Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain

Amphoux, Anne; Vialou, Vincent; Drescher, Eva; Brüss, Michael; Cour, Clotilde Mannoury la; Rochat, Catherine; Millan, Mark J.; Giros, Bruno; Bönisch, Heinz; Gautron, Sophie

doi:10.1016/j.neuropharm.2006.01.005

Cited by 195 publications

(209 citation statements)

References 42 publications

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“…However, these uptake1 transporters were not detected in the endothelium, either luminally or abluminally. The anti-Oct3 antibody labeled some fibers in the mouse brain, particularly near the ventricles ( Figure 5B), in agreement with previous reports (Amphoux et al, 2006;Vialou et al, 2004). However, we detected no Oct3 in the cerebral vessels, suggesting that this transporter is not present at the BBB.…”

Section: Immunodetection Of Transporters At the Blood-brain Barrier Asupporting

confidence: 92%

“…The isolation and culture of endothelial cells for use in in vitro BBB models often leads to the dysregulation of transporters (Lyck et al, 2009). Moreover, brain extracellular fluid microdialysis sampling experiments do not discriminate between the kinetic processes at the BBB and those at the other brain extracellular fluid/ intracellular fluid interfaces where these transporters are present (e.g., neurons and ventricles) (Amphoux et al, 2006;Vialou et al, 2004). Our results indicate that the luminal BBB permeability to MPP + , a broad, high-capacity substrate of biogenic amine uptake1 and uptake2 transporters, and the organic cation transporter Mate1, is not carrier mediated.…”

Section: Discussionmentioning

confidence: 99%

“…We first tested for functional biogenic amine transporters at the BBB and BRB using [ 3 H]-MPP + , one of the highest capacity substrates known for Net, Dat, Sert, Oct1-3, Mate1, and Pmat (Amphoux et al, 2006;Buck and Amara, 1994;Duan and Wang, 2010;Koepsell et al, 2007).…”

Section: Permeability Of the Eye And Blood-brain Barrier For [ 3 H]-1mentioning

confidence: 99%

“…By contrast, carnitine, the amphoteric nutrient substrate of Octn transporters did not modulate the transport of [ 3 H]-MPP + whereas choline only slightly reduced 1.3-fold (P < 0.05) the eye transport ( Figure 3B, solid bars). None of these pharmacologic transport inhibitors affected the luminal transport of [ 3 H]-MPP + at the Swiss mouse BBB ( Figure 3B, H]-dopamine (Dat < Net; Oct1 < < Oct2 < Oct3; Pmat substrate) were measured after in situ carotid perfusion for 60 seconds (Amphoux et al, 2006;Duan and Wang, 2010;Eisenhofer, 2001; Figure 4) Figure 4A) was not inhibited by 1 or 10 mmol/L unlabeled histamine in Swiss mouse and was unchanged in Oct1,2(À/À) Fvb mice ( Figure 4A), suggesting that its membrane permeability does not significantly involve the histamine transporters Oct2 and Oct3 in the Swiss and Fvb mice. The retinal transport of [ 3 H]-serotonin (K in,eye B0.5 mL/s per gram; Figure 4B) was not inhibited by 5 mmol/L L-tryptophan, 10 mmol/L serotonin or Na + /Cl À depletion, and unchanged in Oct1,2(À/À) mice ( Figure 4B, solid bars).…”

Section: Permeability Of the Eye And Blood-brain Barrier For [ 3 H]-1mentioning

confidence: 99%

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Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

André

Saubaméa

Cochois-Guégan

et al. 2012

J Cereb Blood Flow Metab

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Uptake1 and uptake2 transporters are involved in the extracellular clearance of biogenic amine neurotransmitters at synaptic clefts. We looked for them at the blood-brain barrier (BBB) and bloodretina barriers (BRB), where they could be involved in regulating the neurotransmitter concentration and modulate/terminate receptor-mediated effects within the neurovascular unit (NVU). Uptake2 (Oct1-3/ Slc22a1-3, Pmat/Slc29a4) and Mate1/Slc47a1 transporters are also involved in the transport of xenobiotics. We used in situ carotid perfusion of prototypic substrates like-serotonin, and [ 3 H]-dopamine, changes in ionic composition and genetic deletion of Oct1-3 carriers to detect uptake1 and uptake2 at the BBB and BRB. We showed that uptake1 and uptake2 are involved in the transport of [ 3 H]-dopamine and [ 3 H]-MPP + at the blood luminal BRB, but not at the BBB. These functional studies, together with quantitative RT-PCR and confocal imaging, suggest that the mouse BBB lacks uptake1 (Net/Slc6a2, Dat/Slc6a3, Sert/Slc6a4), uptake2, and Mate1 on both the luminal and abluminal sides. However, we found evidence for functional Net and Oct1 transporters at the luminal BRB. These heterogeneous transport properties of the brain and retina NVUs suggest that the BBB helps protect the brain against biogenic amine neurotransmitters in the plasma while the BRB has more of a metabolic/endocrine role.

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Section: Immunodetection Of Transporters At the Blood-brain Barrier Asupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Permeability Of the Eye And Blood-brain Barrier For [ 3 H]-1mentioning

confidence: 99%

Section: Permeability Of the Eye And Blood-brain Barrier For [ 3 H]-1mentioning

confidence: 99%

See 2 more Smart Citations

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

André

Saubaméa

Cochois-Guégan

et al. 2012

J Cereb Blood Flow Metab

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“…GHB-and baclofen-induced catalepsy was studied in animals pretreated with dizocilpine, PCP, or ketamine. Although dizocilpine, PCP, and ketamine are potent antagonists at the NMDA subtype of glutamate receptor, they not only share NMDA antagonist properties but can also produce other effects, such as inhibition of dopamine uptake (e.g., Snell et al 1988) and, discovered recently, inhibition of organic cation transporters (Amphoux et al 2006). Thus, to test the hypothesis that NMDA antagonism enhances GHB, the present study examined if PCP, dizocilpine, and ketamine enhance the cataleptic effects of GHB with relative potencies that correlate with their NMDA antagonist properties and not with their ability to inhibit dopamine uptake or organic cation transporters.…”

Section: Introductionmentioning

confidence: 99%

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

Koek

2008

Psychopharmacology

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Rationale-Gamma-hydroxybutyrate (GHB) is a gamma-aminobutyric acid (GABA) analog that is used to treat narcolepsy but that is also abused. GHB has many actions in common with the GABA B receptor agonist baclofen, but their underlying GABA B receptor mechanisms may be different.Objective-The aim of this study is to further investigate a possible differential role of glutamate in GABA B receptor-mediated effects of GHB and baclofen. Materials and methods-The experiments examined the effects of non-competitive antagonists at the N-methyl-d-asparate (NMDA) subtype of glutamate receptors on GHB-induced catalepsy and compared these effects with those on baclofen-induced catalepsy.Results-In C57BL/6J mice, ketamine, phencyclidine (PCP), and dizocilpine (MK-801) all enhanced GHB-induced catalepsy. They did so with a potency order (i.e., MK-801 > PCP > ketamine) consistent with their relative potencies as NMDA antagonists but not as inhibitors of dopamine or organic cation transporters. Ketamine, PCP, and MK-801 enhanced catalepsy along inverted U-shaped dose-response curves likely because higher doses affected motor coordination, which limited their catalepsy-enhancing effects. Doses that were maximally effective to enhance GHB-induced catalepsy did not affect the cataleptic effects of baclofen.Conclusions-The finding that NMDA receptor antagonists enhance the cataleptic effects of GHB but not those of baclofen is further evidence that the GABA B receptor mechanisms mediating the effects of GHB and GABA B agonists are not identical. Differential interactions of glutamate with the GABA B receptor mechanisms mediating the effects of GHB and baclofen may explain why GHB is effective for treating narcolepsy and is abused, whereas baclofen is not.

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Characterization of murine polyspecific monoamine transporters

et al. 2017

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The dysregulation of monoamine clearance in the central nervous system occurs in various neuropsychiatric disorders, and the role of polyspecific monoamine transporters in monoamine clearance is increasingly highlighted in recent studies. However, no study to date has properly characterized polyspecific monoamine transporters in the mouse brain. In the present study, we examined the kinetic properties of three mouse polyspecific monoamine transporters [organic cation transporter 2 (Oct2), Oct3, and plasma membrane monoamine transporter (Pmat)] and compared the absolute mRNA expression levels of these transporters in various brain areas. First, we evaluated the affinities of each transporter for noradrenaline, dopamine, serotonin, and histamine, and found that mouse ortholog substrate affinities were similar to those of human orthologs. Next, we performed drug inhibition assays and identified interspecies differences in the pharmacological properties of polyspecific monoamine transporters; in particular, corticosterone and decynium‐22, which are widely recognized as typical inhibitors of human OCT3, enhanced the transport activity of mouse Oct3. Finally, we quantified absolute mRNA expression levels of each transporter in various regions of the mouse brain and found that while all three transporters were ubiquitously expressed, Pmat was the most highly expressed transporter. These results provide an important foundation for future translational research investigating the roles of polyspecific monoamine transporters in neurological and neuropsychiatric disease.

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Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain

Cited by 195 publications

References 42 publications

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

Characterization of murine polyspecific monoamine transporters

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