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Female Oxytocin-Deficient Mice Display Enhanced Anxiety-Related Behavior

Departments of Pharmaceutical Sciences (R.C.M., R.R.V., X.L., J.A.A.) and Medicine (J.A.A.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Rose C. Mantella, Department of Pharmaceutical Sciences, University of Pittsburgh, 904 Salk Hall, Pittsburgh, Pennsylvania 15261. E-mail: rcmst22{at}pitt.edu.

	Abstract

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Previous studies have suggested that oxytocin (OT) may be anxiolytic in female laboratory rats and mice. The elevated plus-maze was used to compare anxiety-related behaviors of OT-deficient (OT-/-) and wild-type (OT+/+) mice. Female OT-/- mice displayed increased anxiety-related behavior compared with OT+/+ mice. The percentage of entries (P < 0.0002) and time spent (P < 0.003) in the open arms was less in female OT-/- than OT+/+ mice. Administration of synthetic OT, 2 ng by intracerebroventricular (icv) injection to female OT-/- mice, increased the percentage of entries (P < 0.003) and time spent (P < 0.004) in the open arms compared with artificial cerebrospinal fluid female OT-/- mice. Administration of an OT receptor antagonist (Atosiban, d[Dtyr(Et)², Thr⁴]ornithine vasotocin) 100 ng icv, to female OT+/+ mice increased anxiety-related behavior by decreasing the percentage of entries (P < 0.01) and time spent (P < 0.04) in the open arms compared with artificial cerebrospinal fluid-treated controls. Central infusion of an OT receptor antagonist, 100 ng icv, before administration of synthetic OT, 2 ng icv, in female OT-/- mice blocked the anxiolytic affect of OT. In contrast, male OT-/- mice displayed decreased anxiety-related behavior compared with male OT+/+ mice. The percentage of entries (P < 0.007) and time spent (P < 0.004) in the open arms was greater in male OT-/- vs. OT+/+ mice. Our findings indicate that OT pathways play a role in modulating anxiety in female mice of the C57BL/6 background, and the effect is mediated by the OT receptor.

	Introduction

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OXYTOCIN (OT) is a nonapeptide that is synthesized within the paraventricular (PVN) and supraoptic nuclei of the hypothalamus. Within the PVN, OT cells form discrete subpopulations of either magnocellular neurons that project to the posterior lobe of the pituitary gland, or parvocellular neurons that project from separate subdivisions of the PVN to various extrapituitary loci within the brain (1). Peripherally released OT acts as a hormone and promotes milk ejection during lactation and uterine contractility at parturition (2). Centrally released OT is a neurotransmitter or neuromodulator in diverse processes that include maternal (3) and affiliative behavior (4, 5), lordosis (6), ingestion of food (7) or sodium-containing solutions (8), social memory (9, 10), grooming (11), and the stress response (12, 13).

In addition, OT is believed to be anxiolytic in female laboratory rats (13, 14, 15) and mice (16). Central administration of OT to estrogen-primed ovariectomized rats (13) or mice (16) decreased anxiety-related behavior in the elevated plus-maze (EPM). OT infused into the amygdala of ovariectomized estrogen-treated rats significantly increased open field activity (decreased anxiety) and increased the time spent in open arms of the EPM (anxiolytic effect) but not to a statistically significant degree (15). Collectively, the data support a possible anxiolytic role for OT in female rats or mice.

Neural circuits that coordinate the anxiety response to a novel environment such as the EPM include projections from the amygdala and hippocampus to the PVN, via the bed nucleus of the stria terminalis and select hypothalamic nuclei (17). OT pathways have been identified in these regions of the rat brain, including the hippocampus (18), amygdala (19), bed nucleus of the stria terminalis (20), and select nuclei of the hypothalamus (18). OT receptors are also distributed in these regions of the rat (15, 16) and mouse brain (21). The presence of OT pathways as well as OT receptors in anatomical areas of the rat or mouse brain that regulate anxiety provide a framework for the hypothesis that central OT pathways modulate anxiety.

To further assess the role of central oxytocinergic systems in anxiety-related behavior, we studied OT-deficient (OT-/-) mice. If central OT reduces anxiety, then OT-/- mice that lack OT pathways may display greater anxiety-related behavior than wild-type (OT+/+) mice. Experiments were conducted using the EPM, which has been validated as a test of anxiety in rats (22, 23) and mice (16). We administered synthetic OT into the lateral cerebral ventricles of OT-/- mice and compared their behavior in the EPM with OT-/- mice that received injections of artificial cerebrospinal fluid (aCSF). We also determined whether endogenous OT is anxiolytic by testing OT+/+ mice in the EPM in the presence and absence of a centrally administered OT receptor antagonist, d[Dtyr(Et)²,Thr⁴]ornithine vasotocin (Atosiban).

A subobjective of the present study was to determine if the anxiety-related behavior of male OT-/- mice was similar to that of OT-/- female mice. Male OT-/- mice have been reported to demonstrate less anxiety-like behavior than OT+/+ mice during EPM testing (24). This observation in male mice contrasts with studies suggesting an anxiolytic effect of OT in female rats (13, 15) and female mice (16). Therefore, both female and male mice of each genotype were tested for anxiety related behavior in the EPM.

	Materials and Methods

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Animals
Female and male wild-type (OT+/+) and OT-deficient (OT-/-) mice (6–11 months of age) of the C57BL/6 background strain were used for this study. OT-/- mice were generated by Scott Young, NIMH (25), and the breeding pairs were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were bred and housed in viral-free quarters of the University of Pittsburgh Animal Facility in standard rodent cages in groups of four to five. Mice used for these studies were from the F5 and F6 generation. OT+/+ mice were the offspring of OT+/+ males and OT+/+ females. OT-/- males were mated with heterozygous (OT+/-) females to produce OT-/- mice (26). Mice were maintained in a 12-h light, 12-h dark cycle (lights on at 0700 h) and food and water were provided ad libitum. To identify the genotype of each mouse, DNA from a tail sample was extracted and analyzed by PCR (25, 26). The studies were approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh.

Lateral ventricle cannulation surgery and infusions
Female OT+/+ and OT-/- mice were anesthetized with ketamine (1 mg/10 g body weight, ip) and xylazine (0.025 mg/10 g body weight, ip) for stereotaxic placement of cannulae into the lateral ventricles. The top of the animal’s head was shaved and a 1-mm midline incision was made across the top of the skull. After cleaning the periosteum, a 1-mm hole was drilled 1.00-mm lateral and 0.5-mm posterior to the bregma, and the tip of a 26-gauge stainless steel infusion cannula was placed 2.00 mm below the skull surface in the lateral ventricle. The cannula was secured to the skull with dental cement and a stylus was inserted to maintain patency. Mice were allowed to recover for 1 wk before behavioral testing. Patency of the guided cannula was confirmed by the movement of an air bubble placed in the PE-10 tubing (Plastics One, Inc., Roanoke, VA) connecting a 25-µl Hamilton syringe (Hamilton Co., Reno, NV) to the guide cannula.

The synthetic peptides OT (Bachem, King of Prussia, PA), arginine vasopressin (AVP, Bachem), and Atosiban (Ferring Research, San Diego, CA) were dissolved in aCSF. Peptides were infused into the lateral ventricles in a volume of 2 µl over 2 min. Doses of OT and Atosiban were extrapolated from previous studies performed in OT-/- mice (our unpublished observations). Before euthanizing, we infused 2 µl of India ink dissolved in aCSF to confirm cannula placement. Only mice that showed correct placement of the cannula were included in the analyses.

EPM testing
Approximately 1 wk before testing, mice were transferred from group to individual housing. During a 4-d acclimation and on the test day, mice were brought to the holding area outside of the behavioral testing room for 1 h. Mice were tested in the EPM between 1300 and 1700 h and were paired by genotype and/or treatment during each test session. The EPM, which was positioned on a platform 40 cm above the floor of a dimly lit, quiet room, consisted of two opposite facing open arms (30 x 5 cm) and two closed arms (30 x 5 cm with 15-cm-high walls) with a central area (5 x 5 cm). Mice were placed on the central platform, facing an open arm and the number and duration of entries into open or closed arms were videotaped for each mouse for 5 min and later scored by a single observer blinded to treatment and genotype of each mouse. An arm entry was defined by all four paws entering an arm of the EPM.

Experimental protocols
Experiment I.
The purpose of this experiment was to determine genotype differences in anxiety-related behavior in female mice. Naïve OT+/+ and OT-/- female mice were placed in the EPM, and the number and duration of entries into open or closed arms were recorded for 5 min.

Experiment II.
The purpose of this experiment was to determine if administering OT to OT-/- mice would influence anxiety-related behavior and whether the effect is specific for OT. Female OT-/- mice received infusions of OT (2 ng), AVP (2 ng), or aCSF into the lateral ventricles. Five minutes post infusion, mice were placed in the EPM, and the number and duration of entries into open or closed arms were recorded for 5 min.

Experiment III.
The purpose of this experiment was to determine if blocking endogenous OT would alter anxiety-related behavior. Atosiban (20 or 100 ng) or an equivalent volume of aCSF was infused into the lateral ventricles of female OT+/+ mice. Five minutes after infusion, mice were placed in the EPM, and the number and duration of entries into open or closed arms were recorded for 5 min.

Experiment IV.
The purpose of this experiment was to determine whether the anxiolytic function of OT was at the OT receptor. After a 1-month rest, OT-/- female mice tested in experiments I, II, and III were retested. On the day of testing, female OT-/- mice received central infusions of Atosiban (100 ng) followed by a second infusion of OT (2 ng) 5 min later. Control OT-/- female mice received an infusion of aCSF followed by a second infusion of aCSF 5 min later. Five minutes post infusion, mice were placed in the EPM and the number and duration of entries into open or closed arms were recorded for 5 min.

Experiment V.
To determine genotype differences in anxiety-related behavior in male mice, naïve OT+/+ and OT-/- male mice were tested as described in experiment I.

Statistics
Results are expressed as group mean ± SEM. Behavioral parameters obtained from the EPM test were analyzed using an unpaired t test. Group data were analyzed by a one-way ANOVA. When the overall F ratio was significant, pairwise comparisons were made with the Bonforroni/Dunn post hoc comparison. Differences were considered significant when P < 0.05.

	Results

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Experiment I
Female OT-/- mice displayed more anxiety-like behavior than OT+/+ mice in the EPM. The percentage of entries (P < 0.0002) and time spent (P < 0.003) in the open arms of the EPM was less in OT-/- mice than OT+/+ mice (Fig. 1A). The increase in anxiety-like behavior was not due to altered locomotor activity, as overall activity in the closed and total arm entries was not different between genotype (Fig. 1B).

View larger version (14K): [in this window] [in a new window]   Figure 1. Behavior was observed and scored in female OT-/- and OT+/+ mice in the elevated plus-maze. A, The percentage of entries (P < 0.0002, two-tailed t test) and time spent (P < 0.003, two-tailed t test) in the open arms of the maze was less in OT-/- mice than in OT+/+ mice. B, The number of closed arm or total arm entries was not significantly different between genotypes.

View larger version (14K): [in this window] [in a new window]   Figure 2. A, Administration of synthetic OT (2 ng) into the lateral ventricles of OT-/- mice enhanced the percentage of entries (P < 0.003, two-tailed t test) and time spent (P < 0.004, two-tailed t test) in the open arms of the plus-maze compared with OT-/- mice that received aCSF icv. B, The number of closed arm or total arm entries did not differ between genotype.

View larger version (11K): [in this window] [in a new window]   Figure 3. A, Administration of AVP (2 ng) into the lateral ventricles of OT-/- mice did not alter the percentage of entries (P > 0.05, two-tailed t test) or time spent (P > 0.05, two-tailed t test) in the open arms of the plus-maze compared with artificial cerebrospinal fluid-treated OT-/- mice. B, Closed arm and total arm entries was not significantly different between female OT+/+ and OT-/- mice.

View larger version (20K): [in this window] [in a new window]   Figure 4. A, Administration of an OT receptor antagonist (Atosiban) into the lateral ventricles of OT+/+ mice decreased the percentage of entries [ANOVA, F (2, 19) = 5.35, P < 0.01] and time spent [ANOVA, F (2, 19) = 3.82, P < 0.04] in the open arms of the plus-maze. Post hoc analysis revealed that the decrease in entries (P < 0.004) and time spent (P < 0.012) in the open arms was significant for the 100 ng dose compared with aCSF-treated mice. B, The number of closed arm or total arm entries did not differ between genotypes.

Experiment V
Male OT-/- mice displayed less anxiety-like behavior than OT+/+ mice in the plus-maze (Fig. 5A). The percentage of entries (P < 0.007) and time spent (P < 0.004) in the open arms of the maze was greater in OT-/- mice than OT+/+ mice. The increase in anxiety-like behavior was not due to altered locomotor activity, as overall activity in the closed and total arm entries were not different between genotype (Fig. 5B).

View larger version (13K): [in this window] [in a new window]   Figure 5. A, Behavior was observed and scored in male OT-/- and OT+/+ mice in the elevated plus-maze. The percentage of entries (P < 0.007, two-tailed t test) and time spent (P < 0.004, two-tailed t test) in the open arms of the maze was greater in OT-/- mice than OT+/+ mice. B, The number of closed arm or total arm entries did not differ between genotypes.

	Discussion

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Female OT-/- mice spent less time in the open arms of the EPM, an index of anxiety-related behavior, compared with female OT+/+ mice. This observation is consistent with the concept that activation of oxytocinergic neurons, and the subsequent release of OT reduces the amount of anxiety-related behavior observed in a novel environment. Thus, OT-/- mice, which lack the ability to synthesize and release OT, displayed increased anxiety-related behavior.

Icv administration of OT into the lateral ventricles of female OT-/- mice reduced anxiety-related behavior. Furthermore, our findings are consistent with data showing decreased anxiety-related behavior in female rats (13) and mice (16) administered OT centrally and tested in the EPM. In addition, the decrease in anxiety-related behavior in OT-/- mice is OT dependent. Central administration of an equivalent dose of AVP, a peptide closely related to OT, did not alter anxiety-related behavior. This observation suggests that the OT receptor must be activated for OT to exert its anxiolytic affect.

Similarly, central administration of an OT receptor antagonist into the lateral ventricles of female OT+/+ mice decreased the number of open arm entries in the EPM, demonstrating that blockade of endogenous OT with an OT receptor antagonist increased anxiety-related behavior. This is the first time that blockade of endogenous OT in the mouse has been shown to increase anxiety-related behavior in the EPM. Furthermore, infusion of the same OT receptor antagonist into the lateral ventricles of female OT-/- mice before administration of synthetic OT blocked the anxiolytic affect of OT in OT-/- female mice, supporting that the anxiolytic affect of OT is mediated via the OT receptor. Our findings in female mice are similar to those of female rats, which displayed an increase in anxiety-related behavior in the EPM following administration of an OT receptor antagonist (14). Thus, the anxiolytic effect of OT in C57BL/6 mice is mediated by the OT receptor.

Studies performed in estrogen-primed ovariectomized mice suggest that the anxiolytic effect of OT may be due to binding at the OT receptor in the lateral septum (16), which is in close proximity to the lateral ventricles. The OT receptor is highly expressed in the lateral septum of mice (16, 21). The facility with which exogenously administered OT reduced, and the OT receptor antagonist, inhibited anxiety suggests that following delivery into the lateral ventricles, OT receptors mediating anxiety are anatomically accessible. Although the present study does not identify the area of the brain that mediates the anxiety-like behavior in mice or whether differences in the number and/or affinity of OT receptors account for differences in anxiety-related behavior in OT-/- or OT+/+ mice, these questions can be answered by future studies using mice of both genotypes.

Male OT-/- mice were tested using the same behavioral task, the EPM. Surprisingly, unlike female OT-/- mice, male OT-/- mice displayed decreased anxiety-like behavior in the EPM compared with male OT+/+ mice. Winslow and colleagues (24) also reported decreased anxiety-related behavior in male OT-/- mice compared with male OT+/+ mice in the EPM. Furthermore, in male rats tested in the EPM, infusion of an OT receptor antagonist decreased anxiety-related behavior in the EPM (14). Collectively, our study and those of others do not support an anxiolytic role for OT in male rats or mice tested in the EPM.

In summary, our findings indicate that oxytocinergic pathways play an anxiolytic role in female mice tested in the EPM. The absence of normally functioning OT systems in an OT-deficient mouse results in increased anxiety-related behavior. The enhanced anxiety was reversed by central administration of exogenous OT. Blockade of endogenous OT receptors via central administration of an OT receptor antagonist to OT+/+ female mice resulted in increased anxiety-related behavior in the EPM. In addition, infusion of an OT receptor antagonist before administration of exogenous OT in OT-/- female mice inhibited the anxiolytic effects of OT. These findings suggest that genetic and/or pharmacological interruption of OT may inhibit activation of OT receptors in brain regions involved in the anxiety response.

	Acknowledgments

 
The authors acknowledge Ferring Research (San Diego, CA) for providing the Atosiban for these studies. The authors also acknowledge the technical assistance of Dr. Hou-ming Cai.

	Footnotes

 
The work was supported by NIH Grant HD-37268 (to J.A.A.).

Abbreviations: aCSF, Artificial cerebrospinal fluid; AVP, arginine vasopressin; EPM, elevated plus-maze; icv, intracerebroventricular(ly); OT, oxytocin; OT-/-, OT-deficient mice; OT+/+, wild-type mice; PVN, paraventricular nucleus.

Received December 27, 2002.

Accepted for publication February 12, 2003.

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