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

Abstract

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.

Atomoxetine Increases Extracellular Levels of Norepinephrine and Dopamine in Prefrontal Cortex of Rat A Potential Mechanism for Efficacy in Attention Deficit/Hyperactivity Disorder

“…Reboxetine increased NE EX (Sacchetti et al 1999) and DA EX in the PFC to similar levels and to about the same magnitude as found with atomoxetine, consistent with previous reports (Linnèr et al 2001). In the PFC, methylphenidate caused large increases in NE EX and DA EX , but the increases were of short duration in agreement with previous studies (During et al 1992), and consistent with a short duration of action in humans.…”

Effects of the Selective Norepinephrine Reuptake Inhibitor Reboxetine on Norepinephrine and Serotonin Transmission in the Rat Hippocampus

“…These findings are also consistent with the results of microdialysis studies showing that acute reboxetine administration (15 mg/ kg, i.p.) produces an increased level of NE in the dialysates in the frontal cortex and dorsal hippocampus without altering that of 5-HT in the striatum (Sacchetti et al 1999). When considered together with biochemical binding data on the transporter (Wong et al 2000), such results confirm that acutely administered reboxetine selectively blocks the NE reuptake transporter in vivo without altering the function of the 5-HT reuptake transporter.…”

“…In conclusion, it has been shown that NE availability in the hippocampus is enhanced by reboxetine treatment via blockade of the NE transporter (Sacchetti et al 1999). Since both the acute and long-term administration of reboxetine produced the same degree of enhancement of NE in the extracellular milieu in the same experiments in the hippocampus, the relationship between the delayed clinical response to reboxetine with respect to hippocampal function is not clear.…”

“…Previous studies have shown that antidepressant treatments which increase the concentration of NE in the synaptic cleft desensitize the terminal ␣ 2 -adrenergic heteroreceptors located on 5-HT fibers in the dorsal hippocampus after long-term administration (Mongeau et al 1994a,b;Yoshioka et al 1995), however, leaving ␣ 2 -adrenergic autoreceptors normosensitive (Szabo and Blier 2001;Sacchetti et al 1999;Mateo et al 1998;Mongeau et al 1994a;Moret and Briley 1994). In control (n ϭ 9 rats) and 21-day reboxetine (2.5 mg/kg/day; n ϭ 7) treated rats, 1 Hz electrical stimulations of the ascending 5-HT pathway on the firing activity of dorsal hippocampus CA 3 pyramidal neurons produced similar suppressions of firing which did not statistically differ when compared to each other (p ϭ .27; Figure 7).…”

“…It is not currently known whether atrophy in the hippocampus represents a depressive state or trait (Sheline et al 1999;Bremner et al 2000), however antidepressant treatments have been shown to induce adaptive changes in this structure (see Malberg et al 2000 for review). The effect of reboxetine on NE transmission in this manuscript was not directly assessed as Sacchetti et al (1999) already concluded that acute and sustained treatment with reboxetine leads to similar increases in extracellular levels of NE without producing any adaptive changes in ␣ 2 -autoreceptor sensitivity in the hippocampus. However, given the importance of receptors on 5-HT terminals in the hippocampus, which become altered after long-term antidepressant treatment, ␣ -adrenergic heteroreceptor and 5-HT 1B autoreceptor function was assessed using electrical stimulation of the afferent 5-HT bundle to this postsynaptic structure.…”