatory motor patterns throughout
the encounters. Although mounting latency tended to be
similar between groups, intromission latency roughly
quadruplicated in non-copulator males (Table 3). The
number of mounts and intromissions, as well as the hit
rate, were found decreased in non-copulator males (Ta-
ble 3).
3.2. Serotonin Concentration and TPH Activity
in the Reproductive Organs of Copulator
and Non-Copulator Males
The concentration of serotonin and TPH activity in the
reproductive organs of copulator and non-copulator
males are shown in Figures 1 and 2, respectively. Al

A. I. Pichardo et al. / Advances in Bioscience and Biotechnology 2 (2011) 75-84 78
Table 3. Parameters of the seminal plugs in copulator males*.
Macroscopic Seminal Plug Parameters Microscopic Seminal Plug Parameters
Male Consistency weight
(mg) length (mm) width (mm) volume (mm3)
spermatozoa
(%) flagella (%) heads (%)
1 hardened 90.10 10.45 4.91 72.88 1.76 32.98 65.25
2 hardened 100.72 11.33 4.32 55.05
1.22 20.35 78.42
3 hardened 105.15 12.0 5.21 87.50 0.87 36.44 62.68
4 hardened 75.67 9.78 4.29 46.74 2.78 13.66 83.55
5 hardened 110.82 13.9 4.40 73.65 2.67 32.95 64.37
6 hardened 85.14 11.52 4.11 51.87 3.19 27.99 68.81
7 hardened 95.55 15.84 4.28 74.45 3.82 22.53 73.64
*Values of the third and fourth copulatory encounters were averaged.
though serotonin was readily quantified in all of the re-
productive organs, TPH activity was only detected in
samples from the testicle, epididymis and seminal vesi-
cle in both animal groups. In the testicle and epididymis,
the concentration of serotonin and TPH activity were
significantly higher in copulator than in non-copulator
males. In contrast, the values obtained for both parame-
ters in the seminal vesicle, coagulating gland and bul-
bourethral gland were similar between groups (data for
coagulating and bulbourethral glands are not shown).
Interestingly, even though the ventral prostate showed
significantly higher concentrations of serotonin in copu-
lator than in non-copulator males, TPH activity in this
organ was equally low in both groups of rats. The in-
crement of the serotoninergic tone in the testicles,
epididymis and ventral prostate in copulator males ap-
pears not to be an inherent trait because preliminary ob-
servations show that serotonin concentrations are not
elevated in the testicle and epididymis of this rat group
by the end of the copulatory encounters (Figure 3).
3.3. Relationships among Serotonin
Concentration and Tryptophan
Hydroxylase Activity in Reproductive
Organs with Reproductive Fitness, Fertility
and Sexual Performance in Copulator
Males
Pearson’s coefficient analyses were used to evaluate
possible correlations among serotonin concentration or
TPH activity in the testes, epididymis or ventral prostate
with reproductive, fitness, fertility or sexual performance.
Correlations were only significant for epididymal sero-
tonin and reproductive fitness (Figure 4), number of
pups sired, successful matings and seminal plug volume
(Figure 5).
4. DISCUSSION
Male rats may be either copulators or non-copulators.
Although these phenotypes are characterized by distinct
neurophysiological attributes [3-6], we did not know
whether they also comprise characteristic morpho-
functional traits at the genital level. In this work, we
report data that shows that copulator males have elevated
testicular, epididymal and prostatic serotonin concentra-
tion and TPH activity as compared with non-copulator
males. These differences seem specifically ascribed to
the copulator phenotype because both parameters were
comparable in the seminal vesicles, coagulating and
bulbo-urethral glands of copulator and non-copulator
males. Although differences in copulatory abilities
among male rats may be inherent, our results suggest
that the increment of the serotoninergic tone in some
reproductive organs of copulator males is an acquired
trait. Indeed, the increased testicular, epididymal and
prostatic serotonin concentration and TPH activity were
not observed in copulator males that were sacrificed by
the end of the copulatory encounters. Although the
mechanism by which the increment of the serotoninergic
tone occurs in copulator males is unclear, dynamic ad-
justments (i.e., adaptive plasticity) of the morpho-physi-
ological properties of genital organs in response to social
cues, sexual experience, genital gratification and/or sex-
ual rewarding may be involved since they have been
previously documented in rodents [1,18-20]. But ¿do
increments of testicular, epididymal and prostatic sero-
tonin concentration or TPH activity have any reproduc-
tive value for copulator males? Our study suggests that
at least at the epididymal level, increased serotonin con-
centrations improves the possibility of a copulator male
to achieve paternity. Indeed, resynthesized in this organ.

A. I. Pichardo et al. / Advances in Bioscience and Biotechnology 2 (2011) 75-84 79
Figure 1. Bar graphs that show the concentration of serotonin in the testicle (a), epididymis (b), ventral pros-
tate gland (c) and seminal vesicle (d) of copulator (c) and non-copulator (NC) male rats. U Mann Whitney *P
< 0.05 versus NC males.
Figure 2. Bar graphs that show the levels of tryptophan hydroxylase activity in the testicle (a), epididymis (b),
ventral prostate gland (c) and seminal vesicle (d) of copulator (c) and non-copulator (NC) male rats. U Mann
Whitney *P < 0.05 versus NC males.

A. I. Pichardo et al. / Advances in Bioscience and Biotechnology 2 (2011) 75-84 80
Figure 3. Bar graphs that depict the concentration of serotonin in the testicle (A) and epididymis (B) of copulator (C) and
non-copulator (NC) male rats as determined through ELISA (EIA kit, ALPCO Diagnostics, Salem, NH). Briefly, after
weighing each organ, tissue samples were homogenized in Glycine-HCl buffer pH 2.2 added with 0.1% (w/v) of ascorbic
acid (10 mL of buffer/1g of tissue), and centrifuged at 16000 g for 10 minutes at 4ºC. The supernatants were collected,
light-protected and stored at 4ºC until their use. The day of experiment samples were tempered and acylated during 30
minutes at room temperature. Then, they were incubated with primary polyclonal antibodies raised against serotonin for
20 hours at 4ºC. After three gently washes, the secondary antibodies coupled to peroxidase were added for 30 minutes at
room temperature. Peroxidase activity was revealed using DAB and hydrogen peroxide for 15 minutes at room tempera-
ture. Serotonin was quantified using a microplate reader set at 450nm and the reference wavelength was set between
620nm and 650nm. The calibration curve was elaborated using known concentrations of serotonin (0, 0.0975, 0.325,
0.975, 3.25 and 16.25 ng/ml). Non-significant differences were documented between groups.
Figure 4. Graphs that show the results of the Pearson’s Coefficient test depicting the interaction between epididymal se-
rotonin concentration (a) or TPH activity (b) with reproductive fitness in copulator males.
productive fitness, offspring number, successful matings
and seminal plug volume all correlated positivelywith
epididymal serotonin concentrations. These results agree
with the notion that the epididymis evolved to improve
paternity in mammalian males [21].
A puzzling observation that arises from our experi-
ments is that the prostatic concentration of serotonin was
higher in copulator than in non-copulator males, in spite
of the fact that TPH activity was remarkably low in both
animal groups. These results suggest that serotonin is not

A. I. Pichardo et al. / Advances in Bioscience and Biotechnology 2 (2011) 75-84 81
Figure 5. Graphs that show the results of the Pearson’s Coefficient test depicting the interaction between epididymal serotonin
concentration with parameters that monitor fertility and sexual performance in copulator males.
In agreement with this inference, it is long known that
the prostate comprises a group of neuroendocrine cells
distributed throughout its interstitial space or intermin-
gled among epithelial cells [22]. Neuroendocrine cells
have the ability to uptake serotonin to later release it. So,
neuroendocrine cells could make available serotonin in
the prostate. Interestingly, it is known that the number of
these cells is higher in male rodents kept as breeders
[23].
Several intriguing aspects emerge from the correlation
studies carried out in copulator males:
1) The volume of the seminal plug correlates with fer-
tility in male rats [24,25]. Traditionally, the formation of
this structure is ascribed to the sexual accessory glands
[25,26]. This is why it is surprising that seminal plug
volume and epididymal serotonin concentrations corre-
lated positively in our analyses. The epididymis, how-
ever, produces a variety of proteins that could facilitate,
in addition to improving the capacity of sperm to fertil-
ize ova [27,28], the formation of seminal plugs. Fur-
Se
r
otonin (ng/mg tissure)

A. I. Pichardo et al. / Advances in Bioscience and Biotechnology 2 (2011) 75-84 82
thermore, the release of epididymal secretory products is
modulated by serotonin [29]. Hence, increments in
epididymal serotonin availability could be associated
with factors that control seminal plug volume.
2) Epididymal serotonin concentration did not corre-
late with sperm motility or sperm concentration. This
is intriguing because serotonin increases sperm motility
and concentration [30,31] and the epididymis is the or-
gan from which sperms are ejaculated. We believe the
discrepancy may reflect technical limitations. For in-
stance, although the chromatographic analyses carried
out in our work clearly portrait serotonin availability in
the organ as a whole, they do not allow estimations of
the amount released into the ductal system. In addition,
female factors could modulate sperm parameters [32-34]
regardless of the availability of serotonin in the epidi-
dymis; sperm samples were taken from the uterine
horns.
3) Lastly, the lack of a positive or negative correlation
between testicular serotonin and fertility/reproductive
fitness in copulator males was also unexpected. It is
known that increased production of spermatozoa pro-
vides reproductive advantages to males [19], that tes-
ticular serotonin concentration is increased in breeder
rats [7] and that serotonin modulates spermatogenesis
[35] and testosterone production and release from Ley-
dig cells [14,36,37], a hormone long known to promote
spermatogenesis [38] and sexual behavior [39]. Up to
now, we have no explanation for this counterintuitive
outcome. We believe, however, that female factors may
also explain these observations.
In spite of the unexpected results, we believe that our
observations support that copulator and non-copulator
male rats feature a distinct serotoninergic tone in the
epididymis, testicle and ventral prostate gland, and that
the increment of this trait in copulator males probably is
associated with greater sexual experience. In the future it
would be fundamental to evaluate whether non-copulator
males lack or have a diminished ability to display adap-
tive plasticity when sexually trained for longer times.
Finally, the observation documenting that epididymal
serotonin concentration correlated with parameters that
monitor male fertility and reproductive fitness in copu-
lator males predicts that epididymal factors increase
their chances of parenting offspring.
5. ACKNOWLEDGEMENTS
Authors are grateful to Patricia Padilla Cortés, Jesús Ramírez Santos,
Luz Lilia Jiménez, Rico, Georgina Díaz Herrera, Alfonso Malagón
Mendiola, Raymundo Reyes and Marta Carrasco for their valuable
technical, administrative assistance and animal care. We are indebted
to Dr. John McHaffie for helpful criticisms and manuscript editing.
This work was supported by a grant from the Dirección General de
Asuntos del Personal Académico, Universidad Nacional Autónoma de
México (PAPIIT IN215208). AIPC, JLTL and MLMC are fellows from
the Consejo Nacional de Ciencia y Tecnología.
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