Affinities of venlafaxine and various reuptake inhibitors for the serotonin and norepinephrine transporters

Abstract

In vitro radioligand binding studies were carried out in rat brain membranes to assess the affinity of various reuptake inhibitors for the serotonin (5-hydroxytryptamine, 5-HT) and the norepinephrine transporters using the selective ligands [${}^3\text{H}$]cyanoimipramine and [${}^3\text{H}$]nisoxetine, respectively. The selective 5-HT reuptake inhibitors paroxetine, indalpine and fluvoxamine displayed a high affinity for the 5-HT transporter, whereas the norepinephrine reuptake inhibitor desipramine had a high affinity for the norepinephrine transporter. Duloxetine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed a high affinity for both the 5-HT and the norepinephrine transporters. Interestingly, venlafaxine, a dual 5-HT and norepinephrine reuptake inhibitor, displayed only a moderate affinity for the 5-HT transporter (K_i=74 nM) and a very low affinity for the norepinephrine transporter (K_i=1.26 μM). The relatively low affinities of venlafaxine contrast with its potent in vivo 5-HT and norepinephrine reuptake blocking properties. These results raise the possibility that the in vivo effects on the 5-HT and norepinephrine reuptake observed with venlafaxine may not be mediated solely by its binding to the [${}^3\text{H}$]cyanoimipramine and [${}^3\text{H}$]nisoxetine binding sites.

Introduction

Several lines of evidence point towards the involvement of the serotonergic (5-hydroxytryptamine; 5-HT) and norepinephrine systems in the mechanism of action of antidepressant treatments (Blier and De Montigny, 1994). Hence, a new class of drugs known as dual 5-HT and norepinephrine reuptake inhibitors has been developed. For instance, venlafaxine blocks in vitro the synaptosomal uptake of both [${}^3\text{H}$]5-HT and [${}^3\text{H}$]norepinephrine (Muth et al., 1986; Bolden-Watson and Richelson, 1993). Clinical studies are now suggesting that not only venlafaxine displays antidepressant activity, but that it (i) would also be more efficacious than fluoxetine for the treatment of major depression (Dierick et al., 1996), (ii) would be effective in the treatment of resistant depression (Nierenberg et al., 1994; De Montigny et al., 1996) and, finally, (iii) would show an early onset of action (Rickels, 1991). However, while venlafaxine shows an appreciable potency for inhibiting both 5-HT and norepinephrine reuptakes in vivo (Béı̈que et al., 1996), its potency to block in vitro the uptake of these monoamines is relatively low when compared to other reuptake inhibitors such as paroxetine for 5-HT uptake or desipramine for norepinephrine uptake (Bolden-Watson and Richelson, 1993). This latter observation, combined with the potentially unique therapeutic profile of venlafaxine, thus underscores the importance of a more accurate understanding of its pharmacological actions.

The present study was thus undertaken to directly determine the affinities of venlafaxine for both the 5-HT and norepinephrine transporters. To this end, the selective radioligands [${}^3\text{H}$]cyanoimipramine and [${}^3\text{H}$]nisoxetine, that bind selectively to the 5-HT and norepinephrine transporters, respectively (Burkard, 1980; Dumbrille-Ross and Tang, 1983; Tejani-Butt et al., 1990), were used. In order to provide a direct within study comparison, the affinities for the 5-HT and norepinephrine transporters of other monoamine reuptake inhibitors have also been determined, as well as those of duloxetine, an antidepressant candidate, which is also a dual 5-HT and norepinephrine reuptake inhibitor (Wong et al., 1993; Kasamo et al., 1996).