dizocilpine-maleate and tandospirone

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.

Topics: Animals; Caudate Nucleus; Dizocilpine Maleate; Isoindoles; Lactic Acid; Male; Microdialysis; Models, Animal; Piperazines; Prefrontal Cortex; Putamen; Pyrimidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Stress, Psychological

Augmentation therapy with serotonin-1A receptor (5-HT1A) partial agonists has been suggested to ameliorate psychotic symptoms in patients with schizophrenia.. The objective of the present study was to examine the effect of repeated administration of tandospirone (0.05 and 5 mg/kg) on locomotor activity in a novel environment and on sensorimotor gating in rats treated with the N-methyl-D-aspartate receptor antagonist MK-801, which has been used in animal models of schizophrenia. Furthermore, we sought to determine whether the effect of tandospirone on these behavioural measures is blocked by WAY 100635 (0.3 mg/kg), a 5-HT1A receptor antagonist, and whether there is an interaction between haloperidol (0.1 mg/kg; a dopamine-D2 receptor antagonist) and tandospirone.. Tandospirone at 5 mg/kg, but not 0.05 mg/kg, decreased locomotor activity in saline or MK-801-treated rats, which were not affected by co-treatment with WAY 100635. Haloperidol decreased locomotion both in saline and MK-801-treated animals, and this effect was not evident in the latter group receiving the higher dose of tandospirone. Tandospirone (5 mg/kg)-induced disruption of sensorimotor gating in saline or MK-801-treated animals was reversed by WAY-100635, but not by haloperidol.. These findings suggest that behavioural changes induced by tandospirone are not fully blocked by 5-HT1A antagonists and that tandospirone (5 mg/kg) potentiates the effect of MK-801. Overall, these findings point to an interaction between NMDA and 5-HT(1A) receptors. Part of the effect of tandospirone on locomotor activity may be mediated by the actions of its active metabolites on other neurotransmitter systems.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Haloperidol; Isoindoles; Male; Motor Activity; Piperazines; Pyrimidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Schizophrenia; Sensory Gating; Serotonin Receptor Agonists