**4. Clinical implications**

88 Neuroendocrinology and Behavior

oxytocin [3; 13; 28; 29; 30].

internal standard.

schizophrenia, disturbs social behaviors.

This result from an animal model of schizophrenia is consistent with the observation, discussed above [18], 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 [16] 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 [17]. Similar benefits regarding social behavior have been reported for

We conducted a further analysis of the change in the expression of RNAs encoding 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

**Figure 5.** RNA quantification by means of real-time qPCR. Expression ratios for MK-801-treated rats vs. vehicle-treated animals are shown (n=5-6 for each group). Expression of the arginine-vasopressin (AVP) gene was significantly reduced by treatment with MK-801 (0.13 mg/day) for 14 days, (\*p<0.05 by one-way ANOVA), while the same treatment did not affect the expressions of V1a and V1b receptors.Mx3000P (StrataGene) was used for pPCR with SYBER Premix Ex Taq (Takara Co. Ltd.). GAPDH was used as

Efforts to enhance social ability are 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 antipsychotic drugs, 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 [38]. 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 [39] (Fig. 6). Importantly, this locus harbors four strong candidate genes for the illness, two of which are for oxytocin (*OXT*) and AVP (*AVP*) [39]. Further, examination of the association with gene expression in the brain identified genetic variants in the *OXT-AVP* cluster, and three of these variants were associated with schizophrenia [12]. These findings provide a strong proof for the contribution of these neuropeptides to the etiology of the illness.


**Figure 6.** A scheme of the genes oxytocin and vasopressin on the chromosomal region 20p13 and the positions of the seven examined SNPs. Teltsh et al., *Int J Neuropsychopharmacol* 15;309-19, 2012 (Permission obtained from CINP).

**Table 1.** Nucleotide sequences of RT-qPCR primers for target genes
