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![Concentration-dependent inhibition by antidepressants of [ 3 H] MPP + uptake into transfected tsA201 cells transiently expressing the hPMAT. The effect of the SSRIs fluoxetine, paroxetine, sertraline, and the SNRI reboxetine (a); of the SSNRI venlafxine, the SNDRI bupropion, and the NSMRIs amitriptyline, imipramine, and desipramine (b); and of the atypical antidepressants tianeptine and trimipramine (c) on specific, i.e., decynium-22 (30µM)-sensitive [ 3 H]MPP + (15 nM, 10 min, 37°C) uptake into tsA201 cells heterologously expressing hPMAT was determined. Shown are means±SEM of specific [ 3 H]MPP + uptake (% of control) from three to five separate experiments carried out in triplicates](profile/Heinz-Boenisch/publication/40689698/figure/fig1/AS:601661089271858@1520458590871/Concentration-dependent-inhibition-by-antidepressants-of-3-H-MPP-uptake-into.png)
Concentration-dependent inhibition by antidepressants of [ 3 H] MPP + uptake into transfected tsA201 cells transiently expressing the hPMAT. The effect of the SSRIs fluoxetine, paroxetine, sertraline, and the SNRI reboxetine (a); of the SSNRI venlafxine, the SNDRI bupropion, and the NSMRIs amitriptyline, imipramine, and desipramine (b); and of the atypical antidepressants tianeptine and trimipramine (c) on specific, i.e., decynium-22 (30µM)-sensitive [ 3 H]MPP + (15 nM, 10 min, 37°C) uptake into tsA201 cells heterologously expressing hPMAT was determined. Shown are means±SEM of specific [ 3 H]MPP + uptake (% of control) from three to five separate experiments carried out in triplicates
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![Fig.1 Concentration-dependent inhibition by antidepressants of [ 3 H]...](profile/Heinz-Boenisch/publication/40689698/figure/fig1/AS:601661089271858@1520458590871/Concentration-dependent-inhibition-by-antidepressants-of-3-H-MPP-uptake-into_Q320.jpg)
Monoamine neurotransmission is efficiently terminated through synaptic reuptake of released neurotransmitters by high-affinity Na(+)- and Cl(-)-dependent neuronal monoamine transporters of the SLC6A family located in the plasma membrane of presynaptic nerve terminals. Recently, a low-affinity, high-capacity Na(+)- and Cl(-)-independent plasma membr...
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Context 1
... was examined by deter- mining their IC 50 values for inhibition of hPMAT-mediated [ 3 H]MPP + uptake. For the selective serotonin reuptake inhibitors (SSRIs) sertraline, fluoxetine, and paroxetine, and for the selective norepinephrine reuptake inhibitor (SNRI) reboxetine we found IC 50 values of 5.13, 10.5, 13.7, and 76.7µM, respectively (Fig. 1a and Table 1). The inhibitory potency of the selective serotonin and norepi- nephrine reuptake inhibitor (SSNRI) venlafaxine (IC 50 , 216µM) and of the selective norepinephrine and dopamine reuptake inhibitor (SNDRI) bupropion (IC 50 , 115µM) was relatively low (Fig. 1b and Table 1). The tricyclic ADs and non-selective monoamine ...
Context 2
... reboxetine we found IC 50 values of 5.13, 10.5, 13.7, and 76.7µM, respectively (Fig. 1a and Table 1). The inhibitory potency of the selective serotonin and norepi- nephrine reuptake inhibitor (SSNRI) venlafaxine (IC 50 , 216µM) and of the selective norepinephrine and dopamine reuptake inhibitor (SNDRI) bupropion (IC 50 , 115µM) was relatively low (Fig. 1b and Table 1). The tricyclic ADs and non-selective monoamine reuptake inhibitors (NSMRIs) amitriptyline, imipramine, and desipramine inhibited hPMAT with nearly the same potency (IC 50 , 22.8, 21.1, and 15.0µM, respectively; Fig. 1b and Table 1). The IC 50 values of the so called "atypical" ADs trimipramine and tianeptine were 11.6 and ...
Context 3
... the selective norepinephrine and dopamine reuptake inhibitor (SNDRI) bupropion (IC 50 , 115µM) was relatively low (Fig. 1b and Table 1). The tricyclic ADs and non-selective monoamine reuptake inhibitors (NSMRIs) amitriptyline, imipramine, and desipramine inhibited hPMAT with nearly the same potency (IC 50 , 22.8, 21.1, and 15.0µM, respectively; Fig. 1b and Table 1). The IC 50 values of the so called "atypical" ADs trimipramine and tianeptine were 11.6 and 191µM, respectively (Fig. 1c and Table 1). Thus, the most potent inhibitors of the hPMAT were the SSRIs sertraline, fluoxetine, and paroxetine and the tricyclic atypical antidepressant trimipramine. In sum- mary, the examined ...
Context 4
... 1). The tricyclic ADs and non-selective monoamine reuptake inhibitors (NSMRIs) amitriptyline, imipramine, and desipramine inhibited hPMAT with nearly the same potency (IC 50 , 22.8, 21.1, and 15.0µM, respectively; Fig. 1b and Table 1). The IC 50 values of the so called "atypical" ADs trimipramine and tianeptine were 11.6 and 191µM, respectively (Fig. 1c and Table 1). Thus, the most potent inhibitors of the hPMAT were the SSRIs sertraline, fluoxetine, and paroxetine and the tricyclic atypical antidepressant trimipramine. In sum- mary, the examined antidepressants showed the following order of inhibitory potency at the hPMAT: sertraline > fluoxetine ≈ trimipramine > paroxetine ≈ ...
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Citations
... In the present study, we observed a downregulation in mRNA expression of the PMAT and an upregulation of the DA receptor D1 in the presence of haloperidol. Although it is a DA receptor D2 antagonist, haloperidol has been found to inhibit hPMAT activity at micromolar concentrations [76]. These findings indicate that astrocytes exhibit changes in mRNA expression when treated with dopaminergic drugs, particularly apomorphine and haloperidol. ...
Citation: Sočan, V.; Dolinar, K.; Kržan, M. Kinetic Properties and Pharmacological Modulation of High-and Low-Affinity Dopamine Transport in Striatal Astrocytes of Adult Rats. Int. J. Mol. Sci. 2024, 25, 5135. https://doi.org/10.3390/ ijms25105135 Academic Editors: Anna Stasiak and Dorota Łażewska Abstract: Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their role in dopamine (DA) homeostasis remains understudied. In the present study, we investigated the kinetic and molecular mechanisms of DA transport in cultured striatal astrocytes of adult rats. Kinetic uptake experiments were performed using radiolabeled [ 3 H]-DA, whereas mRNA expression of the dopamine, nore-pinephrine, organic cation and plasma membrane monoamine transporters (DAT, NET, OCTs and PMAT) and DA receptors D1 and D2 was determined by qPCR. Additionally, astrocyte cultures were subjected to a 24 h treatment with the DA receptor agonist apomorphine, the DA receptor antagonist haloperidol and the DA precursor L-DOPA. [ 3 H]-DA uptake exhibited temperature, concentration and sodium dependence, with potent inhibition by desipramine, nortriptyline and decynium-22, suggesting the involvement of multiple transporters. qPCR revealed prominent mRNA expression of the NET, the PMAT and OCT1, alongside lower levels of mRNA for OCT2, OCT3 and the DAT. Notably, apomorphine significantly altered NET, PMAT and D1 mRNA expression, while haloperidol and L-DOPA had a modest impact. Our findings demonstrate that striatal astrocytes aid in DA clearance by multiple transporters, which are influenced by dopaminergic drugs. Our study enhances the understanding of regional DA uptake, paving the way for targeted therapeutic interventions in dopaminergic disorders.
... D22-induced inhibition of DA uptake at higher concentrations (around 10 µM), indicates that PMAT could be involved in astrocyte DA uptake in both striatal and cortical astrocytes, albeit to a limited extent. Additionally, it is worth noting the effect of desipramine on [ 3 H]-DA uptake may be attributed to reported nonspecific inhibitory effects of high concentrations of desipramine on other transporters, such as PMAT, which has been shown to be inhibited by a large array of antidepressants, albeit with affinities in the 5-200 µM range [71,72]. ...
Astrocytes are crucial in the regulation of neurotransmitter homeostasis, and while their involvement in the dopamine (DA) tripartite synapse is acknowledged, it necessitates a more comprehensive investigation. In the present study, experiments were conducted on primary astrocyte cultures from the striatum and cortex of neonatal rats. The pharmacological intricacies of DA uptake, including dependence on time, temperature, and concentration, were investigated using radiolabelled [3H]-DA. The mRNA expression of transporters DAT, NET, PMAT, and OCTs was evaluated by qPCR. Notably, astrocytes from both brain regions exhibited prominent mRNA expression of NET and PMAT, with comparatively lower expression of DAT and OCTs. The inhibition of DA uptake by the DAT inhibitor, GBR12909, and NET inhibitors, desipramine and nortriptyline, impeded DA uptake in striatal astrocytes more than in cortical astrocytes. The mRNA expression of NET and PMAT was significantly upregulated in cortical astrocytes in response to the DA receptor agonist apomorphine, while only the mRNA expression of NET exhibited changes in striatal astrocytes. Haloperidol, a DA receptor antagonist, and L-DOPA, a DA precursor, did not induce significant alterations in transporter mRNA expression. These findings underscore the intricate and region-specific mechanisms governing DA uptake in astrocytes, emphasizing the need for continued exploration to unravel the nuanced dynamics of astrocytic involvement in the DA tripartite synapse.
... Although haloperidol and L-DOPA did not induce any significant change in the expression of NET mRNA, we observed a significant downregulation of PMAT mRNA expression. Haloperidol has been found to inhibit hPMAT at micromolar concentrations (Haenisch & Bönisch, 2010), whereas we have not found similar data on L-DOPA in regard to PMAT. Interestingly, all three compounds affected the expression of the high-capacity transporter PMAT, and only apomorphine induced upregulation of both NET and DRD1. ...
Astrocytes, glial cells in the central nervous system, perform a multitude of homeostatic functions and are in constant bidirectional communication with neuronal cells, a concept named the tripartite synapse; however, their role in the dopamine homeostasis remains unexplored. The aim of this study was to clarify the pharmacological and molecular characteristics of dopamine transport in cultured cortical astrocytes of adult rats. In addition, we were interested in the expression of mRNA of dopamine transporters as well as dopamine receptors D1 and D2 and in the effect of dopaminergic drugs on the expression of these transporters and receptors. We have found that astrocytes possess both Na ⁺ ‐dependent and Na ⁺ ‐independent transporters. Uptake of radiolabelled dopamine was time‐, temperature‐ and concentration‐dependent and was inhibited by decynium‐22, a plasma membrane monoamine transporter inhibitor, tricyclic antidepressants desipramine and nortriptyline, both inhibitors of the norepinephrine transporter. Results of transporter mRNA expression indicate that the main transporters involved in cortical astrocyte dopamine uptake are the norepinephrine transporter and plasma membrane monoamine transporter. Both dopamine receptor subtypes were identified in cortical astrocyte cultures. Twenty‐four‐hour treatment of astrocyte cultures with apomorphine, a D1/D2 agonist, induced upregulation of D1 receptor, norepinephrine transporter and plasma membrane monoamine transporter, whereas the latter was downregulated by haloperidol and L‐DOPA. Astrocytes take up dopamine by multiple transporters and express dopamine receptors, which are sensitive to dopaminergic drugs. The findings of this study could open a promising area of research for the fine‐tuning of existing therapeutic strategies.
... Although haloperidol and L-DOPA did not induce any significant change in the expression of NET mRNA, we observed a significant downregulation of PMAT mRNA expression. Haloperidol has been found to inhibit hPMAT at micromolar concentrations [83], whereas we have not found similar data on L-DOPA in regard to PMAT. Interestingly, all three compounds affected the expression of the high-capacity transporter PMAT, and only apomorphine induced upregulation of both NET and DRD1. ...
Astrocytes, glial cells in the central nervous system, perform a multitude of homeostatic functions and are in constant bidirectional communication with neuronal cells, a concept named the tripartite synapse, however their role in the dopamine homeostasis remains unexplored. The aim of this study was to clarify the pharmacological and molecular characteristics of dopamine transport in cultured cortical astrocytes of adult rats. In addition, we were interested in the expression of mRNA of dopamine transporters as well as dopamine receptors D1 and D2 and in the effect of dopaminergic drugs on the expression of these transporters and receptors. We have found that astrocytes possess both Na-dependent and Na-independent transporters. Uptake of radiolabelled dopamine was time-, temperature- and concentration-dependent and was inhibited by decynium-22, a plasma membrane monoamine transporter inhibitor, tricyclic antidepressants desipramine and nortriptyline, both inhibitors of the norepinephrine transporter. Results of transporter mRNA expression indicate that the main transporters involved in cortical astrocyte dopamine uptake are the norepinephrine transporter and plasma membrane monoamine transporter. Both dopamine receptor subtypes were identified in cortical astrocyte cultures. 24-hour treatment of astrocyte cultures with apomorphine, a D1/D2 agonist, induced upregulation of D1 receptor, norepinephrine transporter and plasma membrane monoamine transporter, whereas the latter was downregulated by haloperidol and L-DOPA. Astrocytes take up dopamine by multiple transporters and express dopamine receptors, which are sensitive to dopaminergic drugs. The findings of this study could open a promising area of research for the fine-tuning of existing therapeutic strategies.
... Arenas for locomotor testing were 45.7 H × 66.0 L × 38.1 cm W. Overhead cameras were used to record locomotor activity using ANY-Maze software (v. 7, Stoelting Co., Wood Dale, IL, USA). Distance traveled was quantified in 5 min bins, and the two bins concurrent with when the TST occurred post-injection (i.e., min [30][31][32][33][34][35][36][37][38][39][40] were analyzed to identify potential locomotor confounds when interpreting TST results. Locomotor activity for the entire 1 h duration of this test is presented in Supplementary Figure S1, and accompanying statistics in Supplementary Table S1. ...
... In our study, bupropion's effects were significant in female knockouts (TST latency), female wildtypes (locomotor activity), and male heterozygotes (locomotor activity). Given the relatively low (4 and 8 mg/kg) doses of bupropion we employed here, these effects are most likely unmasking the contribution of PMAT uptake under conditions when DAT/NET function is impaired, rather than any (lack of) action at PMAT (see also [30]). Likewise, the behavioral influences of escitalopram in male wildtypes (TST immobility), female wildtypes (locomotor activity), male heterozygotes (TST immobility), and female knockouts (TST latency and locomotor activity) illustrate how PMAT likely facilitates the uptake of monoamines when SERT function is blocked. ...
Plasma membrane monoamine transporter (PMAT, Slc29a4) transports monoamine neurotransmitters, including dopamine and serotonin, faster than more studied monoamine transporters, e.g., dopamine transporter (DAT), or serotonin transporter (SERT), but with ~400–600-fold less affinity. A considerable challenge in understanding PMAT’s monoamine clearance contributions is that no current drugs selectively inhibit PMAT. To advance knowledge about PMAT’s monoamine uptake role, and to circumvent this present challenge, we investigated how drugs that selectively block DAT/SERT influence behavioral readouts in PMAT wildtype, heterozygote, and knockout mice of both sexes. Drugs typically used as antidepressants (escitalopram, bupropion) were administered acutely for readouts in tail suspension and locomotor tests. Drugs with psychostimulant properties (cocaine, D-amphetamine) were administered repeatedly to assess initial locomotor responses plus psychostimulant-induced locomotor sensitization. Though we hypothesized that PMAT-deficient mice would exhibit augmented responses to antidepressant and psychostimulant drugs due to constitutively attenuated monoamine uptake, we instead observed sex-selective responses to antidepressant drugs in opposing directions, and subtle sex-specific reductions in psychostimulant-induced locomotor sensitization. These results suggest that PMAT functions differently across sexes, and support hypotheses that PMAT’s monoamine clearance contribution emerges when frontline transporters (e.g., DAT, SERT) are absent, saturated, and/or blocked. Thus, known human polymorphisms that reduce PMAT function could be worth investigating as contributors to varied antidepressant and psychostimulant responses.
... These studies are covered in detail in chapter "Substrates and Inhibitors of Organic Cation Transporters and Plasma Membrane Monoamine Transporter and Therapeutic Implications" of this volume (Bönisch 2021). Briefly, Bönisch and co-workers (Haenisch and Bönisch 2010;Haenisch et al. 2012) screened a large number of commonly prescribed drugs for the treatment of psychiatric disorders. They found that many inhibited OCT1, OCT2, OCT3 and PMAT, however only at supra therapeutic concentrations (i.e., concentrations that greatly exceeded the upper plasma concentrations of therapeutic doses of these drugs). ...
... They found only three of the compounds tested had the potential to interact with OCTs at therapeutic concentrations; bupropion (antidepressant and smoking cessation aid) at OCT2, nefazodone (antidepressant) at OCT3, and clozapine (antipsychotic) at OCT2 and OCT3 (Haenisch et al. 2012). None of the drugs tested had inhibitory actions at PMAT at therapeutically relevant concentrations (Haenisch and Bönisch 2010). Studies by Zhu et al. (2012) and Massmann et al. (2014) indicate potential actions of desipramine, sertraline (Zhu et al. 2012), ketamine, fluoxetine, and diazepam (Massmann et al. 2014) at OCT3. ...
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medications for psychiatric disorders, yet they leave the majority of patients without full symptom relief. Therefore, a major research challenge is to identify novel targets for the improved treatment of these disorders. SSRIs act by blocking the serotonin transporter (SERT), the high-affinity, low-capacity, uptake-1 transporter for serotonin. Other classes of antidepressant work by blocking the norepinephrine or dopamine transporters (NET and DAT), the high-affinity, low-capacity uptake-1 transporters for norepinephrine and dopamine, or by blocking combinations of SERT, NET, and DAT. It has been proposed that uptake-2 transporters, which include organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT), undermine the therapeutic utility of uptake-1 acting antidepressants. Uptake-2 transporters for monoamines have low affinity for these neurotransmitters, but a high capacity to transport them. Thus, activity of these transporters may limit the increase of extracellular monoamines thought to be essential for ultimate therapeutic benefit. Here preclinical evidence supporting a role for OCT2, OCT3, and PMAT in behaviors relevant to psychiatric disorders is presented. Importantly, preclinical evidence revealing these transporters as targets for the development of novel therapeutics for psychiatric disorders is discussed.
... (Tatsumi et al. 1997) Amphetamine: (Amphoux et al. 2006;Eshleman et al. 1994;Giros et al. 1992Giros et al. , 1994Kristensen et al. 2011;Pacholczyk et al. 1991;Sitte et al. 1998;Wagner et al. 2017;Wu and Gu 1999;Wu et al. 1998a;Zhu et al. 2010), Metamphetamine: (Eshleman et al. 1994;Wagner et al. 2017;Wu et al. 1998a), Atomoxetine: (Kristensen et al. 2011;Sandoval et al. 2018), Citalopram: (Ahlin et al. 2008;Apparsundaram et al. 2008;Nies et al. 2011;Owens et al. 1997;Pacholczyk et al. Kristensen et al. 2011;Owens et al. 1997;Sandoval et al. 2018;Tatsumi et al. 1997;Tzvetkov et al. 2018;Zhou et al. 2007;Zhu et al. 2012Zhu et al. , 2018, Sertraline: (Haenisch and Bönisch 2010;Tatsumi et al. 1997;Zhou et al. 2007;Zhu et al. 2012), Amitriptyline: (Ahlin et al. 2008;Belzer et al. 2013;Giros et al. 1992;Hacker et al. 2015;Haenisch and Bönisch 2010;Matthaei et al. 2016;Owens et al. 1997;Pacholczyk et al. 1991;Sandoval et al. 2018;Sata et al. 2005;Tatsumi et al. 1997;Torres et al. 2003;Tzvetkov et al. 2013;Zolk et al. 2009a), Clomipramine: (Ahlin et al. 2008;Apparsundaram et al. 2008;Hendrickx et al. 2013;Millan et al. 2001;Tatsumi et al. 1997), Doxepin: (Belzer et al. 2013;Chen et al. 2017a;Hacker et al. 2015;Mika et al. 2013;Tatsumi et al. 1997;Zolk et al. 2009a), Imipramine: (Ahlin et al. 2008;Belzer et al. 2013;Haenisch and Bönisch 2010;Hendrickx et al. 2013;Kido et al. 2011;Owens et al. 1997;Pacholczyk et al. 1991;Paczkowski et al. 1999;Sandoval et al. 2018;Tatsumi et al. 1997;Torres et al. 2003;Tzvetkov et al. 2013;Wu et al. 2000;Zhu et al. 2012Zhu et al. , 2018Zolk et al. 2009a), Desipramine: (Ahlin et al. 2011;Ahlin et al. 2008;Chen et al. 2017a;Engel et al. 2004;Giros et al. 1992Giros et al. , 1994Gorboulev et al. 1997;Haenisch and Bönisch 2010;Owens et al. 1997;Pacholczyk et al. 1991;Paczkowski et al. 1999;Tatsumi et al. 1997;Torres et al. 2003;Wu et al. 1998aWu et al. , 2000Zhang et al. 1998;Zhu et al. 2012;Zolk et al. 2009a), Sulpiride: 3.2 ...
... (Tatsumi et al. 1997) Amphetamine: (Amphoux et al. 2006;Eshleman et al. 1994;Giros et al. 1992Giros et al. , 1994Kristensen et al. 2011;Pacholczyk et al. 1991;Sitte et al. 1998;Wagner et al. 2017;Wu and Gu 1999;Wu et al. 1998a;Zhu et al. 2010), Metamphetamine: (Eshleman et al. 1994;Wagner et al. 2017;Wu et al. 1998a), Atomoxetine: (Kristensen et al. 2011;Sandoval et al. 2018), Citalopram: (Ahlin et al. 2008;Apparsundaram et al. 2008;Nies et al. 2011;Owens et al. 1997;Pacholczyk et al. Kristensen et al. 2011;Owens et al. 1997;Sandoval et al. 2018;Tatsumi et al. 1997;Tzvetkov et al. 2018;Zhou et al. 2007;Zhu et al. 2012Zhu et al. , 2018, Sertraline: (Haenisch and Bönisch 2010;Tatsumi et al. 1997;Zhou et al. 2007;Zhu et al. 2012), Amitriptyline: (Ahlin et al. 2008;Belzer et al. 2013;Giros et al. 1992;Hacker et al. 2015;Haenisch and Bönisch 2010;Matthaei et al. 2016;Owens et al. 1997;Pacholczyk et al. 1991;Sandoval et al. 2018;Sata et al. 2005;Tatsumi et al. 1997;Torres et al. 2003;Tzvetkov et al. 2013;Zolk et al. 2009a), Clomipramine: (Ahlin et al. 2008;Apparsundaram et al. 2008;Hendrickx et al. 2013;Millan et al. 2001;Tatsumi et al. 1997), Doxepin: (Belzer et al. 2013;Chen et al. 2017a;Hacker et al. 2015;Mika et al. 2013;Tatsumi et al. 1997;Zolk et al. 2009a), Imipramine: (Ahlin et al. 2008;Belzer et al. 2013;Haenisch and Bönisch 2010;Hendrickx et al. 2013;Kido et al. 2011;Owens et al. 1997;Pacholczyk et al. 1991;Paczkowski et al. 1999;Sandoval et al. 2018;Tatsumi et al. 1997;Torres et al. 2003;Tzvetkov et al. 2013;Wu et al. 2000;Zhu et al. 2012Zhu et al. , 2018Zolk et al. 2009a), Desipramine: (Ahlin et al. 2011;Ahlin et al. 2008;Chen et al. 2017a;Engel et al. 2004;Giros et al. 1992Giros et al. , 1994Gorboulev et al. 1997;Haenisch and Bönisch 2010;Owens et al. 1997;Pacholczyk et al. 1991;Paczkowski et al. 1999;Tatsumi et al. 1997;Torres et al. 2003;Wu et al. 1998aWu et al. , 2000Zhang et al. 1998;Zhu et al. 2012;Zolk et al. 2009a), Sulpiride: 3.2 ...
... (Tatsumi et al. 1997) Amphetamine: (Amphoux et al. 2006;Eshleman et al. 1994;Giros et al. 1992Giros et al. , 1994Kristensen et al. 2011;Pacholczyk et al. 1991;Sitte et al. 1998;Wagner et al. 2017;Wu and Gu 1999;Wu et al. 1998a;Zhu et al. 2010), Metamphetamine: (Eshleman et al. 1994;Wagner et al. 2017;Wu et al. 1998a), Atomoxetine: (Kristensen et al. 2011;Sandoval et al. 2018), Citalopram: (Ahlin et al. 2008;Apparsundaram et al. 2008;Nies et al. 2011;Owens et al. 1997;Pacholczyk et al. Kristensen et al. 2011;Owens et al. 1997;Sandoval et al. 2018;Tatsumi et al. 1997;Tzvetkov et al. 2018;Zhou et al. 2007;Zhu et al. 2012Zhu et al. , 2018, Sertraline: (Haenisch and Bönisch 2010;Tatsumi et al. 1997;Zhou et al. 2007;Zhu et al. 2012), Amitriptyline: (Ahlin et al. 2008;Belzer et al. 2013;Giros et al. 1992;Hacker et al. 2015;Haenisch and Bönisch 2010;Matthaei et al. 2016;Owens et al. 1997;Pacholczyk et al. 1991;Sandoval et al. 2018;Sata et al. 2005;Tatsumi et al. 1997;Torres et al. 2003;Tzvetkov et al. 2013;Zolk et al. 2009a), Clomipramine: (Ahlin et al. 2008;Apparsundaram et al. 2008;Hendrickx et al. 2013;Millan et al. 2001;Tatsumi et al. 1997), Doxepin: (Belzer et al. 2013;Chen et al. 2017a;Hacker et al. 2015;Mika et al. 2013;Tatsumi et al. 1997;Zolk et al. 2009a), Imipramine: (Ahlin et al. 2008;Belzer et al. 2013;Haenisch and Bönisch 2010;Hendrickx et al. 2013;Kido et al. 2011;Owens et al. 1997;Pacholczyk et al. 1991;Paczkowski et al. 1999;Sandoval et al. 2018;Tatsumi et al. 1997;Torres et al. 2003;Tzvetkov et al. 2013;Wu et al. 2000;Zhu et al. 2012Zhu et al. , 2018Zolk et al. 2009a), Desipramine: (Ahlin et al. 2011;Ahlin et al. 2008;Chen et al. 2017a;Engel et al. 2004;Giros et al. 1992Giros et al. , 1994Gorboulev et al. 1997;Haenisch and Bönisch 2010;Owens et al. 1997;Pacholczyk et al. 1991;Paczkowski et al. 1999;Tatsumi et al. 1997;Torres et al. 2003;Wu et al. 1998aWu et al. , 2000Zhang et al. 1998;Zhu et al. 2012;Zolk et al. 2009a), Sulpiride: 3.2 ...
Inhibitors of Na ⁺ /Cl ⁻ dependent high affinity transporters for norepinephrine (NE), serotonin (5-HT), and/or dopamine (DA) represent frequently used drugs for treatment of psychological disorders such as depression, anxiety, obsessive-compulsive disorder, attention deficit hyperactivity disorder, and addiction. These transporters remove NE, 5-HT, and/or DA after neuronal excitation from the interstitial space close to the synapses. Thereby they terminate transmission and modulate neuronal behavioral circuits. Therapeutic failure and undesired central nervous system side effects of these drugs have been partially assigned to neurotransmitter removal by low affinity transport. Cloning and functional characterization of the polyspecific organic cation transporters OCT1 ( SLC22A1 ), OCT2 ( SLC22A2 ), OCT3 ( SLC22A3 ) and the plasma membrane monoamine transporter PMAT ( SLC29A4 ) revealed that every single transporter mediates low affinity uptake of NE, 5-HT, and DA. Whereas the organic transporters are all located in the blood brain barrier, OCT2, OCT3, and PMAT are expressed in neurons or in neurons and astrocytes within brain areas that are involved in behavioral regulation. Areas of expression include the dorsal raphe, medullary motoric nuclei, hypothalamic nuclei, and/or the nucleus accumbens. Current knowledge of the transport of monoamine neurotransmitters by the organic cation transporters, their interactions with psychotropic drugs, and their locations in the brain is reported in detail. In addition, animal experiments including behavior tests in wildtype and knockout animals are reported in which the impact of OCT2, OCT3, and/or PMAT on regulation of salt intake, depression, mood control, locomotion, and/or stress effect on addiction is suggested.
... For p.(D29G), the transport defect was restricted to MPP + (Adamsen et al., 2014). A lot of studies have emphasized the importance of OCT3 and PMAT in response to drugs targeting the monoaaminergic systems (Gasser, 2019;Haenisch & Bönisch, 2009;Hensler et al., 2013;Mayer et al., 2018). It is therefore feasible that genetic variations in uptake-2 play a role in many complex neuropsychiatric disorders and/or individual variability in response to therapeutic interventions. ...
Neurotransmitters, such as γ-aminobutyric acid, glutamate, acetyl choline, glycine and the monoamines, facilitate the crosstalk within the central nervous system. The designated neurotransmitter transporters (NTTs) both release and take up neurotransmitters to and from the synaptic cleft. NTT dysfunction can lead to severe pathophysiological consequences, e.g. epilepsy, intellectual disability, or Parkinson's disease. Genetic point mutations in NTTs have recently been associated with the onset of various neurological disorders. Some of these mutations trigger folding defects in the NTT proteins. Correct folding is a prerequisite for the export of NTTs from the endoplasmic reticulum (ER) and the subsequent trafficking to their pertinent site of action, typically at the plasma membrane. Recent studies have uncovered some of the key features in the molecular machinery responsible for transporter protein folding, e.g., the role of heat shock proteins in fine-tuning the ER quality control mechanisms in cells. The therapeutic significance of understanding these events is apparent from the rising number of reports, which directly link different pathological conditions to NTT misfolding. For instance, folding-deficient variants of the human transporters for dopamine or GABA lead to infantile parkinsonism/dystonia and epilepsy, respectively. From a therapeutic point of view, some folding-deficient NTTs are amenable to functional rescue by small molecules, known as chemical and pharmacological chaperones.
... The activity of selected NET radiotracers at various transporters (+) represents positive affinity of the corresponding tracer at the target; (−) represents none or much lower affinity than NET; (?) represents unclear conclusion; ND represents not determined Radiotracer NET DAT SERT/5HTT VMAT2 OCTs PMAT 123 I-MIBG (+) in human neuroblastoma cells (Montaldo et al. 1991;Glowniak et al. 1993;Graefe et al. 1999) (+) bovine chromaffin granule membrane (Gasnier et al. 1986) (−) in monkey kidney cells (Glowniak et al. 1993) (+) in humans (Hanson et al. 1989) (−) in monkey kidney cells (Glowniak et al. 1993) (+) in human platelets (Rutgers 1993) (+) in rabbit platelets (Saihkay et al. 2011) (−) in neuroblastoma and rabbit ) (+) in GOT1 and BON cells (Kölby et al. 2003) (+) bovine chromaffin granule membrane (Gasnier et al. 1986) ( +) human and mouse OCTs in HEK293 (Ito et al. 2012) ( +) in neuroblastoma (Bayer et al. 2009(Bayer et al. ,2016 ND 11 C-HED (+) in C6 rat glial cells (Foley et al. 2002) (-) in tenfold less than NET (Foley et al. 2002) (−) in human platelets (Foley et al. 2002) (−) in bovine chromaffin vesicles, 56-fold less than NET (Foley et al. 2002) ND C-MRB (+) in vivo (Melloni et al. 1984) (+) in mice brain (Ghose et al. 2005) (?) in baboon brain (−) (Melloni et al. 1984) (−) in mice brain (Ghose et al. 2005) (?) in baboon brain (−) in vivo (Melloni et al. 1984) (−) in mice brain (Ghose et al. 2005) ND ND (?) reboxetine ( +) at hPMAT (Haenisch and Bönisch 2010) 18 F-FMeNER-D 2 (+) in monkey (Schou et al. 2004 (+) in MDD patients (Nogami et al. 2013) ND ND ND ND ND 18 F-NS12137 (+) in rat brain (Kirjavainen et al. 2018) ND ND ND ND ND Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH ("Springer Nature"). Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users ("Users"), for smallscale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. ...
The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the therapeutic applications against certain types of neuroendocrine tumors, as exemplified by the clinically used 123/131I-MIBG as theranostic single-photon emission computed tomography (SPECT) agent. With the development of more advanced positron emission tomography (PET) technology, more radiotracers targeting NET have been reported, with superior temporal and spatial resolutions, along with the possibility of functional and kinetic analysis. More recently, fluorine-18-labelled NET tracers have drawn increasing attentions from researchers, due to their longer radiological half-life relative to carbon-11 (110 min vs. 20 min), reduced dependence on on-site cyclotrons, and flexibility in the design of novel tracer structures. In the heart, certain NET tracers provide integral diagnostic information on sympathetic innervation and the nerve status. In the central nervous system, such radiotracers can reveal NET distribution and density in pathological conditions. Most radiotracers targeting cardiac NET-function for the cardiac application consistent of derivatives of either norepinephrine or MIBG with its benzylguanidine core structure, e.g. 11C-HED and 18F-LMI1195. In contrast, all NET tracers used in central nervous system applications are derived from clinically used antidepressants. Lastly, possible applications of NET as selective tracers over organic cation transporters (OCTs) in the kidneys and other organs controlled by sympathetic nervous system will also be discussed.
... However, tactics have largely focused on combined blockade of DAT, NET, SERT, monoamine receptors, and/or metabolism inhibitors (Moret, 2005;Sambunaris et al., 1997). Current selective reuptake inhibitors for the high-affinity/low-capacity transporters (SERT, NET, DAT) have no appreciable activity at OCT2, OCT3, and PMAT (Emberger et al., 2011;Haenisch and Bönisch, 2010;Matthaeus et al., 2015;Wang et al., 2014;Zhou et al., 2007). Work by us and others support the idea for greater therapeutic potential by blockade of the low-affinity/high-capacity transporter system, in tandem with blockers of high-affinity/low capacity transporters, especially in instances of resistance to high-affinity monoamine transporter therapies Hagan et al., 2011;Horton et al., 2013). ...
Growing evidence supports involvement of low-affinity/high-capacity organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in regulating clearance of monoamines. Currently decynium-22 (D22) is the best pharmacological tool to study these transporters, however it does not readily discriminate among them, underscoring a need to develop compounds with greater selectivity for each of these transporters. We developed seven D22 analogs, and previously reported that some have lower affinity for α1-adrenoceptors than D22 and showed antidepressant-like activity in mice. Here, we extend these findings to determine the affinity of these analogs for OCT2, OCT3 and PMAT, as well as serotonin, norepinephrine and dopamine transporters (SERT, NET and DAT) using a combination of uptake competition with [³H]methyl-4-phenylpyridinium acetate in overexpressed HEK cells and [³H]citalopram, [³H]nisoxetine and [³H]WIN 35428 displacement binding in mouse hippocampal and striatal preparations. Like D22, all analogs showed greater binding affinities for OCT3 than OCT2 and PMAT. However, unlike D22, some analogs also showed modest affinity for SERT and DAT. Dual OCT3/SERT and/or OCT3/DAT actions of certain analogs may help explain their ability to produce antidepressant-like effects in mice and help account for our previous findings that D22 lacks antidepressant-like effects unless SERT function is either genetically or pharmacologically compromised. Though these analogs are not superior than D22 in discriminating among OCTs/PMAT, our findings point to development of compounds with combined ability to inhibit both low-affinity/high-capacity transporters, such as OCT3, and high-affinity/low-capacity transporters, such as SERT, as therapeutics with potentially improved efficacy for treatment of psychiatric disorders.
