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Neuroendocrine Research Group, Department of Anatomy, School of Medical Sciences (R.J.W., C.D.I.), Bristol, United Kingdom BS8 1TD; and the Department of Medicine, University of Bristol, Bristol Royal Infirmary (R.J.W., N.S., S.L.L.), Bristol, United Kingdom BS2 8HW
Address all correspondence and requests for reprints to: Dr. Richard Windle, Department of Anatomy, School of Medical Sciences, University of Bristol, University Walk, Bristol, United Kingdom BS8 1TD. E-mail: r.j.windle{at}bris.ac.uk
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent observations have shown that peripheral administration of oxytocin in high doses can both elevate nociceptive thresholds (11, 12) and lessen the anxiety behavior of rats placed in a potentially stressful environment (13). Furthermore, in the rat, lactation is associated with an activation of central oxytocin pathways (6, 14) and with a down-regulation of the endocrine responses to stress (15, 16, 17, 18). In humans, lactation has also been associated with decreased responses to stress (19) as well as decreased levels of anxiety (20) and the incidence of anxiety-related disorders (21). These effects may be a consequence of the increased central oxytocin release that is known to occur at this time (14, 22).
These observations suggest that oxytocin may function to attenuate stress responsiveness. To investigate this hypothesis, groups of rats were infused centrally with different doses of oxytocin, and their hypothalamo-pituitary-adrenal (HPA) responses to noise stress were assessed. These experiments were conducted in freely moving animals on an automated blood sampling apparatus to minimize all nonspecific forms of stress (23). To determine the specificity of the response to oxytocin, parallel groups of animals were infused with vasopressin. In addition, the anxiolytic effects of oxytocin were evaluated using an elevated plus-maze. This paradigm exploits the conflicting motivations experienced by the rat to either explore the maze or remain in the perceived security of the closed arms. Therefore, movement to the open arms of the maze is thought to reflect a lower level of anxiety (24). As the endocrine response to stress is known to vary over the estrous cycle (25) and as changing estradiol levels greatly affect the expression of oxytocin receptors in many areas of the central nervous system (26), all animals used in these studies were ovariectomized and estradiol treated. An abstract discussing some of these studies has been previously published (27).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Central peptide administration and preparation of rats for blood
sampling
Osmotic minipumps (model 1007D, Alzet Corp., Palo Alto, CA) were
used to deliver oxytocin (Bachem, Essex, UK) or vasopressin (Bachem).
The pumps, rated to deliver 0.52 µl/h over a 7-day period, were
filled with the appropriate peptide, connected to an
intracerebroventricular (icv) infusion cannula and then allowed to
equilibrate overnight in isotonic saline. All pumps were assigned to
animals using a coding unknown to those involved in subsequent
procedures. On the day after ovariectomy, each animal was
reanesthetized, an area of the parietal bone was exposed, and the icv
cannula was stereotaxically positioned in the lateral ventricle. The
minipump was positioned sc between the scapulae. To enable blood
samples to be collected, animals used in studies 1 and 2 were also
implanted with a SILASTIC-tipped right jugular venous cannula. This was
passed sc, exteriorized on the top of the head, and passed through a
protective spring held at an angle of 45°. The spring and/or the icv
cannula were secured in position on the skull using self-curing dental
acrylic and stainless steel anchoring screws. After recovery, all
animals were housed individually. Where springs were fitted, these were
attached to mechanical swivels, allowing the animals freedom of
movement.
Study 1: effects of oxytocin and vasopressin on stress-induced
release of corticosterone
To allow frequent small blood samples to be collected without
disturbing the animals, an automated sampling apparatus was employed
(23, 29); this was programmed to collect a 10- to 20-µl sample every
10 min. Sampling began at 0700 h on the fifth day after surgery
and continued for 60 min. At this time a white noise generator was
activated, and the animals were exposed to 114 decibels (dB) for 10
min. Sampling then continued for an additional 180 min. Throughout this
period the behavior of animals from each group was recorded on
videotape. Animals used in this study were infused centrally with
isotonic saline or concentrations of oxytocin to produce infusion rates
of 1, 10, or 100 ng/h oxytocin. To test for the specificity of the
effect, additional groups of animals were infused with the closely
related peptide arginine vasopressin at rates of 0, 10, or 100 ng/h. In
addition, to examine the reversibility of the effect of oxytocin,
groups of animals infused with oxytocin at 0 or 100 ng/h were subjected
to the sampling and noise stress procedures twice, first on the fifth
day after surgery when the pumps were active and then again on the
eighth day, approximately 24 h after they had ceased to deliver
the peptide.
Study 2: effect of oxytocin on anxiety behavior
Animals infused with isotonic saline or 100 ng/h oxytocin were
housed in the behavioral testing facility from the time of implantation
of the minipump. On the fifth day after surgery, each animal was placed
in the center of an elevated plus-maze, and the experimenter
immediately withdrew from the testing room. The maze was made of black
wood. The four arms had equal lengths of 55 cm and were elevated 80 cm
from the ground. The sides of the closed arms had a height of 12 cm.
The behavior of each animal was recorded on videotape for a period of
15 min. Testing commenced at 1000 h and continued until 1600
h, with animals from both groups randomly tested over this time period.
The maze was rigorously cleaned between animals.
To determine whether oxytocin could affect the exploration of the plus-maze in animals that were already mildly stressed, groups of animals infused with saline or 100 ng/h oxytocin were housed away from the behavioral testing facility and not placed in the testing room until 0800 h on the day of trial, a procedure known to have an anxiogenic effect in rats (Shanks, N., and R. Windle, unpublished data). Commencing at 1000 h, these rats were then tested on the plus-maze in exactly the same way as those that had been preconditioned to the testing facility.
Determination of plasma corticosterone concentrations
Total plasma corticosterone concentrations were measured
directly in plasma by RIA using a citrate buffer at pH 3.0 to denature
the binding globulin (1 µl plasma fraction diluted in 100 µl
buffer), antiserum kindly supplied by Prof. G. Makara (Institute of
Experimental Medicine, Budapest, Hungary), and
[125I]corticosterone (ICN Biomedicals, Irvine, CA; SA of
2–3 mCi/µg).
Behavioral analysis
The video recordings collected during the noise stress studies
were divided into 10-min blocks using the start of the noise stress as
the reference point. For each 10-min block, the amount of time that the
animals spent active, engaged in activities such as locomotion,
burrowing, or grooming (total activity), was recorded along with the
number of rearings (defined as the raising of both forepaws and
movement of body to a vertical plane). Behavioral determinations of
animals on the plus-maze included the number of open or closed arm
entries (defined as the movement of all four paws from one arm to
another), and the time that the animals spent in each portion of the
maze.
Statistical analysis
All values are expressed as the mean ± SE.
ANOVA and post-hoc Tukey’s tests were used to determine the
effects of the various doses of oxytocin or vasopressin on plasma
corticosterone and behavioral responses to the noise stress. Student’s
t tests were used to determine the effect of oxytocin
infusion on behavioral activity on the plus-maze compared with that in
the respective control group.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). On
exposure to the noise stress, there was a rapid rise in plasma
corticosterone concentrations in the saline-treated control animals
(Fig. 1A), which reached a peak concentration of 547 ± 102 ng/ml
20 min after the onset of the noise and then declined rapidly to
baseline. Although significant elevations in corticosterone
concentrations were seen in animals treated with all doses of oxytocin
(Fig. 1, B-D), the magnitude of the response was significantly
decreased by the administration of oxytocin (P < 0.05;
Fig. 1, B–D). This effect was statistically significant in animals
given 10 and 100 ng/h oxytocin (Fig. 1, C and D). After the initial
response to the noise, corticosterone concentrations remained low in
all groups. The effect of oxytocin on the corticosterone response to
noise stress was dose dependent (Fig. 1). The area under the response
curve was calculated as 5.8 ± 1.2 µg in animals treated with
saline and 3.6 ± 0.9, 1.7 ± 0.7, and 1.2 ± 0.6 µg
in those animals treated with 1, 10, and 100 ng oxytocin/h,
respectively (by ANOVA, P < 0.02).
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), infusion of 100 ng/h oxytocin significantly
decreased the peak corticosterone response to noise to 43 ± 4%
of that seen in the saline-treated animals (P <
0.005). However, once the pumps had ceased working, the response in the
formerly oxytocin-infused animals was 109 ± 23% of that seen in
animals formerly infused with saline.
No significant differences were seen in the basal corticosterone
concentrations between control animals and those treated with either
dose of vasopressin (Fig. 2). Unlike oxytocin treatment,
neither dose of vasopressin tested had any significant effect on the
corticosterone response to noise stress, which was of similar magnitude
and duration in all groups (Fig. 2, A–C).
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) or the number of rearings (Fig. 3C) seen
before application of the noise stress. In all groups, noise stress
caused a significant increase in both the total activity
(P < 0.001; Fig. 3A) and the number of rearings shown
by the animals (P < 0.001; Fig. 3C). Although oxytocin
had no significant effect on the increase in total activity during
noise stress, the two higher doses of 10 and 100 ng/h significantly
reduced the number of rearing events 0–10 min after introduction of
the noise stress compared to that in the saline-treated controls
(P < 0.002; Fig. 3C). Vasopressin infusion had no
significant effect on the total activity (Fig. 3B) or the number of
rearings (Fig. 3D) seen either before or after application of the noise
stress.
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), the number of
open arm entries (Fig. 4C), the total number of arm entries (Fig. 4E),
or the percentage of arm entries that were into an open arm (Fig. 4G)
between saline- and oxytocin-infused animals. However, when animals
were moved into the testing suite on the day of the trials, the
saline-treated animals spent significantly less time in the open arm of
the maze than those that had not been moved (P <
0.002; Fig. 4, A and B). These animals also showed decreased numbers of
total arm (P < 0.002; Fig. 4, E and F) and open arm
(P < 0.002; Fig. 4, C and D) entries, and a
significant decrease in the percentage of arm entries that were to an
open arm (P < 0.002; Fig. 4, G and H). This suggests
that the movement to the test environment could have been stressful and
induced a mild anxiogenic state. Oxytocin infusion had marked
anxiolytic effects in these animals, significantly increasing the
amount of time spent in the open arm (P < 0.02; Fig. 1B). Oxytocin-treated animals were also more active in their
exploration of the maze, as indicated by the significantly greater
number of total arm entries (P < 0.02; Fig. 4F). These
animals were more willing to enter the open arm, as indicated by the
increased number of open arm entries (P < 0.001; Fig. 4D) and the significantly greater percentage of arm entries that were
into the open arm (P < 0.001; Fig. 4H).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There a several mechanisms by which oxytocin could act to decrease HPA responses to stress. The peptide may have leaked to the periphery during the chronic infusion and acted directly on the pituitary to release ACTH and consequently corticosterone (5), possibly leading to increased negative feedback. Furthermore, as a known PRL secretogogue (30) oxytocin could have stimulated the release of PRL, which is thought to increase the sensitivity of the HPA axis to negative feedback (31). However, a significant peripheral effect seems unlikely, as basal concentrations of corticosterone, which would have been increased by chronic stimulation of the adrenal or decreased by oversensitization to negative feedback, were unaffected by the oxytocin infusion. The lack of any effect of vasopressin on the HPA axis would also contradict the possibility of a peripheral site of action, as vasopressin is a well characterized ACTH secretogogue (32). It should also be noted that the effective dose was extremely low (10 ng/h), so any oxytocin that leaked to the periphery would have been very quickly degraded. It seems much more likely that oxytocin acts via a central site.
Oxytocin could have a direct effect on CRF production and secretion from parvocellular neurons of the paraventricular nucleus (PVN). As CRF itself is thought to stimulate oxytocin release from magnocellular neurons, such an effect might work as a negative feedback loop (33). Because oxytocin has mainly excitatory effects on neuronal activity (6, 7, 8, 34) an inhibitory effect on CRF-producing neurons would most likely need to involve activation of inhibitory interneurons. However, as many brain regions known to affect the HPA axis, such as the BNST (35) and the amygdala (36), also express oxytocin receptors (8, 10), it is possible that oxytocin acts on neurons in these areas to modulate pathways projecting to the PVN.
It is important to note that vasopressin had no central effect on the HPA responses to stress, suggesting that the response to oxytocin was specific and mediated by specific oxytocin receptors. It is interesting that although the V1 receptor is known to be expressed centrally within the PVN and many of the limbic structures associated with the stress response (37), these central receptors appear to play no role in modulation of the HPA response to stress. An acute role for vasopressin cannot be excluded, as an inhibitory effect of acute central vasopressin infusion on corticosterone release in chronically stressed animals with lesions of the suprachiasmatic nuclei has been reported (38).
In the present studies oxytocin was also seen to have significant effects on behavior. During noise stress, the number of rearings, measured as a stereotypical response to a change in the environment signifying exploration and vigilance, was decreased by the same doses of oxytocin that caused down-regulation of the HPA axis. The total activity of the animals was not significantly reduced by oxytocin, thereby excluding a sedative effect of the peptide (13) and suggesting a specific anxiolytic action. This is supported by the observations from the elevated plus-maze, in which oxytocin had a clear anxiolytic effect in animals that were mildly stressed by the change in environment. As no such effects were seen in animals tested in a familiar environment, it would appear that oxytocin is acting specifically to counteract stress-related anxiety. Such an anxiolytic effect has previously been seen in an open field environment (13) when very high peripheral doses of oxytocin increased the amount of time spent away from the perceived security of the boundary wall. How oxytocin exerts its anxiolytic-like effect and whether this is related to its effect on the HPA axis are unclear. However, CRF itself is anxiogenic under many conditions and is associated with the production of rearing behavior and a shift of activity to the closed arms of the plus-maze (39). Oxytocin could, therefore, be acting to inhibit CRF release, causing both a down-regulation of the HPA responses to stress and inhibiting the anxiogenic effects of CRF. This would explain why oxytocin only showed its anxiolytic activity in stressed animals.
These data support the hypothesis that endogenous oxytocin can modulate physiologically important responses to stress. Lactation represents a physiological condition in which endogenous central oxytocin concentrations are elevated, and it is associated with a reduced neuroendocrine response to stress in the rat (15, 16, 17, 18). Interestingly, the down-regulation of the corticosterone response to noise stress by exogenously applied oxytocin seen in these studies is very similar in magnitude and profile to that which we previously reported in the lactating rat (23). The down-regulation of the stress response and conservation of ACTH and corticosterone seem to be important adaptations in the lactating dam (40). Therefore, the changes in the central oxytocinergic systems that accompany the onset of lactation might serve not only to coordinate the milk ejection reflex (41) and the establishment of maternal behavior (6), but also to modify stress responses.
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Acknowledgments |
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Footnotes |
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Received December 16, 1996.
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