[<sup>125</sup>I]RTI‐55 Binding to Cocaine‐Sensitive Dopaminergic and Serotonergic Uptake Sites in the Human Brain

Little, Karley Y.; Kirkman, Jacob A.; Carroll, F. Ivy; Breese, George R.; Duncan, Gary E.

doi:10.1111/j.1471-4159.1993.tb07435.x

Cited by 51 publications

(28 citation statements)

References 44 publications

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“…In contrast, the DAT inhibitors cocaine and methylphenidate increased DAT surface expression (Daws et al, 2002;Little et al, 2002). It is noteworthy that in vivo observations support this scenario; i.e., methamphetamine users had less DAT in the striatum and cocaine users were reported to have an increased level of DAT (Little et al, 1993).…”

Section: E Substrate-and Inhibitor-mediated Traffickingsupporting

confidence: 51%

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

et al. 2011

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Section: E Substrate-and Inhibitor-mediated Traffickingsupporting

confidence: 51%

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

et al. 2011

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“…Biogenic amine transporters are known to be axonal in neurons on the basis of autoradiographic studies with highaffinity ligands (De Souza and Kuyatt, 1987;Richfield, 1991;Tejani-Butt, 1992;Little et al, 1993) and from more recent immunocytochemical studies at the electron microscopic level (Ciliax et al, 1995;Qian et al, 1995;Pickel and Chan, 1999;Schroeter et al, 2000). When transfected into LLC-PK 1 cells, however, these same transporters were found in the basolateral membrane of transfected cells, and in MDCK cells, NET and SERT were localized basolaterally, whereas DAT was also found on the apical surface (Gu et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

The NH₂-terminus of Norepinephrine Transporter Contains a Basolateral Localization Signal for Epithelial Cells

Gu¹,

Caron

Caplan

et al. 2001

MBoC

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When expressed in epithelial cells, dopamine transporter (DAT) was detected predominantly in the apical plasma membrane, whereas norepinephrine transporter (NET) was found in the basolateral membrane, despite 67% overall amino acid sequence identity. To identify possible localization signals responsible for this difference, DAT-NET chimeras were expressed in MDCK cells and localized by immunocytochemistry and transport assays. The results suggested that localization of these transporters in MDCK cells depends on their highly divergent NH 2 -terminal regions. Deletion of the first 58 amino acids of DAT (preceding TM1) did not change its apical localization. However, the replacement of that region with corresponding sequence from NET resulted in localization of the chimeric protein to the basolateral membrane, suggesting that the NH 2 -terminus of NET, which contains two dileucine motifs, contains a basolateral localization signal. Mutation of these leucines to alanines in the context of a basolaterally localized NET/DAT chimera restored transporter localization to the apical membrane, indicating that the dileucine motifs are critical to the basolateral localization signal embodied within the NET NH 2 -terminal region. However, the same mutation in the context of wild-type NET did not disrupt basolateral localization, indicating the presence of additional signals in NET directing its basolateral localization within the plasma membrane. INTRODUCTIONTransporters localized near sites of neurotransmitter release terminate the action of these transmitters by reuptake into neurons and glia (Uhl, 1992;Borowsky and Hoffman, 1995;Rudnick, 1997). The transporters for dopamine, norepinephrine, and serotonin are high-affinity targets for drugs of abuse such as cocaine and amphetamines and for therapeutic drugs used to treat depression, obsessive-compulsive disorder, and other mental diseases (Ritz et al., 1987;Koe, 1990;Barr et al., 1992;Boyer and Feighner, 1992;Giros and Caron, 1993;Gu et al., 1994;Seeman and Madras, 1998;Smith et al., 1998). Successful cloning efforts have established a family of Na ϩ -and Cl Ϫ -dependent transporters for neurotransmitters, amino acids, and other substrates (Guastella et al., 1990;Pacholczyk et al., 1991;Amara and Kuhar, 1993;Rudnick and Clark, 1993;Nelson and Lill, 1994). Like other members of this family, the biogenic amine transporters, including dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), were predicted from hydropathy analysis to contain 12 transmembrane domains with cytoplasmic NH 2 -and COOH-termini Giros et al., 1991;Hoffman et al., 1991;Kilty et al., 1991;Pacholczyk et al., 1991). This topological model has been experimentally verified (Chen et al., 1998). Although much effort has been focused on elucidating the structures and functions of these transporters, little is known about the determinants that allow them to be sorted to their proper domains within the plasma membranes of neurons and other cells. In addition to their neuro...

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“…Two binding sites have been reported in rat caudate putamen (Schoemaker et al 1985;Izenwasser et al 1993) and human caudate (Little et al 1993) and putamen (Schoemaker et al 1985;Staley et al 1994). In monkey brain, the binding of both [ 3 H]cocaine and the more potent cocaine analog [ 3 H]WIN35,428, fit a two-site binding model better than a one-site model (Madras et al 1989a(Madras et al , 1989b.…”

Section: Discussionmentioning

confidence: 99%

Relationships among dopamine transporter affinities and cocaine-like discriminative-stimulus effects

Katz¹,

Izenwasser²,

Terry

2000

Psychopharmacology

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Rationale: The discriminative-stimulus effects of cocaine have been reported to be mediated by indirect agonist actions initiated by the blockade of dopamine uptake, and the potencies of drugs that have discriminativestimulus effects like cocaine are directly related to their dopamine transporter binding affinities. The binding to the dopamine transporter by cocaine and many of its analogs has been reported to fit better using a two-site model than a one-site model. Objectives: The present study examined the relationship among binding affinities of dopamine uptake inhibitors at these two sites and their potencies to produce discriminative-stimulus effects. Methods: The inhibition constants (K i values) were derived for unlabeled dopamine uptake inhibitors for displacement of [ 3 H]WIN 35,428 from rat caudate putamen membranes. These K i values were related to the ED 50 values obtained in rats trained to discriminate 10 mg/kg cocaine from saline injections under a fixed-ratio 20 schedule of food reinforcement. Results: Among the dopamine uptake inhibitors studied, the binding data for eight compounds (WIN 35,428, nomifensine, WIN 35,981, WIN 35,065-2, methylphenidate, cocaine, cocaethylene, and bupropion) were better fit by a two-site model than a one-site model. The data for the remaining eleven compounds (RTI-31, RTI-55, RTI-121, RTI-32, LU19-005, BTCP, GBR12909, GBR12935, mazindol, LU17-133, and EXP561) were better fit by a one-site model. Of the drugs that were fit best by a two-site model, there was a higher correlation among the K i values for the high-affinity site and the ED 50 values (R 2 =0.655; P=0.015) than there was for the low-affinity site (R 2 =0.543; P=0.037). Of the remaining drugs, there was a high correlation among the K i values and the ED 50 values for the discriminative-stimulus effects (R 2 =0.523; P=0.012). Conclusions: These data suggest that the discriminative-stimulus effects of cocaine are more closely related to actions mediated by high-affinity binding to the dopamine transporter than they are to actions mediated by the low-affinity site. The further assessment of the respective contributions of high-and lowaffinity binding to the behavioral effects of cocaine will be greatly enhanced with the development of pharmacological tools that have a high degree of selectivity for one of these components.

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[¹²⁵I]RTI‐55 Binding to Cocaine‐Sensitive Dopaminergic and Serotonergic Uptake Sites in the Human Brain

Cited by 51 publications

References 44 publications

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

The NH₂-terminus of Norepinephrine Transporter Contains a Basolateral Localization Signal for Epithelial Cells

Relationships among dopamine transporter affinities and cocaine-like discriminative-stimulus effects

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[125I]RTI‐55 Binding to Cocaine‐Sensitive Dopaminergic and Serotonergic Uptake Sites in the Human Brain

Cited by 51 publications

References 44 publications

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

The NH2-terminus of Norepinephrine Transporter Contains a Basolateral Localization Signal for Epithelial Cells

Relationships among dopamine transporter affinities and cocaine-like discriminative-stimulus effects

Contact Info

Product

Resources

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[¹²⁵I]RTI‐55 Binding to Cocaine‐Sensitive Dopaminergic and Serotonergic Uptake Sites in the Human Brain

The NH₂-terminus of Norepinephrine Transporter Contains a Basolateral Localization Signal for Epithelial Cells