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.
Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama 930-0194, Japan. uehara@med.u-toyama.ac.jp
Takashi
T
Uehara
Hiroko
H
Itoh
Tadasu
T
Matsuoka
Dan
D
Rujescu
Just
J
Genius
Tomonori
T
Seo
Tomiki
T
Sumiyoshi
D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D054833:Isoindoles / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D023421:Models, Animal; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D013315:Stress, Psychological / Q000378:metabolism*
D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D058825:Serotonin 5-HT1 Receptor Agonists; C055267:tandospirone; D019344:Lactic Acid; D016291:Dizocilpine Maleate