In: Handbook of Social Interactions in the 21st Century
ISBN 978-1-60692-860-8
Editor: A. T. Heatherton and V. A. Walcott, pp
.
© 2009 Nova Science Publishers, Inc.
Expert Commentary
SOCIAL INTERACTION DEFICITS IN SCHIZOPHRENIASPECTRUM DISORDERS AND PHARMACOLOGIC
INTERVENTION
Tomiki Sumiyoshi,11) 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.
1 Corresponding author:Tomiki Sumiyoshi, M.D., Ph.D.Department of NeuropsychiatryUniversity of Toyama
Graduate School of Medicine and Pharmaceutical Sciences 2630 Sugitani, Toyama 930-0194 Japan Phone:
+81-76-434-7321(7323) Fax: +81-76-434-5030 E-mail: tomikisumiyoshi840@hotmail.com.
2
Tomiki Sumiyoshi, Tadasu Matsuoka, Kodai Tanaka et al.
Several lines of recent research indicate some neuropeptides, such as argininevasopressin (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 debilitating neuropsychiatric disorder. Its
symptoms include positive (e.g., delusions, hallucinations, bizarre thoughts) and negative
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 of the
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
Social Interaction Deficits in Schizophrenia…
3
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 MK801, 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 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”, 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
Fig. 1 (see [20,21] for review).
schizophrenia [7,16-19]
A
B
C
D
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 rats with [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.
4
Tomiki Sumiyoshi, Tadasu Matsuoka, Kodai Tanaka et al.
Fig. 2
Figure 2. Real-time quantitative PCR data. Each bar represents mean + SD. Values were considered
statistically significant when P < 0.05 versus Vehicle group.
Fig. 3
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 test shows 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-DPAT blocks the effect of MK801 (## 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 test shows that the
acute administration of MK-801 (0.1 mg/kg) and the high dose of 8-OH-DPAT decreases the social
contact (**p<0.01; ***p<0.001).
Social Interaction Deficits in Schizophrenia…
5
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-HT1A full agonist 8hydroxy-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-DPAT improved MK-801-induced disruption of social behavior (Figure
3). These results are consistent with the concept that optimized stimulation of 5-HT1A
receptors is required to maximize the treatment benefits with 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,
another neuropeptide, 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.
6
Tomiki Sumiyoshi, Tadasu Matsuoka, Kodai Tanaka et al.
REFERENCES
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
Sumiyoshi, T., Kawasaki, Y., Suzuki, M., Higuchi, Y., and Kurachi, M. (2008).
Neurocognitive assessment and pharmacotherapy towards prevention of schizophrenia:
What can we learn from first episode psychosis. Clin Psychopharmacol Neurosci, 6,
57-64.
Kaneda, Y., Sumiyoshi, T., Keefe, R., Ishimoto, Y., Numata, S., and Ohmori, T. (2007).
Brief assessment of cognition in schizophrenia: validation of the Japanese version.
Psychiatry Clin Neurosci, 61, 602-609
Matsui, M., Sumiyoshi, T., Arai, H., Higuchi, Y., and Kurachi, M. (2008). Cognitive
functioning related to quality of life in schizophrenia. Prog Neuropsychopharmacol
Biol Psychiatry, 32, 280-287.
Erlenmeyer-Kimling, L., Rock, D., Roberts, S. A. and et al. (2000). Attention, memory,
and motor skills as childhood predictors of schizophrenia-related psychoses: the New
York High-Risk Project. Am J Psychiatry, 157, 1416-1422
Sumiyoshi, C., Sumiyoshi, T., Roy, A., Jayathilake, K., and Meltzer, H. Y. (2006).
Atypical antipsychotic drugs and organization of long-term semantic memory:
multidimensional scaling and cluster analyses of category fluency performance in
schizophrenia. Int J Neuropsychopharmacol, 9, 677-683.
Sumiyoshi, T., Matsui, M., Itoh, H. and et al. (2008). Essential polyunsaturated fatty
acids and social cognition in schizophrenia. Psychiatry Res, 157, 87-93
Sumiyoshi, T., Higuchi, Y., Ito, T. and et al. (in press). Effect of perospirone on P300
electrophysiological activity in schizophrenia: A three-dimensional analysis with
sLORETA. Psychiatry Res Neuroimag
Horrobin, D. F. (1998). The membrane phospholipid hypothesis as a biochemical basis
for the neurodevelopmental concept of schizophrenia. Schizophr Res, 30, 193-208
Chan, A. S., Chiu, H., Lam, L., Pang, A., and Chow, L. Y. (1999). A breakdown of
event schemas in patients with schizophrenia: an examination of their script for dining
at restaurants. Psychiatry Res, 87, 169-181.
Matsui, M., Sumiyoshi, T., Yuuki, H., Kato, K., and Kurachi, M. (2006). Impairment of
event schema in patients with schizophrenia: examination of script for shopping at
supermarket. Psychiatry Res, 143, 179-187.
Fries, A. B., Ziegler, T. E., Kurian, J. R., Jacoris, S., and Pollak, S. D. (2005). Early
experience in humans is associated with changes in neuropeptides critical for regulating
social behavior. Proc Natl Acad Sci U S A, 102, 17237-17240
Bielsky, I. F., Hu, S. B., Ren, X., Terwilliger, E. F., and Young, L. J. (2005). The V1a
vasopressin receptor is necessary and sufficient for normal social recognition: a gene
replacement study. Neuron, 47, 503-513.
Matsuoka, T., Sumiyoshi, T., Tanaka, K. and et al. (2005). NC-1900, an argininevasopressin analogue, ameliorates social behavior deficits and hyperlocomotion in MK801-treated rats: therapeutic implications for schizophrenia. Brain Res, 1053, 131-136.
Tanaka, K., Suzuki, M., Sumiyoshi, T., Murata, M., Tsunoda, M., and Kurachi, M.
(2003). Subchronic phencyclidine administration alters central vasopressin receptor
binding and social interaction in the rat. Brain Res, 992, 239-245
Social Interaction Deficits in Schizophrenia…
7
[15] Storm, E. E., and Tecott, L. H. (2005). Social circuits: peptidergic regulation of
mammalian social behavior. Neuron, 47(4), 483-486
[16] McGurk, S. R. (1999). The effect of clozapine on cognitive functioning in
schizophrenia. J. Clin. Psychiatry, 60 (suppl 12), 24-29.
[17] Sumiyoshi, T., Jayathilake, K., and Meltzer, H. Y. (2003). The effect of melperone, an
atypical antipsychotic drug, on cognitive function in schizophrenia. Schizophr Res, 59,
7-16
[18] Woodward, N. D., Purdon, S. E., Meltzer, H. Y., and Zald, D. H. (2005). A metaanalysis of neuropsychological change to clozapine, olanzapine, quetiapine, and
risperidone in schizophrenia. Int J Neuropsychopharmacol, 8, 457-472
[19] Bubenikova-Valesova, V., Votava, M., Palenicek, J., Horacek, J., and Hoschl, C.
(2008). Effect of serotonin-1A receptors on behavioral changes in animal model of
schizophrenia-like behavior. In: 16th European Congress of Psychiatry. Nice, France
[20] Horacek, J., Bubenikova-Valesova, V., Kopecek, M. and et al. (2006). Mechanism of
action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS
Drugs, 20, 389-409
[21] Sumiyoshi, T., Kawasaki, Y., Suzuki, M., Higuchi, Y., and Kurachi, M. (2008).
Neurocognitive assessment and pharmacotherapy towards prevention of schizophrenia:
What can we learn from first episode psychosis? Clin Psychopharmacol Neurosci, 6,
57-64
[22] Snigdha, S., and Neill, J. C. (2008). Improvement of phencyclidine-induced social
behaviour deficits in rats: involvement of 5-HT1A receptors. Behav Brain Res, 191, 2631
[23] Depoortere, R., Auclair, A. L., Bardin, L. and et al. (2007). F15063, a compound with
D2/D3 antagonist, 5-HT1A agonist and D4 partial agonist properties. III. Activity in
models of cognition and negative symptoms. Br J Pharmacol, 151, 266-277
[24] Bruins Slot, L. A., Kleven, M. S., and Newman-Tancredi, A. (2005). Effects of novel
antipsychotics with mixed D(2) antagonist/5-HT(1A) agonist properties on PCPinduced social interaction deficits in the rat. Neuropharmacology, 49, 996-1006.
[25] Bubenikova-Valesova, V., Votava, M., Palenicek, T., and Horacek, J. (2007). The
opposite effect of a low and a high dose of serotonin-1A agonist on behavior induced
by MK-801. Neuropharmacology 52, 1071-8.
[26] Sumiyoshi, T., Higuchi, Y., Matsui, M. and et al. (2007). Effective adjunctive use of
tandospirone with perospirone for enhancing verbal memory and quality of life in
schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry, 31, 965-967.
[27] Lee, P. R., Brady, D. L., Shapiro, R. A., Dorsa, D. M., and Koenig, J. I. (2005). Social
interaction deficits caused by chronic phencyclidine administration are reversed by
oxytocin. Neuropsychopharmacology, 30, 1883-1894
[28] Lee, P. R., Brady, D. L., Shapiro, R. A., Dorsa, D. M., and Koenig, J. I. (2007). Prenatal
stress generates deficits in rat social behavior: Reversal by oxytocin. Brain Res, 1156,
152-167
[29] Jin, D., Liu, H. X., Hirai, H. and et al. (2007). CD38 is critical for social behaviour by
regulating oxytocin secretion. Nature, 446, 41-45.