Search Results (4)

Monoamine transporters, including dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively), are important therapeutic targets due to their essential roles in the brain. To overcome the slow action of selective monoamine reuptake inhibitors, dual- or triple-acting inhibitors have been developed. Here, to examine whether combination treatments of selective reuptake inhibitors have synergistic effects, the pharmacological properties of DAT, NET, and SERT were investigated using the selective inhibitors of each transporter, which are vanoxerine, nisoxetine, and fluoxetine, respectively. Potencies were determined via fluorescence-based substrate uptake assays in the absence and presence of other inhibitors to test the multi-drug effects on individual transporters, resulting in antagonistic effects on DAT. In detail, fluoxetine resulted in a 1.6-fold increased IC₅₀ value of vanoxerine for DAT, and nisoxetine produced a more drastic increase in the IC₅₀ value by six folds. Furthermore, the effects of different inhibitors, specifically monovalent ions, were tested on DAT inhibition by vanoxerine. Interestingly, these ions also reduced vanoxerine potency in a similar manner. The homology models of DAT suggested a potential secondary inhibitor binding site that affects inhibition in an allosteric manner. These findings imply that the use of combination therapy with monoamine reuptake inhibitors should be approached cautiously, as antagonistic effects may occur. Full article

The estimated rate of treatment-resistant major depressive disorder (TRD) remains higher than 30%, even after the discovery of multiple classes of antidepressants in the last 7 decades. Toludesvenlafaxine (ansofaxine, LY03005, or LPM570065) is a first-in-class triple monoaminergic reuptake inhibitor (TRI) that has reached clinical use. The objective of this narrative review was to summarize clinical and preclinical evidence about the efficacy, tolerability, and safety of toludesvenlafaxine. Based on the results of 17 reports retrieved in the literature, the safety and tolerability profiles of toludesvenlafaxine were good in all clinical trials, and the pharmacokinetic parameters were well described in the phase 1 trials. The efficacy of toludesvenlafaxine was demonstrated in one phase 2 and one phase 3 trial, both on primary and secondary outcomes. In conclusion, this review highlights the favorable clinical results of toludesvenlafaxine in only two short-term trials that enrolled patients with major depressive disorder (MDD) (efficacy and tolerability were good for up to eight weeks), indicating the need for more good quality, larger-sample, and longer-term trials. Exploring new antidepressants, such as TRI, can be considered a priority for clinical research due to the high rates of TRD, but also due to the significant percentages of relapse in patients with MDD. Full article

It is well known that bacterial lipopolysaccharides (LPS) both increases proinflammatory cytokines and produces sickness behavior, including fatigue and anhedonia (i.e., the inability to experience pleasure). Previously, we have shown that intraperitoneally (i.p.) administered LPS increased extracellular monoamine metabolite levels in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), which was completely, or at least partly, prevented by pretreatment with a triple reuptake inhibitor that also blocks the serotonin (5-HT) transporter (SERT). This suggests indirectly, that LPS may enhance SERT transporter activity, and consequently, increase removal of 5-HT from the synaptic cleft, and increase metabolism of 5-HT. In the present study, we focus more specifically on the role of SERT in this increased metabolism by using rats, that differ in SERT expression. Therefore, the effects of an intraperitoneal LPS injection on extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were investigated by in vivo microdialysis in the NAc and mPFC of wild type (SERT^+/+), heterozygous (SERT^+/−) and knockout (SERT^−/−) rats. Here, we show that LPS-induced 5-HIAA formation in male rats, is significantly increased in SERT^+/+ rats in both the NAc and mPFC, whereas this increase is partly or totally abolished in SERT^+/− and SERT^−/− rats, respectively. Thus, the present study supports the hypothesis that systemic LPS in male rats increases SERT function and consequently enhances 5-HT uptake and metabolism in both the NAc and mPFC. Full article

Over 75% of depressed patients suffer from painful symptoms predicting a greater severity and a less favorable outcome of depression. Imaging, anatomical and functional studies have demonstrated the existence of common brain structures, neuronal pathways and neurotransmitters in depression and pain. In particular, the ascending serotonergic and noradrenergic pathways originating from the raphe nuclei and the locus coeruleus; respectively, send projections to the limbic system. Such pathways control many of the psychological functions that are disturbed in depression and in the perception of pain. On the other hand, the descending pathways, from monoaminergic nuclei to the spinal cord, are specifically implicated in the inhibition of nociception providing rationale for the use of serotonin (5-HT) and/or norepinephrine (NE) reuptake inhibitors (SSRIs, NRIs, SNRIs), in the relief of pain. Compelling evidence suggests that dopamine (DA) is also involved in the pathophysiology and treatment of depression. Indeed, recent insights have demonstrated a central role for DA in analgesia through an action at both the spinal and suprasinal levels including brain regions such as the periaqueductal grey (PAG), the thalamus, the basal ganglia and the limbic system. In this context, dopaminergic antidepressants (i.e., containing dopaminergic activity), such as bupropion, nomifensine and more recently triple reuptake inhibitors (TRIs), might represent new promising therapeutic tools in the treatment of painful symptoms with depression. Nevertheless, whether the addition of the dopaminergic component produces more robust effects than single- or dual-acting agents, has yet to be demonstrated. This article reviews the main pathways regulating pain transmission in relation with the monoaminergic systems. It then focuses on the current knowledge regarding the in vivo pharmacological properties and mechanism of action of monoaminergic antidepressants including SSRIs, NRIs, SNRIs and TRIs. Finally, a synthesis of the preclinical studies supporting the efficacy of these antidepressants in analgesia is also addressed in order to highlight the relative contribution of 5-HT, NE and DA to nociception. Full article