A Reduced Rate of In Vivo Dopamine Transporter Binding is Associated with Lower Relative Reinforcing Efficacy of Stimulants

Abstract α-Pyrrolidinovalerophenone (αPVP) is a psychostimulant and drug of abuse associated with severe intoxications in humans. αPVP exerts long-lasting psychostimulant effects, when compared to the classical dopamine transporter (DAT) inhibitor cocaine. Here, we compared the two enantiomeric forms of αPVP, the R- and the S-αPVP, with cocaine using a combination of in silico, in vitro and in vivo approaches. We found that αPVP enantiomers substantially differ from cocaine in their binding kinetics. The two enantiomers differ from each other in their association rates. However, they show similar slow dissociation rates leading to pseudo-irreversible binding kinetics at DAT. The pseudo-irreversible binding kinetics of αPVP is responsible for the observed non-competitive pharmacology and it correlates with persistent psychostimulant effects in mice. Thus, the slow binding kinetics of αPVP enantiomers profoundly differ from the fast kinetics of cocaine both in vitro and in vivo, suggesting drug-binding kinetics as a potential driver of psychostimulant effects in vivo.

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Brief, repeated exposure to substrates down-regulates dopamine transporter function in Xenopus oocytes in vitro and rat dorsal striatum in vivo

Journal of Neurochemistry ◽

10.1046/j.1471-4159.2002.01133.x ◽

2002 ◽

Vol 83 (2) ◽

pp. 400-411 ◽

Cited By ~ 60

Author(s):

Joshua M. Gulley ◽

Suzanne Doolen ◽

Nancy R. Zahniser

Keyword(s):

Dopamine Transporter ◽

Xenopus Oocytes ◽

Dorsal Striatum ◽

Repeated Exposure

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Maternal separation affects dopamine transporter function in the Spontaneously Hypertensive Rat: An in vivo electrochemical study

Behavioral and Brain Functions ◽

10.1186/1744-9081-7-49 ◽

2011 ◽

Vol 7 (1) ◽

pp. 49 ◽

Cited By ~ 21

Author(s):

Jacqueline S Womersley ◽

Jennifer H Hsieh ◽

Lauriston A Kellaway ◽

Greg A Gerhardt ◽

Vivienne A Russell

Keyword(s):

Dopamine Transporter ◽

Maternal Separation ◽

Spontaneously Hypertensive Rat ◽

Electrochemical Study ◽

Spontaneously Hypertensive ◽

Hypertensive Rat

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Purine metabolism in Neisseria gonorrhoeae: the requirement for hypoxanthine

Canadian Journal of Microbiology ◽

10.1139/m80-003 ◽

1980 ◽

Vol 26 (1) ◽

pp. 13-20 ◽

Cited By ~ 50

Author(s):

Stephen A. Morse ◽

Lynne Bartenstein

Keyword(s):

Neisseria Gonorrhoeae ◽

Growth Medium ◽

De Novo ◽

Defined Medium ◽

Purine Metabolism ◽

Purine Biosynthesis ◽

Free Medium ◽

De Novo Purine Biosynthesis ◽

Reduced Rate

Strains isolated from disseminated gonococcal infections often require hypoxanthine for growth. The biochemical bases for the requirement for hypoxanthine in strains isolated from both disseminated (Ile−Val−Arg−Hyx−Ura−phenotype) and non-disseminated (Hyx−phenotype) infections were compared. The requirement for hypoxanthine was dependent upon the composition of the growth medium. In a complete defined medium, hypoxanthine was replaced by a mixture of adenine and guanine but not by either purine alone. The addition of adenine alone inhibited gonococcal growth. This inhibition was reversed by the addition of guanine and most likely resulted from an inhibition of de novo purine biosynthesis. In a histidine-free medium, adenine replaced the hypoxanthine requirement in Ile−Val−Arg−Hyx−Ura− strains. Adenine did not replace the hypoxanthine requirement in Hyx− strains. The Ile−Val−Arg−Hyx−Ura− strains exhibited a markedly reduced rate of de novo purine biosynthesis while Hyx− strains were blocked in this pathway. In vivo concentrations of purines are important factors which may limit the intracellular or extracellular growth of these strains.

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Abstract 18: Increasing in vivo Apoa1/HDL Levels Negates the Cardiotoxic Effects of Doxorubicin, and Involves Signalling Through SR-BI, PI3K, and AKT1

Circulation Research ◽

10.1161/res.117.suppl_1.18 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Kristina Durham ◽

Cyrus Thomas ◽

Bernardo L Trigatti

Keyword(s):

Fold Increase ◽

Left Ventricular ◽

Cardiomyocyte Apoptosis ◽

Cross Sectional ◽

Over Expression ◽

Pressure Development ◽

Reduced Rate ◽

Induced Apoptosis ◽

Developed Pressure

Doxorubicin (DOX) is a clinically used anti-tumor drug, though the use of DOX is limited by its potent cardiotoxic side effect that can lead to heart failure. HDL protects isolated cardiomyocytes against DOX induced apoptosis, though whether this effect translates in vivo has yet to be determined. Here we assess whether ApoA1/HDL overexpression can protect mice in vivo against DOX induced cardiotoxicity, and explore the intracellular signalling mechanisms involved in protection. Mice overexpressing human ApoA1 (ApoA1tg/tg) and ApoA1+/+ mice were treated chronically with DOX, and effects on cardiac function and cardiomyocyte health were assessed. Over expression of human ApoA1 in mice corresponded to ~2.5 fold increase in plasma HDL-C as compared to ApoA1+/+ mice. Following 5 weekly injections of 5mg/kg DOX, ApoA1+/+ mice displayed cardiac dysfunction as evidenced by reduced left ventricular developed pressure, and reduced rate of pressure development. In contrast, left ventricular function was maintained following DOX treatment in ApoA1tg/tg mice. Histological analysis revealed reduced cardiomyocyte cross-sectional area and increased cardiomyocyte apoptosis following DOX treatment in ApoA1+/+ mice. ApoA1tg/tg mice, on the other hand, were protected against DOX induced cardiomyocyte atrophy and apoptosis. Interestingly, pAKT:tAKT was reduced in ApoA1+/+ by treatment with DOX, but the ratio was maintained in ApoA1tg/tg mice. We evaluated the roles of SR-BI, PI3K, and AKT1/2 in the signalling cascade of HDL in neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes. Through inhibition of AKT and PI3K, and knockdown or knockout of SR-BI, AKT1, and AKT2, we demonstrated that SR-BI, PI3K and AKT1 are required for HDL mediated protection against DOX induced cardiomyocyte apoptosis. Our results provide evidence for ApoA1 mediated protection against DOX cardiotoxicity in vivo and demonstrate the roles of SR-BI, PI3K, and AKT1 as mediators in the protective effect.

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