The cocaine analog WIN 35,428 binds to two sites in fresh rat caudate-putamen: Significance of assay procedures

Izenwasser, Sari; Rosenberger, John; Cox, Brian M.

doi:10.1016/0024-3205(93)90179-7

Cited by 18 publications

(28 citation statements)

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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: 98%

“…Details of the procedures used have been published previously (Izenwasser et al 1993). In brief, male Sprague-Dawley rats Taconic,Germantown,N.Y.…”

Section: Dopamine Transporter Bindingmentioning

confidence: 99%

“…For example, Madras et al (1989a) showed that saturable binding of cocaine was better fit by a two-site model than a one-site model. Others have demonstrated multiple-site binding for cocaine analogs (Madras et al 1989b;Izenwasser et al 1993) and the existence of two binding sites on the cloned (Boja et al 1992;Pristupa et al 1994;Eshleman et al 1995) and solubilized (Gracz and Madras 1995) dopamine transporter. It has also been suggested that mazindol and GBR12935 may bind to a different site on the dopamine transporter than cocaine (Berger et al 1990), and that there are differences in the binding domains of the GBR12935 analog, DEEP, or the benztropine analog, GAII-34, and cocaine (Vaughan et al 1999).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 98%

“…Details of the procedures used have been published previously (Izenwasser et al 1993). In brief, male Sprague-Dawley rats Taconic,Germantown,N.Y.…”

Section: Dopamine Transporter Bindingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Katz¹,

Izenwasser²,

Terry

2000

Psychopharmacology

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“…Thus, the evidence from behavioral studies indicates that cocaine and GBR 12909 may interact differently with the dopamine transporter, and in fact, it has been suggested that these drugs bind to different sites on the dopamine transporter. The cocaine analog [ 3 H]WIN 35,428, under certain binding conditions, binds to two distinct sites on the dopamine transporter, one with high affinity and the other with low affinity, in cynomologus monkey (Madras et al 1989), in rat tissue (Boja et al 1991;Izenwasser et al 1993), and in transfected cells expressing the rat dopamine transporter (Boja et al 1992). GBR 12909 binding to the dopamine transporter is best-fit by a single site model, and it binds with comparable affinity in both nigrostriatal and mesolimbic terminal fields (Berger et al 1990;Izenwasser et al 1990b).…”

Section: Discussionmentioning

confidence: 99%

Chronic administration of the selective dopamine uptake inhibitor GBR 12909, but not cocaine, produces marked decreases in dopamine transporter density

Kunko

Loeloff

Izenwasser

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The chronic continuous infusion of cocaine produces partial behavioral tolerance to cocaine and tolerance to the inhibition of dopamine uptake by cocaine, without changing dopamine transporter binding. In order to examine more closely the dopaminergic contribution to this effect, the selective dopamine uptake inhibitor GBR 12,909 (30 mg/kg/day), cocaine (50 mg/kg/day), or vehicle, were continuously infused via osmotic minipump, and their effects on the dopamine transporter examined. Drug and vehicle pumps were implanted into male Sprague-Dawley rats and removed after seven days. [3H]WIN 35,428 binding and [3H]dopamine uptake were measured in caudate putamen and nucleus accumbens at varying intervals after pump removal. The Bmax for [3H]WIN 35,428 binding was decreased by approximately 75% in the caudate putamen and by 40% in the nucleus accumbens of GBR 12,909-treated rats both 1 and 4 days after pump removal, and was still significantly decreased after 10 days, but had returned to normal by 20 days post-treatment. In contrast, cocaine did not significantly alter [3H]WIN 35,428 binding. GBR 12,909 produced both tolerance to the inhibition of [3H]dopamine uptake by cocaine, and a decrease in total uptake of dopamine, in the caudate putamen, with no change in the nucleus accumbens. The persistent reduction of [3H]WIN 35,428 binding following continuous GBR 12,909 does not appear to result from residual drug binding. These findings suggest that GBR 12,909 and cocaine may bind to and regulate the dopamine transporter in different ways.

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“…Cocaine's pharmacological effects have been shown to be influenced by a number of different gene products, including various components of the dopaminergic system (Reith et al 1987;Ritz et al 1987;Wise and Rompre 1989;Erwin et al 1993;Izenwasser et al 1993;Self et al 1996), NMDA (Karler et al 1989(Karler et al , 1990Haracz et al 1995) and AMPA (Kaddis et al 1993(Kaddis et al , 1995 glutamate receptors, GABA receptors (Dunwiddie et al 1988;McAllister et al 1988;Goeders 1990), and components of the serotonergic system (Elsworth et al 1993). It is conceivable that any or all of these systems could have been altered during the selection process.…”

Section: Amphetamine Dose-response Studiesmentioning

confidence: 96%

Sensitivity to cocaine and amphetamine among mice selectively bred for differential cocaine sensitivity

et al. 1998

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Selective breeding of mice for differences in response to a drug offers a powerful means for testing hypotheses regarding underlying mechanisms and relationships between drug-induced behaviors. Starting from a heterogeneous stock of mice, we have selectively bred lines of mice for extreme differences in their locomotor response to 10 mg/kg cocaine HCl. Selection pressure has been maintained for 12 generations and has resulted in two cocaine sensitive (CAHI) and two cocaine insensitive (CALO) lines. Across the generations of selection, the CAHI lines showed progressively greater amounts of cocaine-induced locomotion, with mice from the S12 generation traveling over 21,000 cm/30 min. following 10 mg/kg cocaine. The CALO lines, in contrast, did not substantially diverge from control values until the S8 generation. By generation 12, however, the LO lines traveled no further following 10 mg/kg cocaine (7000 cm/30 min), than they did following an initial saline injection. Cocaine and amphetamine dose-response analyses were conducted on drug-naive mice from the tenth generation. The CAHI lines were extremely sensitive to the locomotor activating effects of all doses of cocaine, displaying from 2- to 6-fold greater amounts of cocaine-induced locomotion than the CALO lines. The CALO lines, in contrast, were completely insensitive to the psychomotor stimulant effects of cocaine. The CAHI lines were also more sensitive to the locomotor activating effects of amphetamine. Both lines showed dose-dependent amphetamine-induced locomotion that peaked at 3 mg/kg. However, at all doses, the CAHI lines showed a 2- to 4-fold greater amount of locomotion than CALO lines. Thus, the sensitivity to cocaine developed through selection using a single dose of cocaine has generalized to a range of doses of cocaine and to at least one other psychostimulant.

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The cocaine analog WIN 35,428 binds to two sites in fresh rat caudate-putamen: Significance of assay procedures

Cited by 18 publications

References 3 publications

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

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

Chronic administration of the selective dopamine uptake inhibitor GBR 12909, but not cocaine, produces marked decreases in dopamine transporter density

Sensitivity to cocaine and amphetamine among mice selectively bred for differential cocaine sensitivity

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