Social Interaction Deficits in Schizophrenia

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Social Interaction Deficits in Schizophrenia…

Expert Commentary

Social Interaction Deficits in Schizophrenia-Spectrum Disorders and Pharmacologic Intervention

Tomiki Sumiyoshi,[1]1) Tadasu Matsuoka1), Kodai Tanaka1),

and Vera Bubenikova-Valesova2)

1)Department of Neuropsychiatry, University of Toyama Graduate

School of Medicine and Pharmaceutical Sciences, Toyama, Japan

2)Prague Psychiatric Center, Prague, Czech Republic

Abstract

Disturbances of social interaction in people suffering from major psychiatric illnesses have attracted concerns from clinicians, researchers, and healthcare administrators, as these deficits are a major determinant of outcome for patients. Impaired social abilities in schizophrenia-spectrum disorders and autism are thought to be partly attributable to specific aspects of symptomatology, such as negative symptoms (blunt affect, social withdrawal, anhedonia) and disturbances of several domains of cognitive function, e.g. verbal memory, working memory, attention/vigilance, and information processing. We recently found that severity of social cognition deficits is correlated with decreased concentrations of essential polyunsaturated fatty acids in the erythrocyte membrane in subjects with schizophrenia.

Psychotropic drugs acting on monoamine receptors, such as serotonin (5-HT)-5HT1A, and 5-HT2A receptors, have been shown to improve social behavior and cognitive function in rodents.For example, 5HT1A agonists enhance social interaction and reduce anxiety in rodents, while the newer class antipsychotic drugs with 5-HT2A antagonist actions, e.g. clozapine, melperone, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, and perospirone improve negative symptoms and social cognition.

Several lines of recent research indicate some neuropeptides, such as arginine-vasopressin (AVP) and oxytocin, regulate social interaction in mammalian species, including humans. We have reported that NC-1900, an AVP analogue and agonist at AVP-V1a receptors, ameliorates social interaction deficits in rats treated with MK-801, an antagonist at N-methyl-D-aspartate (NMDA) receptors. This result from an animal model of schizophrenia is consistent with our earlier observation that chronic administration of the NMDA antagonist phencyclidine reduces the V1a receptor number in some brain regions in rats showing social interaction deficits.

These findings warrant further research into the serotonergic and neuropeptidergic system, or the interaction of the above, to facilitate the development of therapeutic tools to target disturbances of social interaction in patients with schizophrenia or other psychiatric disorders.

I. Introduction

Disturbances of social interaction in people suffering from major psychiatric illnesses have attracted concerns from clinicians, researchers, and healthcare administrators, as these deficits are a major determinant of outcome for patients (see [1] for review). Impaired social abilities in schizophrenia-spectrum disorders and autism are thought to be partly attributable to specific aspects of symptomatology, such as negative symptoms (blunt affect, social withdrawal, anhedonia) and disturbances of several domains of cognitive function, e.g. verbal memory, working memory, attention/vigilance, and information processing [1-3].

In this chapter, the authors will provide an overview of some of the recent findings regarding the neural substrates for social interaction deficits in schizophrenia, developmental disorders, and related psychiatric disorders. Emphasis will be placed on the possible therapeutic targets for the improvement of social disturbances, e.g. serotonin (5-HT) receptor subtypes and the neuropeptidergic system.

Social Interaction Deficits in Schizophrenia and Developmental Disorders

Schizophrenia is a relatively common and often debilitatingneuropsychiatric disorder. Its symptoms include positive(e.g., delusions, hallucinations, bizarre thoughts) andnegative symptoms,as well as deficits in various cognitive domains as mentioned above. Specifically, minor impairments of social cognition are often observed during the premorbid stage ofthe illness [4]. Impaired social abilities in schizophrenia-spectrum disorders are thought to be partly attributable to negative symptoms and disturbances of cognitive function[5-7].

Altered composition of phospholipids, a major component of neural membranes, has been suggested to be related to the pathophysiology of schizophrenia [8]. We recently found decreased concentrations of essential polyunsaturated fatty acids (EPUFAs), e.g. eicosapentaenoic acid and docosahexaenoic acid, in the erythrocyte membrane in subjects with schizophrenia, and that the decrease in the EPUFAs levels were positively correlated with severity of verbal social cognition, as evaluated by the script tasks [9,10], in these patients[6].

Impaired social abilities have been also implicated in subjects with developmental disorders, such as autism.Thus, Fries and colleagues (2005) [11] reported decreased urine levels of neuropeptides, arginine vasopressin (AVP) and oxytocin, in children reared in orphanage settings compared to those in infants who received normal care-giving from their parents. Since it has been suggested that previously institutionalized children frequently experience problems in establishing social bonds and regulating social behavior [11], these results provide an excellent addition to the growing evidence for the contribution of the neuropeptidergic systems to social behavior in mammalian species (e.g. [12-14]: see [15] for review).Particularly impressive was the finding that infants who experienced early neglect showed lower basal levels of AVP than family-reared children [11].

These clinical observations in schizophrenia and developmental disorders are consistent with experimental data from our laboratory, suggesting a role for altered AVP activity in social interaction deficits. Thus, Tanaka et al. (2003) observed chronic administration of phencyclidine, an antagonist at N-methyl-D-aspartate (NMDA) receptors, impaired social interaction behavior, and reduced the density of AVP-V1a receptor binding sites in several brain regions, including the lateral septum in rats (Figure 1). Accordingly, 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 (Figure 2). These findings provide a basis for the ability of AVP analogues to ameliorate abnormalities of social interaction in animal models of schizophrenia, as discussed below.

Psychotropic/Antipsychotic Drugs in the Treatment of Impaired Social Behavior

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”, e.g. clozapine, melperone, risperidone, olanzapine, quetiapine, ziprasidone, and perospirone have been shown to be partially effective to treat negative symptoms and cognitive disturbances of schizophrenia [7,16-19] (see [20,21] for review).

Figure 1.Autoradiographic localization of V1a receptor binding sites in coronal sections of the brain of the vehicle group (A, B) and PCP group (C, D) of ratswith [125I]-Linear AVP antagonist.

Abbreviations: Acb, nucleus accumbens; LS, lateral septum; Ce, central amygdaloid nucleus; DG, dentate gyrus; VM, ventromedial thalamic nucleus; LH, lateral hypothalamic area.

Figure 2.Real-time quantitative PCR data. Each bar representsmean +SD. Values wereconsidered statistically significant whenP 0.05 versus Vehicle group.

Figure 3. The effect of 5-HT1A receptor agonist (8-OH-DPAT) on social interaction. The number of animals in each group is 16. Two-way ANOVA shows the effect of MK-801 [F1,60=14.1; p<0.001] and an interaction between the low dose of 8-OH-DPAT and MK-801 [F1,60=6.7;p<0.05].The Newman-Keuls testshows that the acute administration of MK-801 (0.1 mg/kg) decreases the social contact (***p<0.001). The acute application of the low dose of 8-OH-DPATblocks the effect of MK-801 (## p<0.01).

Two-way ANOVA shows the effect of MK-801 [F1,60=35.3; p<0.001] and an interaction between the high dose of 8-OH-DPAT and MK-801 [F1,60=8.4;p<0.01].The Newman-Keuls testshows that the acute administration of MK-801 (0.1 mg/kg) and the high dose of 8-OH-DPATdecreases the social contact (**p<0.01; ***p<0.001).

Specifically, psychotropic drugs acting on monoamine receptors, such as 5-HT1A agonists, have been shown to improve social behavior in animals [19,22,23].For example, Bubenikova-Valesova et al. (2008) investigated the effect of the 5-HT1Afull agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on social interaction deficits in rats acutely administered MK-801 (0.1 mg/kg), and found low (0.025 mg/kg) but not high (1 mg/day) dose 8-OH-DPATimproved MK-801-induced disruption of social behavior (Figure 3). These results are consistent with the concept that optimized stimulation of 5-HT1Areceptors is required to maximize the treatment benefitswith regard to some aspects of cognition and social abilities [23-26].

The Neuropeptidergic System as a Therapeutic Target For Social Interaction Deficits in Schizophrenia

As discussed above, the AVP system has been indicated as a therapeutic target for social interaction deficits in schizophrenia. Accordingly, we reported that NC-1900, an AVP analogue and agonist at AVP-V1a receptors, ameliorates social interaction deficits in rats chronically treated with MK-801 [13]. This result from an animal model of schizophrenia is consistent with our earlier observation [14] that chronic administration of the NMDA antagonist phencyclidine reduces the density of V1a receptor binding sites in several brain regions, including the lateral septum, in rats showing social interaction deficits. These findings from our laboratory are in concert with Bielsky et al (2005)[12] 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 [13]. Oxytocin, anotherneuropeptide, also has been suggested to play a key role in the regulation of social behavior in mammals, including humans [27-29].

Conclusion

Although several issues await to be addressed before the neurobiology of social behavior in rodents can be generalized to humans [15], it is reasonable to consider that further research into the serotonergic and neuropeptidergic system, or the interaction of the above, will facilitate the development of therapeutic tools targeting disturbances of social interaction in patients with schizophrenia or other psychiatric disorders.

Acknowledgment

The authors declare no conflict of interest for this work.

References

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[1]Corresponding author:Tomiki Sumiyoshi, M.D., Ph.D.Department of NeuropsychiatryUniversity of Toyama Graduate School of Medicine and Pharmaceutical Sciences2630 Sugitani, Toyama930-0194 JapanPhone: +81-76-434-7321(7323)Fax: +81-76-434-5030E-mail: .