Elsevier

Behavioural Brain Research

Volume 178, Issue 1, 12 March 2007, Pages 123-127
Behavioural Brain Research

Research report
Impaired social interaction and reduced anxiety-related behavior in vasopressin V1a receptor knockout mice

https://doi.org/10.1016/j.bbr.2006.12.009Get rights and content

Abstract

The arginine vasopressin (AVP) system plays an important role in social behavior. Autism, with its hallmark disturbances in social behavior, has been associated with the V1a receptor (V1aR) gene. Furthermore, impairments of social function are often observed in symptoms of schizophrenia. Subchronic phencyclidine (PCP) produces behaviors relating to certain aspects of schizophrenic symptoms such as impairing social interaction in animals and it reduces the density of V1aR binding sites in several brain regions. Here, we report that V1aR knockout (KO) mice exhibited impairment of social behavior in a social interaction test, and showed reduced anxiety-related behavior in elevated plus-maze and marble-burying behavior tests. Given the current findings, the V1aR may be involved in the regulation of social interaction, and V1aR KO mice could be used as an animal model of psychiatric disorders associated with social behavior deficits, such as autism and schizophrenia.

Introduction

Arginine vasopressin (AVP) is a neurohypophyseal peptide. AVP receptors have been classified into three subtypes: V1a, V1b and V2 receptors [14], [29], based on their intracellular transduction mechanisms. The V1a and V1b receptors are associated with phosphoinositol turnover, while the V2 receptor activates adenylate cyclase [9], [23]. The V1a receptor (V1aR) is widely distributed in the central nervous system including the septum, cerebral cortex, hippocampus and hypothalamus [10], [27], [31]. A recent study showed that V1aR play a critical role in regulating behavior such as learning and memory, social recognition and anxiety-like behavior. We have previously reported that V1aR knockout (KO) mice exhibit an impairment of spatial learning in comparison to wild-type (WT) mice in an eight-arm radial maze [7]. Moreover, a selective V1aR antagonist mildly impaired spatial memory in WT mice [7]. V1aR KO mice also exhibit a profound impairment in social recognition and reduction in anxiety-like behavior, and re-expressing V1aR in the lateral septum of V1aR KO mice using a viral vector resulted in a complete rescue of social recognition [3], [4]. Furthermore, overexpression of the V1aR in the lateral septum of WT mice resulted in a potentiation of social recognition behavior and a mild increase in anxiety-related behavior [3].

AVP plays an important role in social behavior in comparative neurobiological studies [12]. Most recently, intranasally delivered AVP has been reported to affect social communication processes in humans [30]. One of the core features of autism is impairment in social behavior, such as reciprocal social interaction and communication. Interestingly, three independent reports demonstrated that autism has been associated with the V1aR gene [15], [33], [34]. On the other hand, impairments of social function are often observed in symptoms of schizophrenia. Phencyclidine (PCP) has been known to evoke increased severity of symptoms in schizophrenia and to induce schizophrenia-like symptoms in healthy individuals [20], [32]. Moreover, PCP decreases social behavior in the rat social interaction test [26]. Similarly, subchronic treatment with PCP results in impaired social interaction and reduced density of V1aR in several brain regions such as the hypothalamus in rats [28]. There is a possibility that V1aR may play an important role in the regulation of social interaction. This idea is of special interest because impaired social interaction is among the core deficits of autistic disorders. However, whether V1aR is involved in the regulation of social interaction has remained untested. Therefore, we investigated whether mice lacking V1aR would exhibit impairment of social interaction. We also examined whether these V1aR KO mice would exhibit changes in anxiety levels and depression-related emotional responses.

Section snippets

Animals

Fifty-six male WT and 60 male V1aR KO mice (V1aR−/−), which were generated by gene targeting as previously reported [16], were used at ages 7–13 weeks for all of the experiments. All mice analyzed were from F3 to F5, which carried the genetic background of 129Sv and C57Black/6J strains. They were kept under a constant light–dark cycle (light 7:00–19:00) in a temperature-controlled (23 ± 2 °C) room. Experiments were conducted during the light phase between 9:00 a.m. and 5:00 p.m. The animals had

Open-field, traction-meter, rota-rod and forced swimming tests

No significant differences were observed between WT mice and V1aR KO mice at 10–12 weeks of age in detailed analyses of their motor function with open-field testing, the traction-meter test for muscle tone and the rota-rod test for motor coordination (Table 1). Moreover, there was no significant difference between WT mice and V1aR KO mice for the immobility time in the forced swimming test for measuring depression. In addition, there was no difference between WT mice and V1aR KO mice for their

Discussion

The major finding in the present study is that V1aR KO mice exhibited an impairment of social interaction compared to the WT mice in the social interaction test. The results of the study also showed that the number of ambulation and rearing in the V1aR KO mice was normal in the open-field test. Moreover, we did not observe differences between V1aR KO mice and WT mice in the traction-meter and rota-rod tests. Thus, motor function in V1aR KO mice was normal. Moreover, there was no significant

Acknowledgements

This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 18591318).

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