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

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.

Keywords: 5-HT1A; NMDA receptor; animal model; cognition; glutamate; lactate; microdialysis; schizophrenia.

Figure 1

Schematic representation of the experimental protocol for microdialysis experiments. Upper parts in each figure reveals drug treatment for 4 days and lower parts time course in the 4th day (experiment day).

Figure 2

Time course of the effect of 4 days treatment of MK-801 on the extracellular lactate concentrations (eLAC) in the medial prefrontal cortex. Rats were treated with saline (saline group, n = 6; open circle) or MK-801 (MK-801 group, n = 5; closed circle). Lactate levels in the dialysates are expressed as μmol/l calculated by a standard solution of 100 μmol/l lactate. Data are mean ± s.e.m. The arrow indicates the timing of the last injection. Asterisk showed p < 0.05 vs. saline group in each time point.

Figure 3

Effect of tandospirone on foot-shock stress-induced increment of the extracellular lactate concentrations (eLAC) in the medial prefrontal cortex in rats treated with (A) saline (saline-saline group, n = 5; MK-801-saline group, n = 5), (B) tandospirone 0.05 mg/kg (saline-low-T group, n = 5; MK-801-low-T group, n-5) and (C) 5.0 mg/kg tandospirone (saline-high-T group, n = 5; MK-801-high-T group, n = 5). Rats were simultaneously treated with saline (open circle) or MK-801 (closed circle), respectively. Lactate levels in the dialysates are expressed as μmol/l calculated by a standard solution of 100 μmol/l lactate. Data are mean ± s.e.m. The arrow indicates the timing of the last injection. Foot-shock is indicated by solid bars. Asterisk showed p < 0.05 vs. saline group in each time point.

Figure 4

Total increase of lactate after injection (from time 0 to time 110 min) calculated by sum of (each eLAC concentration—basal concentration of eLAC). Basal concentration of eLAC is the average of eLAC during the period preceding the last injection (four measurements performed every 5 min). Asterisk showed p < 0.05 between groups.