Age-dependent effects of (+)-MK801 treatment on glutamate release and metabolism in the rat medial prefrontal cortex

Abstract

NMDAR antagonist treatments in adolescent/young adult rodents are associated with augmented glutamate (Glu) release and perturbed Glu/glutamine (Gln) metabolism in the medial prefrontal cortex (mPFC) resembling those found in first-episode schizophrenia. Few studies, however, investigated NMDAR antagonist-induced changes in the adult mPFC and whether there is an age-dependence to this end. In this study, the effects of acute/repeated (+)-MK801 treatment on Glu release/metabolism were measured in the mPFC of male adolescent (postnatal day 30) and adult (14 weeks) rats. Acute (+)-MK801 treatment at 0.5 mg/kg body weight induced an approximately 4-fold increase of extracellular Glu concentration in the adolescent rats, and repeated treatment for 6 consecutive days significantly increased the levels of Glu + Gln (Glx) and glial metabolites 7 days after the last dose. Histologically (+)-MK801 treatments induced reactive astrocytosis and elevated oxidative stress in the mPFC of adolescent rats, without causing evident neuronal degeneration in the region. All (+)-MK801-induced changes observed in the mPFC of adolescent rats were not present or evident in the adult rats, suggesting that the treatments might have caused less disinhibition in the adult mPFC than in the adolescent mPFC. In conclusion, the effects of (+)-MK801 treatments on the Glu release/metabolism in the mPFC were found to be age-dependent; and the adult mPFC is likely equipped with more robust neurobiological mechanisms to preserve excitatory-inhibitory balance in response to NMDAR hypofunction.