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Have you read ? Best of the Best: Basic Research
by Javier Angulo
Javier angulo, Phd
Associate Editor
Departamento de Investigación
IRYCIS Hospital Universitario
Ramón y Cajal
Madrid, Spain
Female Sexual Dysfunction – Incentive mo-
tivational animal model
Ågmo A:
Animal models of female sexual
dysfunction: Basic considerations on drugs,
arousal, motivation and behavior.
Pharmacol Biochem Behav 2013,
doi: 10. 1016/j. pbb.2013.10.003 / Oct 11
[Epub ahead of print].
The availability of adequate and convenient
animal models is fundamental for preclinical re-
search in every specific field. Animal models are
especially important for the development of new
therapeutic strategies. However, it is essential
to perfectly know the divergences with respect
to humans and the limitations of these models
to make an adequate choice and to provide a
correct interpretation of the results obtained with
their use. This is obviously applicable to preclini-
cal research in Sexual Medicine and the search
for most reliable and informative animal models
is an essential focus of researchers.
Anders Ågmo provides a critical review of the
utility of behavioral animal models for the study
of female sexual dysfunction but also provides a
nice discussion of important concepts of female
sexual function and dysfunction that need to be
considered when facing preclinical research
in this field. A first important concept is that
the term female sexual dysfunction comprises
different disorders, such as hypoactive desire
disorder, sexual arousal disorder and orgasmic
disorder that represent different entities. Thus, it
makes no much sense to look for female sexual
dysfunction models and seems more reasonable
to use different models that respond to the ques-
tions raised by each specific problem to solve.
The model should be ideally based on the cause
or causes of the dysfunction but unfortunately
the causes for most, if not all sexual disorders
remain obscure. Ågmo suggests that models
should, at least, reproduce the particular behav-
ioral characteristics of the dysfunction we want to
model. He also highlights the fact that diagnostic
criteria of most female sexual disorders do not
only include the existence of behavioral or or-
ganic alterations but also require the presence
of marked distress or interpersonal difficulty: The
symptom and the perception of the symptom
as problematic. Animal models are inevitably
limited to model symptoms and cannot reflect
the complexity of human disorder. However, this
is not the purpose of any model. Human social
context cannot be reproduced in non-human
animal models but
no animal model has the
pretension of being an image of the human
condition, it concentrates in some aspect
that can be reproduced in non-humans
.
Ågmo considers that sexual behavior is depend-
ent on a
central motive state
that determines
the ability of the organism to respond to sexual
stimuli. In fact, no response is produced in the
absence of a
sexually relevant stimulus
. This
stimulus may substantially vary, being learned
or unlearned, but only in humans the external
incentive can be replaced by a
mental repre-
sentation
. This is never the case in rodents.
Central motive state responds to adequate incen-
tive stimuli with sexual behaviors: Approach and
copulatory behaviors.
There are substantial differences
in the neu-
robiology of the sexual central motive state
in non-humans and humans.
Estrogens are
essential for sexual behavior in rodents while
estrogens do not seem to be essential for
sexual response in women while andro-
gens appear as responsible for sexual drive
in women but not in rats
. The role of neuro-
transmitters, namely acetylcholine, serotonin,
norepinephrine, oxytocin and melanocortin,
with demonstrated relevance in female sexual
responses in rodents is unknown in humans.
However, drugs acting on serotonin receptors,
such as flibanserin, or melanocortin receptors,
such as bremelanotide, proceeded into clinical
development for hypoactive sexual desire dis-
order and sexual arousal disorder, respectively,
without achieving satisfactory results.
Most of drugs intended for treating female sexual
dysfunctions have been evaluated in behavioral
studies determining copulatory behaviors in
rodents that consist of lordosis and procep-
tive behaviors. Since the structure of copula-
tory behavior in rodents and humans is entirely
different, the adequacy of this model could be
compromised. Ågmo suggests that approach
behaviors in rodents and humans could share
important similarities since both implies the re-
duction of the distance between the individuals
involved and both end in tactile stimulation of
the partner, particularly at perigenital area. He
proposes that
analyses of rodent sexual ap-
proach behaviors offer more information of
relevance for human sexual behavior than
analyses of copulation do
. These studies can
be easily performed evaluating the willingness of
female rats to approach incentive sexual stimuli
(male rat) and the time spent approached.
Based on results obtained in preclinical mod-
els,
oxytocin agonists
are proposed to be the
most obvious candidates for pharmacological
treatment of sexual disorders since they have
prosexual effects and do not have dramatic side
effects.
Cholinergic agonists
have prosexual
effects but are likely to have relevant side ef-
fects.
Serotonin antagonists
are not consid-
ered by Ågmo as an attractive alternative due
to their complex, often contradictory effects on
sexual behavior.
Probably only the availability of a pharmacologi-
cal strategy proving undoubtedly clinical benefit
for the treatment of any specific female sexual
disorder would allow for establishing what model
is the more predictive for a success in the thera-
peutic application.
