D2 receptor-mediated miRNA-143 expression is associated with the effects of antipsychotic drugs on phencyclidine-induced schizophrenia-related locomotor hyperactivity and with Neuregulin-1 expression in mice

Abstract

Non-coding RNA molecules such as miRNAs have emerged as critical regulators of neuronal functions. The present study investigates a role for miRNA-143, a highly conserved miRNA, in locomotorhyperactivity induced bythe psychotomimetic phencyclidine (PCP), a non-selective antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor. Following acute PCP administration to mice, the content of miRNA-143 was reduced in plasma, prefrontal cortex (PFC) and hippocampus, reaching a minimum after 2 h. The antipsychotics haloperidol and clozapine attenuated hyperlocomotion and the decrease in miR-143 expression induced by PCP, as did the selective D2 dopamine receptor antagonist eticlopride but not the selective D1 antagonist SCH23390. To further confirm D2 receptor-mediated miRNA-143 expression, HT-22 neuronal cell line and primary cortical cultured neuronswere studied. Stimulation of D2 receptors with the selective D2 receptor agonist quinpirole decreased expression of miRNA-143 in a time-dependent manner. This inhibition was blocked by pretreatment with eticlopride, indicating that the D2 receptor directly regulates the expression of miRNA-143. We further demonstrated that miRNA-143 directly targeted to the 3' un-translated region of neuregulin-1 (NRG1) mRNA to reduce protein expression of NRG1 in HT-22 cells and that administration of the D2 receptor agonist quinpirole to mice enhanced expression of NRG1 in PFC. The present data provide the first evidence that D2 receptors are involved in the expression ofmiRNA-143 in association with antipsychotic drug action and the developmental regulator NRG1.

Keywords: D2 dopamine receptor; Neuregulin-1; Neurobehavioral abnormalities; Phencyclidine; Schizophrenia; miRNA-143.