**1. Introduction**

94 Neuroendocrinology and Behavior

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The neuropeptide oxytocin (OT) is synthesized in magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus and released from axon terminals in the neurohypophysis into the general circulation. However, OT is also released from somata and dendrites of magnocellular neurons into the brain [1]. OT release from axon terminals, somata and dendrites is regulated by not only activity-dependent Ca2+ influx, but also by mobilization of Ca2+ from intracellular Ca2+ stores [2, 3]. CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, plays a critical role in mobilization of intracellular Ca2+, and therefore CD38 gene knockout (CD38-/-) mice show low plasma OT concentrations [2]. On the other hand, CD38 is not responsible for the secretion of arginine vasopressin, which is another neurohypophyseal hormone [2].

Perioherally, OT promotes milk ejection in females and penile erection in males [4]. In addition, studies using OT gene knockout (OT-/-), OT receptor gene knockout (OTR-/-), or CD38-/- mice, in which OT signaling would be disrupted, were performed to investigate the roles of OT in the central nervous system [5, 6].

While OT+/+ male mice showed a decline in the time investigating a female mouse during repeated pairings with full recovery following the introduction of a new female, OT-/- male mice show no such decline [7]. The results suggested that OT-/- male mice fail to develop social memory. Moreover, in a different experimental paradigm, OT-/- mice showed the same sociability, which was reflected as more time spent with a novel mouse as compared to time spent with a novel object, and preference for social novelty, which is reflected as more time spent with a second novel mouse as compared to time spent with a non-stranger mouse, as

© 2012 Munesue et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 Munesue et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

OT+/+ mice [8]. This experimental paradigm contains no memory component. Taken together, OT-/- mice exhibit impairments specific to social memory rather than deficits in general sociability. In addition, OT-/- infant mice show fewer call rates in ultrasonic vocalizations in response to maternal separation compared to OT+/+ infant mice [9], so OT-/ mice may be less emotional in the mother-infant relationship.

Is Intranasal Administration of Oxytocin Effective for Social Impairments in Autism Spectrum Disorder? 97

of age [18]. These results imply that ASD is a nearly innate rather than acquired disease, although it could not be excluded that exogenous factors may exert adverse effects on newborns within the 6 months after birth. However, the clear boundary between the conditions with and without ASD could not be defined in research or from a clinical perspective. Autistic traits in the general population are common and show a continuous distribution [19]. Moreover, the symptom of social impairment has a different meaning in nature compared to all other medical symptoms. A fasting blood sugar level of 150 mg/dL in an individual with diabetes mellitus is an objective and independent measurement. Social impairments in an individual with ASD are by no means objective and independent, especially in the boundary region between the conditions with and without ASD. The term "social" has relevance to human "society." Human society is the whole that has been shaped by innumerably iterated social interactions among humans from time immemorial, and cannot be defined from an external standpoint. While behaviors exhibited by individuals with ASD may look more or less deviant from the viewpoint of human society, they adapt themselves to human society unremarkably in some cases and deviate from it directly in other cases. Social impairments in ASD subjects cannot be anchored exactly in the context of real-life environments. Therefore, it is very difficult to determine how symptoms of social impairment should be evaluated in treatment of

In this article, we first discuss the influence of intranasally administered OT on sociality in human adults. We further examine the results obtained from four studies in which the effectiveness of intranasally or intravenously administered OT was investigated in ASD subjects. Moreover, we discuss long-term clinical trials in progress, for which we searched the public databases, of intranasally administered OT in subjects with ASD in randomized, double-blind, placebo-controlled designs. Finally, we consider the improvements in social

**2. Effectiveness of intranasally administered OT on social cognition and** 

We consider that reciprocal interaction with others would go through the processes of selfconsciousness as a construct deeply embedded in human society, social cognition, and prosocial behavior. Self-consciousness (i.e., self-representation or self-reference) may be a key concept in considering the psychopathology of ASD [20]. Can individuals with attenuated self-consciousness distinguish self from others in a social context? Children and adolescents with ASD made fewer statements classified as the social not but physical, active and psychological category compared to non-ASD subjects [21]. Typical interaction with others may be realized only under the conditions of typical self-consciousness. While biological investigations of self-consciousness have been performed using functional magnetic resonance imaging in ASD and healthy individuals [22, 23], the effects of OT on

patients with ASD.

impairments in the treatment of patients with ASD.

**prosocial behaviors in healthy adults** 

self-consciousness in humans remain unclear.

When OTR-/- dams retrieve their infant mice scattered in the home gage, they take a longer time and spend less time crouching over infant mice than OTR+/+ dams. OTR-/- infant mice show decreased ultrasonic vocalizations as seen in OT-/- infant mice [10]. While OTR+/+ mice spend a longer time exploring a cage occupied by an unfamiliar mouse than an empty cage, OTR-/- mice spend the same time in exploring both cages [11]. Interestingly, forebrainrestricted OTR-/- male mice show a decline in the investigation time with the same female mice during repeated pairings and show full recovery following the introduction of a new female as with OTR+/+ male mice [12].

CD38-/- male mice also show no decline in the investigation time with the same female mouse during repeated pairings unlike CD38+/+ male mice [2]. CD38-/- infant mice show fewer call rates in ultrasonic vocalizations in response to maternal separation compared with CD38+/+ infant mice [13].

OT-/-, OTR-/-, and CD38-/- mice show similar impairments in social memory and emotional relationship to the dam on isolation. Thus, investigations performed in OT-related knockout mice suggested the possible roles of OT as a sociability hormone. OT signaling in the brain was expected to play an important role in sociality in humans and to contribute to the etiologies of psychiatric disorders with social deficits, such as autism, which has been suggested to involve low plasma concentrations of OT [14].

Autism spectrum disorder (ASD) is a diagnostic continuum, which encompasses autistic disorder (autism), childhood disintegrative disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified in the Diagnostic and Statistical Manual of Mental Disorders (DSM) [15] and is intended to be designated so in a new version (DSM-5). Qualitative impairments of social interaction (social impairments) would be regarded as the major core symptom of ASD with repetitive and restrictive behaviors as another core symptom. However, social impairments imply wide-ranging symptoms from lack of declarative pointing, immediate echolalia, and failure to develop reciprocal peer relationships to very slight deficits identified only by detailed examinations combined with diagnostic tools, such as an advanced task for theory of mind [16]. Individuals with ASD, therefore, may not be diagnosed until adulthood [17].

While symptoms designated and conceptualized as impairments of social interaction are indispensable to the diagnosis of ASD and are easily identified in mentally retarded subjects with typical ASD, such as autism, weaker phenotypes of social impairments would involve a complicated subject of considering the symptomatology of ASD. Behavioral signs of social impairments in ASD have been suggested to emerge as a decline in social engagement, such as gazing on faces and social smiles, between 6 and 12 months

female as with OTR+/+ male mice [12].

with CD38+/+ infant mice [13].

OT+/+ mice [8]. This experimental paradigm contains no memory component. Taken together, OT-/- mice exhibit impairments specific to social memory rather than deficits in general sociability. In addition, OT-/- infant mice show fewer call rates in ultrasonic vocalizations in response to maternal separation compared to OT+/+ infant mice [9], so OT-/-

When OTR-/- dams retrieve their infant mice scattered in the home gage, they take a longer time and spend less time crouching over infant mice than OTR+/+ dams. OTR-/- infant mice show decreased ultrasonic vocalizations as seen in OT-/- infant mice [10]. While OTR+/+ mice spend a longer time exploring a cage occupied by an unfamiliar mouse than an empty cage, OTR-/- mice spend the same time in exploring both cages [11]. Interestingly, forebrainrestricted OTR-/- male mice show a decline in the investigation time with the same female mice during repeated pairings and show full recovery following the introduction of a new

CD38-/- male mice also show no decline in the investigation time with the same female mouse during repeated pairings unlike CD38+/+ male mice [2]. CD38-/- infant mice show fewer call rates in ultrasonic vocalizations in response to maternal separation compared

OT-/-, OTR-/-, and CD38-/- mice show similar impairments in social memory and emotional relationship to the dam on isolation. Thus, investigations performed in OT-related knockout mice suggested the possible roles of OT as a sociability hormone. OT signaling in the brain was expected to play an important role in sociality in humans and to contribute to the etiologies of psychiatric disorders with social deficits, such as autism, which has been

Autism spectrum disorder (ASD) is a diagnostic continuum, which encompasses autistic disorder (autism), childhood disintegrative disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified in the Diagnostic and Statistical Manual of Mental Disorders (DSM) [15] and is intended to be designated so in a new version (DSM-5). Qualitative impairments of social interaction (social impairments) would be regarded as the major core symptom of ASD with repetitive and restrictive behaviors as another core symptom. However, social impairments imply wide-ranging symptoms from lack of declarative pointing, immediate echolalia, and failure to develop reciprocal peer relationships to very slight deficits identified only by detailed examinations combined with diagnostic tools, such as an advanced task for theory of mind [16]. Individuals with ASD,

While symptoms designated and conceptualized as impairments of social interaction are indispensable to the diagnosis of ASD and are easily identified in mentally retarded subjects with typical ASD, such as autism, weaker phenotypes of social impairments would involve a complicated subject of considering the symptomatology of ASD. Behavioral signs of social impairments in ASD have been suggested to emerge as a decline in social engagement, such as gazing on faces and social smiles, between 6 and 12 months

mice may be less emotional in the mother-infant relationship.

suggested to involve low plasma concentrations of OT [14].

therefore, may not be diagnosed until adulthood [17].

of age [18]. These results imply that ASD is a nearly innate rather than acquired disease, although it could not be excluded that exogenous factors may exert adverse effects on newborns within the 6 months after birth. However, the clear boundary between the conditions with and without ASD could not be defined in research or from a clinical perspective. Autistic traits in the general population are common and show a continuous distribution [19]. Moreover, the symptom of social impairment has a different meaning in nature compared to all other medical symptoms. A fasting blood sugar level of 150 mg/dL in an individual with diabetes mellitus is an objective and independent measurement. Social impairments in an individual with ASD are by no means objective and independent, especially in the boundary region between the conditions with and without ASD. The term "social" has relevance to human "society." Human society is the whole that has been shaped by innumerably iterated social interactions among humans from time immemorial, and cannot be defined from an external standpoint. While behaviors exhibited by individuals with ASD may look more or less deviant from the viewpoint of human society, they adapt themselves to human society unremarkably in some cases and deviate from it directly in other cases. Social impairments in ASD subjects cannot be anchored exactly in the context of real-life environments. Therefore, it is very difficult to determine how symptoms of social impairment should be evaluated in treatment of patients with ASD.

In this article, we first discuss the influence of intranasally administered OT on sociality in human adults. We further examine the results obtained from four studies in which the effectiveness of intranasally or intravenously administered OT was investigated in ASD subjects. Moreover, we discuss long-term clinical trials in progress, for which we searched the public databases, of intranasally administered OT in subjects with ASD in randomized, double-blind, placebo-controlled designs. Finally, we consider the improvements in social impairments in the treatment of patients with ASD.
