1 The e ect of reboxetine, a novel antidepressant drug that potently and selectively inhibits neuronal noradrenaline (NA) uptake, on brain extracellular monoamines was studied by microdialysis. 2 Fifteen mg kg 71 i.p. reboxetine raised extracellular NA in the frontal cortex (by 242%) and dorsal hippocampus (by 240%). 3 Idazoxan (1 mg kg 71 s.c.), given 60 min after 15 mg kg 71 reboxetine, markedly potentiated the e ect on extracellular NA in the frontal cortex (by 1580%) and dorsal hippocampus (by 1360%), but had no e ect by itself. 4 Twenty-four hours after the last injection of a chronic schedule (15 mg kg 71 i.p. once daily for 14 days) reboxetine had no e ect on basal extracellular concentrations of NA in the dorsal hippocampus and a challenge dose of reboxetine (15 mg kg 71 ) raised extracellular NA similarly in rats treated chronically with reboxetine (by 353%) and saline (by 425%). 5 Ten and 20 mg kg 71 i.p. clonidine dose-dependently reduced hippocampal extracellular NA similarly in rats given chronic reboxetine (by 32% and 57%) and saline (by 42% and 56%). 6 Extracellular concentrations of dopamine and 5-HT in the striatum were similar in rats treated chronically with reboxetine and saline. A challenge dose of reboxetine (15 mg kg 71 ) had no e ect on striatal extracellular dopamine and slightly increased striatal extracellular 5-HT to a similar extent in rats treated chronically with reboxetine (by 137%) and saline (by 142%). 7 The results suggest that combining reboxetine with an a 2 -adrenoceptor antagonist may facilitate its antidepressant activity. Repeated treatment con®rmed that reboxetine is fairly selective for the noradrenergic system but provided no evidence of adaptive changes in that system that could facilitate its e ect on extracellular NA.
1 This study investigated the e ect of acute (2 days) and chronic (14 days) treatment with a selective inhibitor of noradrenaline uptake, reboxetine (10 mg kg 71 day 71 ) by osmotic pumps, on extracellular noradrenaline and the sensitivity of a 2 -adrenoceptors in the prefrontal cortex of rats.2 The e ect of continuous infusion of reboxetine for 14 days on cortical extracellular noradrenaline was signi®cantly 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 37.9+17.8 and 37.1+7.7 ng g 71 , respectively. 4 Reboxetine infused for 2 and 14 days signi®cantly increased extracellular dopamine in the prefrontal cortex, to a similar extent (257 and 342% of vehicle levels, respectively), whereas extracellular 5-HT was not modi®ed by either treatment. 5 Clonidine (10 and 30 mg kg 71 i.p.) reduced cortical extracellular noradrenaline similarly in animals treated with reboxetine or vehicle for 2 days whereas the e ects in rats infused with reboxetine for 14 days were markedly less than in vehicle-treated animals. 6 Clonidine (0.05 and 0.2 mM), 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 e ect on extracellular noradrenaline in the prefrontal cortex was greater after chronic treatment and could be associated with desensitization of terminal a 2 -adrenoceptors that normally serve to inhibit noradrenaline release.
1 Using in vivo intracerebral microdialysis in conscious, freely moving rats, we examined the effect of flibanserin, a potential antidepressant drug with high affinity for human 5-HT 1A receptors and four -50-fold lower affinity for 5-HT 2A and D 4 receptors, on basal extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA) and noradrenaline (NA) in selected regions of the rat brain. 2 Flibanserin at 3 and 10 mg kg À1 significantly reduced extracellular 5-HT in the prefrontal cortex (by 30 and 45%) and dorsal raphe (35 and 44%), but had no effect on extracellular 5-HT in the ventral hippocampus. The 3 and 10 mg kg À1 doses raised extracellular NA to a similar extent in the prefrontal cortex (47 and 50%). In all, 10 mg kg À1 raised extracellular DA in the prefrontal cortex (63%) whereas 3 mg kg À1 had no significant effect. 3 Pretreatment with the selective 5-HT 1A receptor antagonist WAY100,635 (0.3 mg kg
À1) 30 min before 10 mg kg À1 flibanserin completely antagonized the latter's effects on extracellular 5-HT, DA and NA in the prefrontal cortex. WAY100,635 by itself had no effect on cortical extracellular monoamines. 4 The results show that the stimulation of 5-HT 1A receptors plays a major role in the effect of flibanserin on brain extracellular 5-HT, DA and NA.
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