Effects of acute and chronic administration of MCI-225, a new selective noradrenaline reuptake inhibitor with 5-HT3 receptor blocking action, on extracellular noradrenaline levels in the hypothalamus of stressed rats

In the present study, we investigated the effects of acute and chronic syst emic administration of MCI-225 (4-(2-fluorophenyl)-6-methyl-2-(1-piperaziny l)thieno[2,3-d]pyrimidine monohydrate hydrochloride), a newly-developed sel ective noradrenaline (NA) reuptake inhibitor with 5-HT3-receptor-blocking a ction, on extracellular NA levels in the hypothalamus of stressed and non-s tressed rats by utilizing intracerebral microdialysis. Acute administration of MCI-225 (3 and 10 mg/kg, p.o.) significantly and dose-dependently incre ased extracellular NA levels in the hypothalamus in non-stressed rats. Foot shock for 20 min also significantly increased NA levels in the hypothalamus of both groups of rats pretreated with vehicle and MCI-225. Although chron ic administration of MCI-225 (3 or 10 mg/kg, p.o. for 14 days) did not alte r the basal extracellular NA levels in the hypothalamus, the stress-induced increases in extracellular NA levels were significantly lower in rats chro nically treated with MCI-225 (10 mg/kg) than those of rats pretreated with vehicle for the same period. The increase in extracellular NA levels induce d by MCI-225 challenge (3 or 10 mg/kg, p.o.) were not different between rat s chronically treated with MCI-225 or vehicle. These results suggest that M CI-225 enhances extracellular NA levels in the hypothalamus in both non-str essed and stressed rats by inhibiting NA uptake and that chronic systemic a dministration of MCI-225 did not alter basal extracellular NA levels, but r educed the increase in NA release caused by footshock stress. These data su ggest the possibility that MCI-225 might possess anxiolytic and/or antidepr essant properties.