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.

Takashi Uehara,Tadasu Matsuoka,Tomiki Sumiyoshi

doi:10.3389/fnbeh.2014.00291

Abstract

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.

Highlights

Disturbances of cognitive function, evaluated by psychological and neurophysiological methods, have been shown to predict social outcome in patients with schizophrenia (Meltzer and McGurk, 1999; McGurk and Meltzer, 2000)
Four-day treatment with MK-801, an N-methyl-D-asparate receptor (NMDA-R) antagonist, prolonged extracellular lactate concentration (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. These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the medial prefrontal cortex (mPFC) due to blockade of NMDA receptors

Summary

Introduction

Disturbances of cognitive function, evaluated by psychological and neurophysiological methods, have been shown to predict social outcome in patients with schizophrenia (Meltzer and McGurk, 1999; McGurk and Meltzer, 2000). It is reported that adjunctive treatment with selective 5-HT1A receptor (partial) agonists, e.g., tandospirone or buspirone, was associated with improvements in some types of cognitive function in patients with schizophrenia (Sumiyoshi et al, 2001b, 2007; Sumiyoshi and Higuchi, 2013). These observations provide the basis for the ability of 5-HT1A receptor stimulation to enhance cognition, a therapeutic approach that have promoted the development of novel antipsychotic drugs (Sumiyoshi, 2013; Sumiyoshi et al, 2013). Numerous studies reported that NMDA-R antagonists, such as phencyclidine (PCP), MK-801 and ketamine, produce hyperlocomotion, stereotypy, information processing deficits, impairments of cognitive functions and social interactions, behavioral changes reminiscent of symptoms of schizophrenia (Breese et al, 2002; Moghaddam and Jackson, 2003; Bubenikova-Valesova et al, 2008; Jones et al, 2011)

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Conclusion