Tadasu Matsuoka

NC-1900, an arginine-vasopressin analogue, ameliorates social behavior deficits and hyperlocomotion in MK-801-treated rats: therapeutic implications for schizophrenia.

We previously reported that chronic administration of N-methyl-D-aspartate (NMDA) antagonists reduced the density of vasopressin V1a receptors in several brain regions in rats that demonstrated social interaction deficits and increased locomotor activity. These observations indicate the ability of arginine-vasopressin (AVP), or its analogues, to modulate behavioral abnormalities associated with blockade of NMDA receptors. The present study was performed to investigate the effect of NC-1900, an AVP analogue, on social behavior and locomotor activity in rats treated with MK-801, a non-competitive NMDA receptor antagonist. Male Wistar rats were administered MK-801 (0.13 mg/kg/day ip) or saline for 14 days. Social behavior and locomotor activity were measured 45 min after the injection of NC-1900 (10 ng/kg sc) or saline together with the last MK-801 or vehicle administration. Social interaction was quantified by an automated video-tracking system, and stereotyped behavior and ataxia were manually measured. Acute administration of NC-1900 partially reversed MK-801-induced hyperlocomotion and deficits in social interaction, while NC-1900 itself did not affect these behavioral measures in animals chronically treated with vehicle saline. These results suggest that the central AVP system may interact with glutamatergic and dopaminergic transmissions, and indicate potential therapeutic effects of AVP analogues on positive and negative symptoms of schizophrenia.

Neonatal exposure to MK-801, an N-methyl-d-aspartate receptor antagonist, enhances methamphetamine-induced locomotion and disrupts sensorimotor gating in pre- and postpubertal rats

Administration of non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. phencyclidine, MK-801) has been shown to elicit behavioral abnormalities related to symptoms of schizophrenia, such as spontaneous locomotor activity and impaired sensorimotor gating, as represented by deficits of prepulse inhibition (PPI). We sought to determine whether transient blockade of NMDA receptors at the neonatal stage would produce dopamine supersensitivity around puberty, as manifested by these behavioral measures. For this purpose, we examined methamphetamine (MAP; 1.0mg/kg, i.p.)-induced locomotor activity and PPI in pre- (postnatal day; PD 36-38) or post- (PD 64-66) puberty in rats administered MK-801 (0.2mg/kg/day, s.c.) between PD 7 and PD 10. Neonatal MK-801 treatment augmented MAP-induced hyperlocomotion especially in the early adulthood, whereas spontaneous locomotor activity and rearing were not changed. MK-801 administration also disrupted PPI without affecting startle amplitudes around puberty. These findings suggest that transient exposure to MK-801 in the neonatal stage causes exaggerated dopamine transmission and cognitive deficits, particularly in the post-puberty stage.

Enhancement of lactate metabolism in the basolateral amygdala by physical and psychological stress: Role of benzodiazepine receptors

Lactate is considered to play a significant role in energy metabolism and reflect neural activity in the brain. Using in vivo microdialysis technique, we measured extracellular lactate concentrations in the basolateral amygdaloid nucleus (BLA) of rats under electric footshock or psychological stress. We also attempted to determine whether the stress-induced changes of extracellular lactate concentrations in the BLA are attenuated by diazepam, an agonist at benzodiazepine receptors, and whether FG7142, an inverse agonist at benzodiazepine receptors, have a facilitative effect on energy metabolism in the BLA. Both footshock and psychological stress led to an increase in extracellular lactate concentrations in the BLA. Similar increment of extracellular lactate levels was observed by administration of FG7142. Pretreatment with diazepam attenuated the ability of FG7142, as well as physical or psychological burden, to increase lactate levels in the BLA. These results indicate that a variety of stressors enhances energy metabolism in the BLA, and suggest that some stress-induced changes in energy metabolism are regulated by benzodiazepine receptors.

T-817MA, a novel neurotrophic agent, ameliorates loss of GABAergic parvalbumin-positive neurons and sensorimotor gating deficits in rats transiently exposed to MK-801 in the neonatal period

T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate] is a newly synthesized neuroprotective agent for the treatment of psychiatric disorders characterized by cognitive disturbances, such as Alzheimers disease. Cognitive impairment has also been suggested to be a cardinal feature of schizophrenia. We sought to determine whether T-817MA would ameliorate sensorimotor gating deficits and loss of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) neurons in the brain of rats transiently exposed to MK-801, an N-methyl-d-aspartate receptor blocker, in the neonatal stage, as an animal model of schizophrenia. Prepulse inhibition (PPI) was examined in rats treated neonatally with MK-801 (postnatal day; PD 7-10, 0.2 mg/kg/day, s.c.) or vehicle at PD 35 and PD 63. The number of PV-positive GABAergic neurons in the medial prefrontal cortex (mPFC) and the hippocampus was measured after the behavioral assessments. T-817MA (10 or 20 mg/kg) or vehicle was administered for 14 days (on PD 49-62). Administration of T-817MA at 20 mg/kg, but not 10 mg/kg, ameliorated PPI deficits and completely reversed the decrease in the number of PV-positive GABAergic neurons in rats given MK-801. These results indicate that T-817MA may provide a novel therapeutic approach for the treatment of cognitive deficits of schizophrenia.

Novel G423S mutation of human α7 nicotinic receptor promotes agonist-induced desensitization by a protein kinase C-dependent mechanism

The α7 nicotinic acetylcholine receptor subunit (CHRNA7) gene harbors a high degree of polymorphism. In this study, we found a novel variant (1267 G to A) in exon 10 of the CHRNA7 gene in a Japanese population. This variant results in glycine-to-serine substitution at position 423 (G423S) located in the large cytoplasmic loop of the protein. To clarify the possibility that the G423S mutation alters the pharmacological properties of α7 receptors, acetylcholine (ACh)-elicited current through α7-G423S mutant receptors expressed in Xenopus laevis oocytes was measured using the two-electrode voltage-clamp technique. We found that the current elicited by ACh (1 mM, 5 s) through α7-G423S receptors, but not through α7 receptors, was significantly decreased by treatment with a protein kinase C activator, phorbol-12-myristate-13-acetate (PMA, 10–30 nM). In addition, PMA (10 nM) selectively promoted a progressive decrease in α7-G423S current induced by repetitive application of ACh pulses (1 mM, 0.1 s, 0.17–0.33 Hz) compared with α7 current. PMA also enhanced the inactivation of α7-G423S mutant receptors induced by a prolonged application of choline (30 μM) without affecting α7 receptor responses. Western blot analysis showed that the treatment with PMA (30 nM) increased the serine phosphorylation level of the α7-G423S mutant receptors but not that of the wild-type receptors. These findings demonstrate that the G423S mutation promotes receptor desensitization by a protein kinase C-dependent mechanism. Thus, we provide the first evidence that a variant in the human CHRNA7 gene alters the function of α7 nicotinic receptors.

Effect of transient blockade of N-methyl-D-aspartate receptors at neonatal stage on stress-induced lactate metabolism in the medial prefrontal cortex of adult rats: Role of 5-HT1A receptor agonism

Decreased activity of the medial prefrontal cortex (mPFC) has been considered a basis for core symptoms of schizophrenia, an illness associated with a neurodevelopmental origin. Evidence from preclinical and clinical studies indicates that serotonin (5‐HT)1A receptors play a crucial role in the energy metabolism of the mPFC. This study was undertaken to determine (1) if transient blockade of N‐methyl‐D‐aspartate receptors during the neonatal stage inhibit energy demands in response to stress, as measured by extracellular lactate concentrations, in the mPFC at the young adult stage, and (2) if tandospirone, a 5‐HT1A partial agonist, reverses the effect of the neonatal insult on energy metabolism. Male pups received MK‐801 (0.20 mg/kg) on postnatal days (PDs) 7–10. On PD 63, footshock stress‐induced lactate levels were measured using in vivo microdialysis technique. Tandospirone (0.1, 1.0, and 5.0 mg/kg) was administered once daily for 14 days before the measurement of lactate levels. Neonatal MK‐801 treatment suppressed footshock stress‐induced lactate production in the mPFC, but not caudate‐putamen, whereas basal lactate levels were not significantly changed in either brain region. The MK‐801‐induced suppression of footshock stress‐induced lactate production in the mPFC was attenuated by tandospirone at 1.0mg/kg/day, but not 0.1 or 5.0 mg/kg/day, which is an effect antagonized by coadministration of WAY‐100635, a selective 5‐HT1A antagonist. These results suggest a role for impaired lactate metabolism in some of the core symptoms of schizophrenia, for example, negative symptoms and cognitive deficits. The implications for the ability of 5‐HT1A agonism to ameliorate impaired lactate production in the mPFC of this animal model are discussed. Synapse, 2012.

Change in the expression of myelination/oligodendrocyte-related genes during puberty in the rat brain

Age-dependent changes of gene expression in the prefrontal cortex (PFC) of rats around the time of puberty were investigated by means of microarray and quantitative polymerase chain reaction (qPCR). About 127 and 138 genes were increased and decreased, respectively, in the PFC of rats at post-puberty (PD56) compared with those at pre-puberty (PD35). Functional analysis showed significant associations of these genes with aging, cellular development, and neuropsychological disorders. qPCR analysis confirmed down-regulation of seven genes related to myelination. As these genes have been reported to be diminished in the brain of patients with schizophrenia, the results of this study suggest an exaggerated maturation process may contribute to the pathogenesis of psychotic disorders.

T-817MA, but Not Haloperidol and Risperidone, Restores Parvalbumin-Positive γ-Aminobutyric Acid Neurons in the Prefrontal Cortex and Hippocampus of Rats Transiently Exposed to MK-801 at the Neonatal Period

The number of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) neurons is decreased in the brain of rats transiently exposed to MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in the neonatal stage (Uehara et al. (2012)). T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate] is a neuroprotective agent synthesized for the treatment of psychiatric disorders characterized by cognitive disturbances, such as dementia. We herein sought to determine whether T-817MA, haloperidol (HPD), or risperidone (RPD) would ameliorate the decrease in the number of PV-positive GABA neurons in the medial prefrontal cortex (mPFC) and hippocampus of the model animals. Rats were treated with MK-801 (0.2 mg/kg/day) or vehicle on postnatal days (PD) 7–10, and the number of PV-positive neurons in the mPFC and hippocampus were measured on PDs 63. T-817MA (20 mg/kg), HPD (1 mg/kg), or RPD (1 mg/kg) were administered during PDs 49–62. Fourteen-day administration of T-817MA reversed the decrease in the number of PV-positive neurons in the above brain regions of rats given MK-801, whereas HPD and RPD were ineffective. These results indicate that T-817MA provides a novel pharmacologic strategy to enhance cognitive function in patients with schizophrenia.

Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Toward the therapeutics of cognitive impairment of schizophrenia.

Rationale: Augmentation therapy with serotonin-1A (5-HT1A) receptor partial agonists has been suggested to improve cognitive impairment in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production. Objectives and methods: The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days) of tandospirone (0.05 or 5 mg/kg) on brain energy metabolism, as represented by extracellular lactate concentration (eLAC) in the medial prefrontal cortex (mPFC) of a rat model of schizophrenia. Results: Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot-shock stress (FS). Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment. Conclusions: These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism, based on brain energy metabolism, by which 5-HT1A agonism improve cognitive impairment of schizophrenia and related disorders.

Calcineurin A gamma and B gene expressions in the whole blood in Japanese patients with schizophrenia

Calcineurin (CaN) has been regarded as a candidate gene for vulnerability of schizophrenia. Although CaN gene expression has been investigated with postmortem brain specimens or in association studies, little information is available about CaN gene expression levels in peripheral sources. We obtained whole blood samples from 16 patients with schizophrenia and 16 controls, and total RNA was extracted. CaN A gamma and CaN B genes were analyzed by quantitative RT-PCR. In the patient group, expression levels of both genes were correlated with psychopathology, as measured by the Brief Psychiatric Rating Scale (BPRS), and neuroleptic dose. No significant differences in CaN A gamma or CaN B gene expression were observed between patients with schizophrenia and normal controls. Linear regression analysis revealed that the CaN A gamma gene expression level was associated with the BPRS score but not with neuroleptic dose. Neither of the clinical variables was associated with the CaN B gene expression level. The results of this study suggest that the CaN A gamma gene may be an effective predictor of the progression of psychosis. The effect of medications on expression of CaN genes requires further study.