In vivo occupancy of the striatal dopamine uptake complex by various inhibitors does not predict their effects on locomotion

Vaugeois, Jean-Marie; Bonnet, J.; Duterte-Boucher, Dominique; Costentin, Jean

doi:10.1016/0014-2999(93)90802-o

Cited by 39 publications

(35 citation statements)

References 21 publications

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“…For example, Ritz et al (1987) reported that the potencies of a number of dopamine uptake inhibitors in maintaining drug self-administration were more closely related to affinities for the dopamine transporter than to affinities at other monoamine transporters. A number of other studies have established similar relationships for reinforcing effects of dopamine uptake inhibitors , behavioral stimulant effects (Heikkila et al 1979a, 1979b, 1981, Heikkila and Manzino 1984Spealman et al 1989;Cline et al 1992a; though see Rothman et al 1992;Vaugueois et al 1993;Izenwasser et al 1994), and, to a somewhat lesser extent, for discriminative-stimulus effects (Balster et al 1991;Cline et al 1992b). Consistent with those findings, in the present study, all of the structurally di-95 that for ED 50 and K 0.5 values (line 2) and the analysis combining these two sets of data ( Fig.…”

Section: Discussionmentioning

confidence: 78%

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: 78%

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

Katz¹,

Izenwasser²,

Terry

2000

Psychopharmacology

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“…Despite the widespread use of MDPV, no information is available regarding its molecular mechanism of action. Older literature demonstrates that pyrovalerone, a compound with structural similarity to MDPV, displays amphetamine-like stimulant properties in rodents (Fauquet et al, 1976;Vaugeois et al, 1993) and humans (Goldberg et al, 1973;Holliday et al, 1964). Bonnet and colleagues (Heron et al, 1994;Tidjane Corera et al, 2001) showed that pyrovalerone is a dopamine uptake blocker that interacts with transporter proteins in a manner similar to cocaine.…”

Section: Introductionmentioning

confidence: 99%

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

Baumann

Partilla

Lehner

et al. 2012

Neuropsychopharmacol

371

453

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The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods. In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats. We found that MDPV blocks uptake of [ 3 H]dopamine (IC 50 ¼ 4.1 nM) and [ 3 H]norepinephrine (IC 50 ¼ 26 nM) with high potency but has weak effects on uptake of [ 3 H]serotonin (IC 50 ¼ 3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats. Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations.

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“…Despite these indications that MDPV may be a growing public health concern, it remains the case that scant information is available regarding its mechanism of action or in vivo effects. In this regard, the structurally similar pyrovalerone has been shown to stimulate spontaneous locomotor activity in rodents (Fauquet et al, 1976;Vaugeois et al, 1993) and to induce stimulant-like actions in humans (Holliday et al, 1964;Goldberg et al, 1973). More recently, it was demonstrated that pyrovalerone has cocaine-like effects at dopamine reuptake transporters (Heron et al, 1994;Tidjane Corera et al, 2001;Meltzer et al, 2006) and that these effects are also apparent in MDPV itself (Baumann et al, 2012b;Simmler et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity

Fantegrossi

Gannon

Zimmerman

et al. 2012

Neuropsychopharmacol

138

151

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In recent years, synthetic analogues of naturally occurring cathinone have emerged as psychostimulant-like drugs of abuse in commercial 'bath salt' preparations. 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of these illicit products, and its structural similarities to the more well-known drugs of abuse 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) suggest that it may have similar in vivo effects to these substances. In these studies, adult male NIH Swiss mice were trained to discriminate 0.3 mg/kg MDPV from saline, and the interoceptive effects of a range of substitution doses of MDPV, MDMA, and METH were then assessed. In separate groups of mice, surgically implanted radiotelemetry probes simultaneously monitored thermoregulatory and locomotor responses to various doses of MDPV and MDMA, as a function of ambient temperature. We found that mice reliably discriminated the MDPV training dose from saline and that cumulative doses of MDPV, MDMA, and METH fully substituted for the MDPV training stimulus. All three drugs had similar ED 50 values in this procedure. Stimulation of motor activity was observed following administration of a wide range of MDPV doses (1-30 mg/kg), and the warm ambient temperature potentiated motor activity and elicited profound stereotypy and self-injurious behavior at 30 mg/kg. In contrast, MDPV-induced hyperthermic effects were observed in only the warm ambient environment. This pattern of effects is in sharp contrast to MDMA, where ambient temperature interacts with thermoregulation, but not locomotor activity. These studies suggest that although the interoceptive effects of MDPV are similar to those of MDMA and METH, direct effects on thermoregulatory processes and locomotor activity are likely mediated by different mechanisms than those of MDMA.

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In vivo occupancy of the striatal dopamine uptake complex by various inhibitors does not predict their effects on locomotion

Cited by 39 publications

References 21 publications

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

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

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity

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