Studies on the acute and chronic effects of reboxetine on extracellular noradrenaline and other monoamines in the rat brain

Abstract

1 The effect 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-1 i.p. reboxetine raised extracellular NA in the frontal cortex (by 242%) and dorsal hippocampus (by 240%). 3 Idazoxan (1 mg kg-1 s.c.), given 60 min after 15 mg kg-1 reboxetine, markedly potentiated the effect on extracellular NA in the frontal cortex (by 1580%) and dorsal hippocampus (by 1360%), but had no effect by itself. 4 Twenty-four hours after the last injection of a chronic schedule (15 mg kg-1 i.p. once daily for 14 days) reboxetine had no effect on basal extracellular concentrations of NA in the dorsal hippocampus and a challenge dose of reboxetine (15 mg kg-1) raised extracellular NA similarly in rats treated chronically with reboxetine (by 353%) and saline (by 425%). 5 Ten and 20 microg kg-1 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-1) had no effect 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 alpha2-adrenoceptor antagonist may facilitate its antidepressant activity. Repeated treatment confirmed that reboxetine is fairly selective for the noradrenergic system but provided no evidence of adaptive changes in that system that could facilitate its effect on extracellular NA.

Figure 1

Extracellular concentrations of NA in the dorsal hippocampus of rats given saline (Sal+Sal), 15 mg kg⁻¹ reboxetine (Reb+Sal), saline+1 mg kg⁻¹ idazoxan (Sal+IDZ) and reboxetine+idazoxan (Reb+IDZ). Inset: AUC calculated from 0–180 min. Each group is the mean±s.e.mean of 6–7 rats. ^*P<0.05 vs Sal+Sal; °P<0.05 vs Reb+Sal; #Fint. P<0.05 (two-way ANOVA). The arrows indicate drug injection.

Figure 2

Extracellular concentrations of NA in the frontal cortex of rats given saline (Sal+Sal), 15 mg kg⁻¹ reboxetine (Reb+Sal), saline+1 mg kg⁻¹ idazoxan (Sal+IDZ) and reboxetine+idazoxan (Reb+IDZ). Inset: AUC calculated from 0–180 min. Each group is the mean±s.e.mean of 6–7 rats. ^*P<0.05 vs Sal+Sal; °P<0.05 vs Reb+Sal; #Fint. P<0.05 (two-way ANOVA). The arrows indicate drug injection.

Figure 3

Effect of 15 mg kg⁻¹ i.p. reboxetine on extracellular NA in the dorsal hippocampus of rats given saline or 15 mg kg⁻¹ reboxetine once daily for 14 days. Each group is the mean±s.e.mean of 6–7 rats. ^*P<0.05 vs respective basal values (time 0). The arrow indicates drug injection.

Figure 4

Effect of 10 (a) and 20 (b) μg kg⁻¹ i.p. clonidine on extracellular NA in the dorsal hippocampus of rats given saline or 15 mg kg⁻¹ reboxetine once daily for 14 days. Each group is the mean±s.e.mean of 5–6 rats. ^*P<.05 vs respective basal values (time 0). The arrow indicates drug injection.

Figure 5

Effect of 15 mg kg⁻¹ i.p. reboxetine on extracellular DA (a) and 5-HT (b) in the striatum of rats given saline or 15 mg kg⁻¹ reboxetine once daily for 14 days. Each group is the mean±s.e.mean of 6–8 rats. ^*P<0.05 vs respective basal values (time 0). The arrow indicates drug injection.