Institute of Physiology,
Benemerita Universidad Autonoma de Puebla,
Puebla, Mexico
Abstract
Central administration of oxytocin has been
shown to induce yawning, penile erection,
grooming and scratching. Yawning and penile
erections are due to activation of oxytocinergic
neurons in the paraventricular nucleus of the
hypothalamus. We selectively bred two sublines
from Sprague-Dawley rats, one with a
high-yawning frequency (HY) of 20yawns/h, and
one with a low-yawning (LY) frequency of
2yawns/h. The aim of the current study was to
analyze the behavioral effects of
centrally-administered oxytocin
[15ng-10É g;
intracerebroventricularly (i.c.v.)] on
yawning, penile erections, grooming and
scratching in adult male rats from both
sublines. Oxytocin produced a dose-dependent
increase in yawning and penile erection
frequencies and this effect was significantly
higher in the HY, compared to the LY, subline.
However, the number of oxytocin-induced
scratching bouts was significantly higher in the
LY, compared to the HY group. In conclusion,
these sublines represent a suitable model for
detailed analysis of behavior induced by
oxytocin and other neuropeptides in animals with
different spontaneous expression of behavioral
traits.
Central administration of several
neuropeptides such as adrenocorti-cotrophic
hormone (ACTH), alphamelanocyte stimulating
hormone (Éø- MSH), prolactin and
oxytocin produce a behavioral syndrome
characterized by yawning, penile erections,
grooming and scratching. Of these
neuropeptides, it is suggested that the
magnitude of the effect is greatest with
oxytocin (Argiolas and Melis, 1998; Collins and
Eguibar, 2010).
In fact, oxytocinergic neurons, in the
paraventricular nucleus (PVN) of the
hypothalamus, represent the key region for the
induction of yawning and penile erections
(Melis and Argiolas, 2011). In addition to the
ability of oxytocin to induce yawning and penile
erection, other pharmacological agents, such as
dopamine agonists (via activation of D2-like
receptors) and excitatory amino acids (via
activation of N- methyl-D-aspartate receptors),
can induce yawning and penile erection (Roeling
et al., 1991; Melis et al., 1989a, 1989b, 1994).
Moreover, all of these agents activate nitric
oxide synthase which in turn, increases the
release of this gas and reactivates
oxytocinergic neurons.
Ultimately, this releases more oxytocin in
the projecting oxytocinergic pathways due to a
positive feedback mechanism (Moos et al., 1984).
Although oxytocin induces a more robust effect
in yawning compared to grooming (Melis et al.,
1986; 1994; Melis and Argiolas, 2011), the
underlying mechanisms mediating these effects
are similar. For example, oxytocin-induced
yawning and grooming are both blocked by
pretreatment with haloperidol (administered
centrally via intracerebroventricularly (i.c.v.)
or intra-accumbens injections), sug- gesting
that dopamine neurons mediate, in part, these
effects (Drago et al., 1986b).
However, it is thought that the
septo-hippocampal pathway (Argiolas and Gessa,
1991) plays a role in oxytocin-induced grooming,
but not yawning and penile erection. We
selectively bred two sublines from the
Sprague&endash;Dawley rat, which differ in their
mean spontaneous yawning frequency. The
high-yawning (HY) subline have an average of 20
yawns/h and the low-yawning (LY) subline yawn
only twice per hour (Urbá-Holmgren et
al., 1990). Previous research has shown that
systemic administration of D2-like dopaminergic
agonists or central administration of
adrenocorticotrophic hormone fraction
1&endash;24 (ACTH1&endash;24) produces more
yawning and penile erections in the HY than the
LY subline (Urbá-Holmgren et al., 1993;
Eguibar et al., 2003; 2004). Furthermore, i.c.v.
administration of bombesin has been shown to
significantly reduce yawning frequency and
increase the frequency of scratching bouts in
the HY, but not the LY, rats (Diaz- Romero et
al., 2002).
Finally, the HY rats have more grooming
bouts after exposure to a novel environment
(Eguibar and Moyaho, 1997), or after wetting
their fur, compared to LY rats (Moyaho et al.,
1995). Because both sublines differ in
spontaneous (i.e. drug-naïve) yawning and
grooming responses under various environmental
conditions, the current study investigated
whether HY and LY rats also differ in their
pharmacological response to central
administration of the pituitary oxytocin
neuropeptide.
Thus, the aim of this study was to analyze
the following behaviors: yawning, penile
erections, grooming and scratching in both
sublines induced by right lateral ventricle
administration of oxytocin.
Discussion
Oxytocin is a potent inducer of yawning and
penile erections (Argiolas et al., 1985), as
well as grooming and scratching (Drago et al.,
1986a). Parvocellular oxytocinergic neurons in
the PVN of the hypothalamus are associated with
oxytocin-induced yawning and penile erections
(Kita et al., 2006). For example, oxytocin,
administered in the PVN and CA1 fields of the
hippocampus, induces a significant increase in
yawning and penile erection frequencies (Melis
et al., 1986), presumably through activation of
the uterine type of oxytocin receptors and
subsequent increased activity of brainstem or
spinal cord relay neurons (Swanson and Kuypers,
1980).
Previous research has shown that D2-like
dopaminergic agonists induce higher yawning
frequencies in HY rats compared to the LY
subline (Urbá-Holmgren et al., 1993;
Eguibar et al., 2003). A differential effect in
drug-induced yawning between the HY and LY
sublines has also been reported after central
administration of ACTH1&endash;24 (Eguibar et
al., 2004). Similarly, the present results
demonstrate that the HY subline have a greater
increase in yawning and penile erection
frequencies compared to LY rats after central
administration of oxytocin. On the contrary,
scratching bouts are higher in the LY, compared
to the HY, subline. Notably, oxytocin increases
the turnover of dopamine in the mesolimbic and
mesocortical pathways and these pathways are
associated with yawning and penile erection
(Sanna et al., 2012).
In fact, dopaminergic and oxytocin pathways
play a key role in motivation and reward, as
well as goal-directed behaviors such as yawning
as a social behavior related to empathy.
Patients affected with schizophrenia or
autism show a significant diminution in yawning
(Walusinski, 2009) and functional resonance
imaging studies have shown that contagious
yawning stimuli activate the para hippocampal
gyrus, a part of the limbic system that
includes the amygdala and hippocampus
(Schu_rmann et al., 2005). Furthermore, yawning
behavior is related to the operation of the
limbic system in close association with oxytocin
in the PVN in the hypothalamus to mediate
positive rewarding mechanisms (Melis and
Argiolas, 2011).
We have previously reported that HY rats
have more D1 receptors in the ventral striatum
compared to LY rats (Díaz-Romero et al.,
2005), and it has recently been demonstrated
that D3 receptors are also higher in the HY,
compared to the LY, subline (data not shown).
Thus, increased expression of dopamine
receptors in the HY subline might account, at
least in part, for the different responses
between sublines in yawning and penile
erections after administration of oxytocin or
D2-like agonists (present results and Eguibar
et al., 2003). The dopamine&endash;oxytocin link
in the PVN of the hypothalamus is responsible
for the correlation between yawning and penile
erections induced either spontaneously, by
D2-like dopaminergic receptor activation, or
after i.c.v. administration of oxytocin
(Holmgren et al., 1985 and present results).
Dopaminergic pathways also mediate
oxytocin-induced grooming because it is well
demonstrated that lesions or intra-accumbens
administration of haloperidol, a dopaminergic
antagonist, completely suppress grooming induced
by i.c.v. administration of oxytocin (Drago et
al., 1986a).
Recently it has been reported that Roman
high- (RHA) rats are more sensitive to low doses
of apomorphine-induced yawning and penile
erections compared to low-avoidance (RLA) rats
(Sanna et al., 2013). Importantly, RHA rats
exhibit proactive coping behavior and a greater
decrease in locomotion following low doses of
apomorphine, compared to RLA rats
(Giménez-Llort et al., 2005). Similarly,
in comparing the LY and HY sublines, the HY
subline are more anxious and have greater stress
responses in the open-field arena and elevated
plus-maze (Moyaho et al., 1995; Palacios et al.,
2014).
Taken together, these data suggest that HY
and RHA show similar responses to stress
situations and have higher sensitivity to
D2-like dopaminergic- or oxytocin-induced
yawning, compared to LY and RLA sublines. These
results imply that during inbreeding processes
of HY and RHA rats, we selected different coping
strategies that are opposite to that shown by LY
and RLA rats (Melis and Argiolas, 2011; Eguibar
et al., 2003; present results). It has been
reported that central administration of oxytocin
in doses higher than 1 É g produce
motor disturbances such as sprawled out posture,
discrete myoclonic jerks, exaggerated
scratching, barrel rotation and even fully
myoclonic convulsions (Melis et al., 1989b).
These symptoms were not observed in the current
experiments with higher doses of oxytocin.
Although at certain doses in LY rats, oxytocin-
induced scratching was similar to scratches
observed spontaneously, other doses of oxytocin
increased scratching significantly more than
levels that occurred spontaneously. The central
pattern generator (CPG) of scratching is
localized at the lumbo-sacral spinal cord level
where motoneurons that execute the pattern
receive synapses from descending oxytocinergic
pathways and then activate the rhythmic pattern
(Spruijt et al., 1988). It is conceivable that
the activation of descending oxytocinergic
pathways is responsible for the higher responses
obtained with oxytocin in LY, compared to HY,
rats.
Grooming and scratching are different
sub-behaviors of the total skin maintenance
behavior. The PVN of the hypothalamus appears to
be important in the integration of grooming, but
not in the case of scratching. Scratching and
grooming are incompatible responses because
scratching requires the recruitment of
motoneurons that control the hind legs while the
front paws remain on the ground, whereas
grooming of the body requires the hind legs
firmly on the ground while front paws and snout
are active in body care.
In fact, ACTH-enhanced grooming is
frequently interspersed with episodes of
stretching and yawning, and this element
composition is identical to that of grooming
behavior in control animals (Gispen et al.,
1975; Drago et al., 1986b; Eguibar et al., 2004;
Van Erp et al., 1991). These findings clearly
suggest a physiological type of grooming induced
by these peptides because they produce
behavioral arousal similar to that obtained in
birds under stressful situations, such as a
clear response characterized by progression of
alertness, grooming, yawning and finally
somnolence or even sleep (Delius et al., 1988).
We have previously demonstrated that HY rats
show a higher frequency of. grooming when
exposed to a novel environment (Eguibar and
Moyaho, 1997), and this subline changes the
cephalo-caudal organization of the grooming
sequence when wetting the fur, compared to LY
rats (Moyaho et al., 1995).
In conclusion, HY rats are more sensitive to
central administration of oxytocin-induced
yawning and penile erections, compared to LY
rats. Furthermore, LY rats display more
oxytocin-induced scratching, compared to HY
rats. These results demonstrate that these
genetically homogenous sublines react
differently to central administration of
oxytocin, possibly suggesting differences in the
neural ensembles, such as the diencephalon or in
the commanders in the medulla oblongata or
spinal cord, that gate motor display and hence
control these behaviors.
