Differential inhibitory effects of drugs acting at the noradrenaline and 5‐hydroxytryptamine transporters in rat and human neocortical synaptosomes*

Abstract

Background and purpose:Although the amino acid sequences of rat and human 5-hydroxytryptamine (5-HT) and noradrenaline (NA) transporters (i.e. SERT and NET) are highly homologous, species differences exist in the inhibitory effects of drugs acting at these transporters. Therefore, comparison of the potencies of drugs acting at SERT and NET in native human and rat neocortex may serve to more accurately predict their clinical profile. Experimental approach: Synaptosomes prepared from fresh human and rat neocortical tissues were used for [ ]-NA uptake, the dissociation constants did not indicate species differences although a smaller density of both SERT and NET was observed in human tissues. In competition experiments with the various drugs, marked species differences in their potencies were observed, especially at SERT. The rank order of selectivity ratios (SERT/NET) in human neocortex was as follows: citalopram Ն duloxetine = fluvoxamine Ն fluoxetine > milnacipran > desipramine = atomoxetine > (S,S)-reboxetine. Significant species differences in these ratios were observed for duloxetine, atomoxetine and desipramine. Conclusions and implications:This study provides the first compilation of drug potency at native human neocortical SERT and NET. The significant species differences (viz., human vs. rat) in drug potency suggest that the general use of rodent data should be limited to predict clinical efficacy or profile.

Chronic effects of antidepressants on serotonin release in rat raphe slice cultures: high potency of milnacipran in the augmentation of serotonin release

“…1 is almost the same as the order of K i values for SERT, as previously reported (Bolden-Watson and Richelson, 1993;Thomas et al, 1987). Among SNRIs, there seems to be a correlation between the optimal concentration and K i values for SERT (Mantovani et al, 2009;Bolden-Watson and Richelson, 1993), indicating that an inhibition of SERT is required to cause the augmentation of 5-HT release. To our knowledge, this is the first in vitro report that compares the effects of a number of antidepressant classes on extracellular 5-HT levels, especially after chronic exposure to these agents.…”

“…Because SSRIs, SNRIs, and TCAs commonly block SERT (Mantovani et al, 2009;Vaishnavi et al, 2004), this result is likely due to an acute inhibition of 5-HT reuptake by the blockade of the transporter. In vivo microdialysis studies have demonstrated that acute administration of SSRIs, SNRIs, or TCAs elicits a pronounced increase in 5-HT levels in the raphe, prefrontal cortex, striatum, hypothalamus and hippocampus (Bel and Artigas, 1999;Gartside et al, 1995;Invernizzi et al, 1997;Matos et al, 1990).…”

“…In contrast to these studies, the acute increase in extracellular 5-HT levels in the raphe slice cultures in our study was not so large, suggesting weak spontaneous activity of raphe serotonergic neurons in slice cultures under normal conditions, although basal 5-HT levels were still dependent on both action potentials and exocytosis. In addition to the blockade of SERT, SNRIs and TCAs also inhibit the reuptake of NE by the blockade of NET (Sparatore et al, 1982;Mantovani et al, 2009). Therefore, it is possible that an acute inhibition of NET by SNRIs or TCAs may induce an activation of serotonergic neurons through α 1 -adrenoceptors.…”

“…By contrast, sustained exposure to TeCAs (mianserin) and NaSSA (mirtazapine) did not induce the augmentation of 5-HT release. The former class of antidepressants, which induced the augmentation of 5-HT release in this study, commonly inhibit SERT, while the latter do not (Bolden-Watson and Richelson, 1993;Mantovani et al, 2009;Thomas et al, 1987). Furthermore, the order of optimal concentrations of SSRIs and TCAs determined from Fig.…”

Norepinephrine Transporter Inhibition with Desipramine Exacerbates L-DOPA–Induced Dyskinesia: Role for Synaptic Dopamine Regulation in Denervated Nigrostriatal Terminals

“…We also point out that the serotonin terminals or transporter (SERT) can affect LID severity in preclinical models Eskow et al, 2007;Bishop et al, 2012). However, chronic DMI is not reported to alter SERT expression or function (Hyttel, 1994;Mantovani et al, 2009), thus making it unlikely that changes in SERT expression or SERT-mediated uptake are associated with our behavioral observations. From a clinical perspective, this leads to questions as to whether an antidepressant with NET affinity could produce, hasten the onset of, or worsen the severity of LID, given the prevalence of PD-related depression and that depression commonly precedes motor manifestations (Burn, 2002;Aarsland et al, 2012;Brichta et al, 2013).…”