Risperidone Reverses the Downregulation of BDNF in Hippocampal Neurons and MK801-Induced Cognitive Impairment in Rats

MK-801, also known as dizocilpine, is a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. Our previous study showed that brain-derived neurotrophic factor (BDNF) signaling was upregulated in cultured hippocampal astrocytes in response to MK-801. However, dysfunctional NMDA receptors are mainly expressed in neurons. The effects of MK-801 on neuron-derived BDNF expression and of risperidone on MK-801-induced cognitive impairment and changes in BDNF expression are unclear. To address this issue, we examined BDNF expression in the hippocampus of rats that received repeated injections of MK-801 (0.5 mg/kg body weight for 6 days) and in primary cultured hippocampal neurons incubated with 20 μM MK-801 for 24 h. BDNF expression and cognitive function were also evaluated in rats receiving intraperitoneal injections of risperidone (1 mg/kg body weight) once daily for 7 days and in hippocampal neurons incubated with 10 μM risperidone following MK801 treatment. MK-801 treatment decreased BDNF expression in the rat hippocampus as well as the expression and secretion of BDNF in hippocampal neurons in vitro. However, risperidone reversed the effects of MK801 on BDNF level and improved cognitive function in rats treated with MK801. These findings suggest that risperidone may alleviate cognitive impairment caused by MK801 via upregulation of BNDF signaling in the hippocampus.