Nucleotide sequences of RT-qPCR primers for target genes
Derangement of hormonal milieu has been associated with the pathophysiology of psychiatric illnesses, such as schizophrenia, mood disorders, and developmental disorders [1; 2; 3]. Among them, schizophrenia is a relatively common neuropsychiatric disorder, and has been associated with debilitating consequences if not treated properly [4; 5]. The illness is characterized by positive (e.g., delusions, hallucinations, bizarre thoughts) and negative (blunt affect, avolition, anhedonia, social withdrawal) symptoms, as well as deficits in various cognitive abilities, e.g. verbal memory, working memory, attention/vigilance, and information processing [4; 6; 7]. Minor impairments of social cognition are often observed during the premorbid stage of the disease .
The role for endocrinological dysregulation in the development of psychotic symptoms has been suggested by brain imaging studies. For example, a larger than normal volume of the pituitary gland has been reported in patients with first-episode schizophrenia (Fig. 1). Further, these patients exhibit an increase in the pituitary volume overtime, unlike the case with normal volunteers, the degree of which is correlated with the change in positive symptoms . These findings, representing mainly a morphological change of the anterior pituitary , are consistent with the concept of HPA axis hyperactivity in response to stress during psychotic experience .
Hormones secreted from the posterior portion of the pituitary gland, i.e. vasopressin and oxytocin, have also been a focus in schizophrenia research from the perspective of social behavior disturbances [2; 11; 12]. In this chapter, we provide an overview of preclinical and clinical evidence for contribution of the vasopressin and oxytocin systems in social behavior deficits of schizophrenia and related disorders, as well as their treatment. Related discussions on the role of these neuropeptides in the coping of stressors and psychiatric conditions are provided in other Chapters [3; 13].
2. Vasopressin (arginine-vasopressin, AVP), oxytocin and behaviors
The two neuro-hormones are nona-peptides closely related each other, while their functions are sometimes in opposite directions, e.g. facial cognition and responses to stress . Also, there is a suggestion that oxytocin is responsible for maternal behavior whereas male-typical social behavior is associated with AVP . As a neuromodulator, AVP has been suggested to play a role in some of the cognitive abilities, including social memory, as well as emotionality (Fig 2). Neurotransmissions by AVP are mediated by three receptor subtypes, namely, V1A, V1B, and V2 receptors, all of which are coupled to G-proteins . Information about oxytocin is reviewed elsewhere in this Book 
Impaired social abilities have been particularly implicated in subjects with developmental disorders, such as autism. Thus, Fries et al (2005)  reported decreased urine levels of AVP and oxytocin, in children reared in orphanage settings compared to those in infants who received normal care-giving from their parents. Previously institutionalized children have been suggested to frequently experience problems in establishing social bonds and regulating social behavior . Accordingly, infants who experienced early neglect showed lower basal levels of AVP than family-reared children . These observations support the growing evidence for the role of the neuropeptidergic systems in social behaviors in mammals (e.g. [16; 17; 18]: see  for review).
3. Sociality deficits in animal models of schizophrenia; Effect of neuropeptides
Social behaviors comprise various domains, such as social (learning) memory and social bonding [20; 21]. The intracerebroventricular administration of AVP has been shown to facilitate social memory, as measured by the social discrimination test (SDT), in rats [22; 23].
The neural substrates governing the ability of AVP to enhance sociality include the lateral septum (LS), bed nucleus of the stria terminalis, and medial amygdala . Specifically, overexpression of the V1A receptors in the LS enhanced SDT performance, an effect blocked by application of a V1A antagonist, but not oxytocin receptor antagonist . By contrast, administration of oxytocin into the medial amygdala restored impaired social recognition in oxytocin knockout mice, while vasopressin was ineffective . Overall, these observations are consistent with the contribution of V1 receptors in the LS to the maintenance of long-term potentiation , which is crucial for learning and memory.
Experimental data from our laboratory also suggest a role for altered AVP transmissions in social interaction deficits. Thus, chronic administration of phencyclidine, an antagonist at N-methyl-D-aspartate (NMDA) receptors, impaired social interaction behavior, and reduced the density of V1A receptors in several brain regions, including the LS in rats  (Figure 3). In a subsequent study, Matsuoka et al. (2008)  found decreased levels of mRNA encoding AVP in the amygdala, as measured by a microarray system and real-time quantitative PCR assay, in rats chronically treated with MK-801, a non-competitive antagonist at the NMDA receptor. These findings provide a basis for the ability of AVP or its analogues to ameliorate social interaction deficits in animal models of schizophrenia.
This result from an animal model of schizophrenia is consistent with the observation, discussed above, that chronic administration of the NMDA antagonist phencyclidine reduces the density of V1a receptor binding sites in several brain regions, including the LS, in rats showing social interaction deficits. These findings from our laboratory are consistent with Bielsky et al who reported that re-expressing of V1a receptors in the lateral septum of V1a receptor knockout mice exhibits complete recovery from impaired social recognition. Down-regulation of the AVP gene in the amygdala of MK-801-treated rats may provide a basis for the ability of AVP-analogues to ameliorate the behavioral disturbances by blockade of NMDA receptor . Similar benefits regarding social behavior have been reported for oxytocin [3; 13; 28; 29; 30].
We conducted a further analysis of the change in the expression of RNAsencoding AVP and its receptor subtypes (V1A, V1B) in the amygdala of the model rat by means of qPCR (Table 1). As shown in Fig 5, expression of the AVP gene was significantly reduced by treatment with MK-801 (0.13 mg/day) for 14 days, while the same treatment did not affect the expressions of V1A, and V1B receptors. These results may help understand a mechanism by which impaired NMDA receptor-mediated transmissions, a putative pathophysiology of schizophrenia, disturbs social behaviors.
4. Clinical implications
Efforts to enhance social abilityare important from the perspective of adjusting patients to the community, thus improving functional outcome. Social ability disturbances in schizophrenia are thought to be partly attributable to negative symptoms and disturbances of cognitive function[4; 31; 32]. Although treatment with the first generation antipsychoticdrugs, e.g. haloperidol, has been shown to ameliorate positive symptoms, only a limited number of agents, such as the second generation antipsychotics, or so-called “atypical antipsychotic drugs (AAPDs)”, e.g. clozapine, melperone, risperidone, olanzapine, quetiapine, ziprasidone, and perospirone, with variable affinities for serotonin (5-HT) receptor subtypes, have been shown to be partially effective to treat negative symptoms and cognitive disturbances of schizophrenia [32; 33; 34; 35; 36] (see [4; 37] for review). Thus, more effective strategy to treat neurocognition, in addition to social abilities, is needed to enhance quality of life for patients.
In this context, the results from a recent study of the effect of augmentation therapy with oxytocin on cognitive function in patients with schizophrenia are noteworthy. The investigators report a significant enhancement of verbal learning memory, a cognitive domain thought to largely influence the outcome, in subjects receiving daily intranasal oxytocin (twice daily) for 3 weeks. Further controlled study is warranted to confirm the cognition-boosting effect of neuropeptides in the treatment of schizophrenia.
As has been discussed, neuropeptides, e.g., vasopressin and oxytocin, have been suggested to be associated with the pathophysiology of schizophrenia. Accordingly, a whole-genome scan for schizophrenia in a large inbred Arab-Israeli pedigree has found a possible linkage on chromosome 20p13  (Fig. 6). Importantly, this locus harbors four strong candidate genes for the illness, two of which are for oxytocin (
Psychotropic drugs acting on 5-HT receptors, such as AAPDs and 5-HT1A agonists, have been shown to improve social behavior in animals [36; 40; 41].These results are consistent with the concept that the AVP and 5-HT systems interact both neuroanatomically and neurochemically in the brain areas, e.g. anterior hypothalamus, as demonstrated in Fig. 7 . Therefore,it is reasonable that further research into the neuropeptidergic system, in conjunction with other neurotransmitter/modulator systems, will facilitate the therapeutic strategy for social behavior deficits in patients with schizophrenia and related disorders.
The authors declare no conflict of interest for this work.
We are grateful for fruitful discussions with Drs. Michio Suzuki, Tsutomu Takahashi and Kodai Tanaka.
This work was supported by Health and Labour Sciences Research Grants from Comprehensive Research on Disability, Health and Welfare, Grants-in—Aid for Scientific Research from the Japanese Society for the Promotion of Science, SENSHIN Medical Research Foundation, and Takeda Scientific Foundation.
Mechanisms leading to disease. Arch Intern Med Mc Ewen B. S. Stellar E. Stress the individual. 153 1993 1993 2093 2101
Eur JPharmacol Frank E. Landgraf R. The vasopressin. system--from antidiuresis. to psychopathology. 583 2008 2008 226 242
Sumiyoshi, (Ed.), Neuroendocrinology and Behavior, InTech, Rijeka, Munesue T. Ashimura K. Nakatani H. Kikuchi M. Yokoyama S. Oi M. Higashida H. Minabe Y. Is intranasal. administration of. oxytocin effective. for social. impairments in. autism spectrum. disorder? in. T. 2012pp. ( ).
Clin Psychopharmacol Neurosci Sumiyoshi T. Kawasaki Y. Suzuki M. Higuchi Y. Kurachi M. Neurocognitive assessment. pharmacotherapy towards. prevention of. schizophrenia What. can we. learn from. first episode. psychosis 6 2008 2008 57 64
Sumiyoshi, (Ed.), Schizophrenia Research: Recent Advances, Nova Science Publishers, New York, Bouza C. Lopez-Cuadrado T. Saz-Parkinson Z. Alcazar R. Maria J. Blanco A. Natural mortality. in schizophrenia. an updated. meta-analysis in. T. 2012 61 80
Psychiatry Clin Neurosci Kaneda Y. Sumiyoshi T. Keefe R. Ishimoto Y. Numata S. Ohmori T. Brief assessment. of cognition. in schizophrenia. validation of. the Japanese. version 61 2007 2007 602 609
Prog Neuropsychopharmacol Biol Psychiatry Matsui M. Sumiyoshi T. Arai H. Higuchi Y. Kurachi M. Cognitive functioning. related to. quality of. life in. schizophrenia 32 2008 2008 280 287
Am J Psychiatry Erlenmeyer-Kimling L. Rock D. Roberts S. A. Janal M. Kestenbaum C. Cornblatt B. Adamo U. H. Gottesman I. I. Attention memory. motor skills. as childhood predictors. of schizophrenia-related. psychoses the. New York. High-Risk Project. 157 2000 2000 1416 1422
Prog in Neuro-Psychopharmacology &BiolPsychiat Takahashi T. Zhou S. Y. Nakamura K. Tanino R. Furuichi A. Kido M. Kawasaki Y. Noguchi K. Seto H. Kurachi M. Suzuki M. Longitudinal volume. changes of. the pituitary. gland in. patients with. schizotypal disorder. first-episode schizophrenia. 35 2011 2011 177 183
JPsychiatry : Pariante C. M. Vassilopoulou K. Velakoulis D. Phillips L. Soulsby B. Wood S. J. Brewer W. Smith D. J. Dazzan P. Yung A. R. Zervas I. M. Christodoulou G. N. Murray R. Mc Gorry P. D. Pantelis C. Pituitary volume. in psychosis. J. 185 2004 2004 5 10
Heatherton, V.A. Walcott, (Eds.), Handbook of Social Interactions in the 21st Century, Nova Science Publishers, New York, Sumiyoshi T. Matsuoka T. Tanaka K. Bubenikova-Valesova V. Social interaction. deficits in. schizophrenia-spectrum disorders. pharmacologic intervention. in A. T. 2009 363 370
Int.Neuropsychopharmacol ( Teltsh O. Kanyas-Sarner K. Rigbi A. Greenbaum L. Lerer B. Kohn Y. Oxytocin vasopressin genes. are significantly. associated with. schizophrenia in. a. large-Israeli Arab. pedigree Int. 2011
Sumiyoshi, (Ed.), Neuroendocrinology and Behavior, InTech, Rijeka, Nephew B. C. Behavioral roles. of oxytocin. vasopressin in. T. 2012pp. ( ).
Schizoph Res Goldman M. Marlow-O’Connor M. Torres I. Carter C. S. Diminished plasma. oxytocin in. schizophrenic patients. with neuroendocrine. dysfunction emotional deficits. 98 2008 2008 247 255
Proc Natl Acad Sci U S A Fries A. B. Ziegler T. E. Kurian J. R. Jacoris S. Pollak S. D. Early experience. in humans. is associated. with changes. in neuropeptides. critical for. regulating social. behavior 102 2005 2005 17237 17240
Bielsky I. F. Hu S. B. Ren X. Terwilliger E. F. Young L. J. The V1a. vasopressin receptor. is necessary. sufficient for. normal social. recognition a. gene replacement. study 47 2005 2005 503 513
Brain Res Matsuoka T. Sumiyoshi T. Tanaka K. Tsunoda M. Uehara T. Itoh H. Kurachi M. C-190 N. an arginine-vasopressin. analogue ameliorates. social behavior. deficits hyperlocomotion in. M. K-801-treated rats. therapeutic implications. for schizophrenia. 1053 2005 2005 131 136
Brain Res Tanaka K. Suzuki M. Sumiyoshi T. Murata M. Tsunoda M. Kurachi M. Subchronic phencyclidine. administration alters. central vasopressin. receptor binding. social interaction. in the. rat 992 2003 2003 239 245
E.E. Storm, L.H. Tecott, Social circuits: peptidergic regulation of mammalian social behavior. 47 2005 2005 483 486
Eur ArchPsychiatrNeurol Sci de Wied D. van Ree J. M. Neuropeptides animal. behaviour human psychopathology. 238 1989 1989 323 331
Winslow J. T. Hastings N. Carter C. S. Harbaugh C. R. Insel T. R. role A. for central. vasopressin in. pair bonding. in monogamous. prairie voles. 365 1993 1993 545 548
Dantzer R. Bluthe R. M. Koob G. F. Le Moal M. Modulation of. social memory. in male. rats by. neurohypophyseal peptides. 91 1987 1987 363 368
Neurosc Lett Le Moal M. Dantzer R. Michaud B. Koob G. F. Centrally injected. arginine vasopressin. . A. V. P. facilitates social. memory in. rats 77 1987 1987 353 359
G.J. De Vries, R.M. Buijs, The origin of the vasopressinergic and oxytocinergic innervation of the rat brain with special reference to the lateral septum.Brain Res 273 1983 1983 307 317
J.N. Ferguson, J.M. Aldag, T.R. Insel, L.J. Young, Oxytocin in the medial amygdala is essential for social recognition in the mouse.Neurosc 21 2001 2001 8278 8285
Eur JPharmacol Joels M. Modulatory actions. of steroid. hormones neuropeptides on. electrical activity. in brain. 405 2000 2000 207 216
Matsuoka T. Tsunoda M. Sumiyoshi T. Takasaki I. Tabuchi Y. Seo T. Tanaka K. Uehara T. Itoh H. Suzuki M. Kurachi M. Effect of. M. K-8 on gene. expressions in. the amygdala. of rats. 62 2008 2008 1 7
P.R. Lee, D.L. Brady, R.A. Shapiro, D.M. Dorsa, J.I. Koenig, Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin.Neuropsychopharmacology 30 2005 2005 1883 1894
P.R. Lee, D.L. Brady, R.A. Shapiro, D.M. Dorsa, J.I. Koenig, Prenatal stress generates deficits in rat social behavior: Reversal by oxytocin.Brain Res 1156 2007 2007 152 167
Jin D. Liu H. X. Hirai H. Torashima T. Nagai T. Lopatina O. Shnayder N. A. Yamada K. Noda M. Seike T. Fujita K. Takasawa S. Yokoyama S. Koizumi K. Shiraishi Y. Tanaka S. Hashii M. Yoshihara T. Higashida K. Islam M. S. Yamada N. Hayashi K. Noguchi N. Kato I. Okamoto H. Matsushima A. Salmina A. Munesue T. Shimizu N. Mochida S. Asano M. Higashida H. C. D. is critical. for social. behaviour by. regulating oxytocin. secretion 446 2007 2007 41 45
Int J Neuropsychopharmacol Sumiyoshi C. Sumiyoshi T. Roy A. Jayathilake K. Meltzer H. Y. Atypical antipsychotic. drugs organization of. long-term semantic. memory multidimensional. scaling cluster analyses. of category. fluency performance. in schizophrenia. 9 2006 2006 677 683
Psychiatry Res ( Sumiyoshi C. Ertugrul A. Anil A. E. Yagcioglu Semantic. memory deficits. based on. category fluency. performance in. schizophrenia Similar. impairment patterns. of semantic. organization across. Turkish Japanese patients. 2009 47 EOF 57 EOF
S.R. McGurk, The effect of clozapine on cognitive functioning in schizophrenia.J Clin Psychiatry 60 (suppl 12) ( 1999 24 EOF 9 EOF
Int J Neuropsychopharmacol Woodward N. D. Purdon S. E. Meltzer H. Y. Zald D. H. meta-analysis A. of neuropsychological. change to. clozapine olanzapine. quetiapine risperidone in. schizophrenia 8 2005 2005 457 472
Schizophr Res Sumiyoshi T. Jayathilake K. Meltzer H. Y. The effect. of melperone. an atypical. antipsychotic drug. on cognitive. function in. schizophrenia 59 2003 2003 7 16
- 36. M. Bubenikova-Valesova, M. Votava, J. Palenicek, J. Horacek, C. Hoschl, Effect of serotonin-1A receptors on behavioral changes in animal model of schizophrenia-like behavior, in, 16th European Congress of Psychiatry, Nice, France, 2008.
Horacek . Bubenikova-Valesova V. Kopecek M. Palenicek T. Dockery C. Mohr P. Hoschl C. Mechanism of. action of. atypical antipsychotic. drugs the neurobiology. of schizophrenia. C. N. 20 2006 2006 389 409
Schizoph Res Feifel D. Macdonald K. Cobb P. Minassian A. Adjunctive intranasal. oxytocin improves. verbal memory. in people. with schizophrenia. 139 2012 2012 207 210
Teltsh O. Kanyas-Sarner K. Rigbi A. Greenbaum L. Lerer B. Kohn Y. Oxytocin vasopressin genes. are significantly. associated with. schizophrenia in. a. large Arab. Israeli pedigree. Int J. Neuropsychopharmacol . 2012 309 EOF 319 EOF
Behav Brain Res Snigdha S. Neill J. C. Improvement of. phencyclidine-induced social. behaviour deficits. in rats. involvement of. . receptors H. T. A. 191 2008 2008 26 31
III. Activity in models of cognition and negative symptoms. Br J Pharmacol Depoortere R. Auclair A. L. Bardin L. Bruins L. Slot M. S. Kleven F. Colpaert B. Vacher A. Newman-Tancredi F1506. compound a. with D. antagonist D. . agonist H. T. A. partial D. agonist properties. I. I. 151 2007 2007 266 277
Jr., G. Koppel, K.W. Perry, R.W. Fuller, Y. Delville, Ferris C. F. Melloni R. H. Jr Koppel G. Perry K. W. Fuller R. W. Delville Y. Vasopressin/serotonin interactions. in the. anterior hypothalamus. control aggressive. behavior in. golden hamsters. Vasopressin/serotonin interactions in the anterior hypothalamus control aggressive behavior in golden hamsters.J Neurosci 17 1997 1997 4331 4340