Jpn. J. Pharmacol. 83 (1), 31-38 (2000)

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

Ying-Liang Wu^1,2, Masami Yoshida¹, Hiroyuki Emoto¹, Hideo Ishii¹, Kiminori Koga¹ and Masatoshi Tanaka^1,*


¹Departmentﾊof Pharmacology, Kurume University School of Medicine, Asahi-Machi 67, Kurume 830-0011, Japan
²Departmentﾊof Physiology, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, Liaoning 110015, China
*ﾊTo whom correspondence should be addressed.

Abstract: In the present study, we investigated the effects of acute and chronic systemic administration of MCI-225 (4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine monohydrate hydrochloride), a newly-developed selective noradrenaline (NA) reuptake inhibitor with 5-HT₃-receptor-blocking action, on extracellular NA levels in the hypothalamus of stressed and non-stressed rats by utilizing intracerebral microdialysis. Acute administration of MCI-225 (3 and 10ﾊmg/kg, p.o.) significantly and dose-dependently increased extracellular NA levels in the hypothalamus in non-stressed rats. Footshock for 20ﾊmin also significantly increased NA levels in the hypothalamus of both groups of rats pretreated with vehicle and MCI-225. Although chronic administration of MCI-225 (3 or 10ﾊmg/kg, p.o. for 14ﾊdays) did not alter the basal extracellular NA levels in the hypothalamus, the stress-induced increases in extracellular NA levels were significantly lower in rats chronically treated with MCI-225 (10ﾊmg/kg) than those of rats pretreated with vehicle for the same period. The increase in extracellular NA levels induced by MCI-225 challenge (3 or 10ﾊmg/kg, p.o.) were not different between rats chronically treated with MCI-225 or vehicle. These results suggest that MCI-225 enhances extracellular NA levels in the hypothalamus in both non-stressed and stressed rats by inhibiting NA uptake and that chronic systemic administration of MCI-225 did not alter basal extracellular NA levels, but reduced the increase in NA release caused by footshock stress. These data suggest the possibility that MCI-225 might possess anxiolytic and/or antidepressant properties.

Keywords: MCI-225, Footshock stress, Noradrenaline, Hypothalamus, Intracerebral microdialysis