Chronic treatment with reboxetine by osmotic pumps facilitates its effect on extracellular noradrenaline and may desensitize alpha(2)-adrenoceptors in the prefrontal cortex

1 This study investigated the effect of acute (2 days) and chronic (14 days ) treatment with a selective inhibitor of noradrenaline uptake, reboxetine (10 mg kg(-1) day(-1)) by osmotic pumps, on extracellular noradrenaline and the sensitivity of alpha (2)-adrenoceptors in the prefrontal cortex of rat s. 2 The effect of continuous infusion of reboxetine for 14 days on cortical e xtracellular noradrenaline was significantly higher (599% of vehicle levels ) than after 2 days (263% of vehicle levels). 3 Brain concentrations of reboxetine after 2 and 14 days of infusion were 3 7.9 +/- 17.8 and 37.1 +/- 7.7 ng g(-1), respectively. 4 Reboxetine infused for 2 and 14 days significantly increased extracellula r dopamine in the prefrontal cortex, to a similar extent (257 and 342% of v ehicle levels, respectively), whereas extracellular 5-HT was not modified b y either treatment. 5 Clonidine (10 and 30 mug kg(-1) i.p.) reduced cortical extracellular nora drenaline similarly in animals treated with reboxetine or vehicle for 2 day s whereas the effects in rats infused with reboxetine for 14 days were mark edly less than in vehicle-treated animals. 6 Clonidine (0.05 and 0.2 muM), infused through the dialysis probe into the prefrontal cortex, reduced cortical extracellular noradrenaline much less in rats treated with reboxetine for 14 days than in vehicle-treated animals . 7 Reboxetine's effect on extracellular noradrenaline in the prefrontal cort ex was greater after chronic treatment and could be associated with desensi tization of terminal alpha (2)-adrenoceptors that normally serve to inhibit noradrenaline release.