Relationships Between the Catechol Substrate Binding Site and Amphetamine, Cocaine, and Mazindol Binding Sites in a Kinetic Model of the Striatal Transporter of Dopamine In Vitro

Wayment, Hollie; Meiergerd, Susan M.; Schenk, James O.

doi:10.1046/j.1471-4159.1998.70051941.x

Cited by 40 publications

(46 citation statements)

References 12 publications

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“…Furthermore, recent analyses of cocaine and dopamine substrate analogue interactions preliminarily confirm allosteric interactions between the catechol/phenethylamine binding sites on the dopamine transporter and the site at which cocaine binds (Wayment and Schenk, 1996).…”

Section: Comments On the Mechanism Of Inhibition Of Cocaine To Inhibimentioning

confidence: 88%

A Multisubstrate Kinetic Mechanism of Dopamine Transport in the Nucleus Accumbens and Its Inhibition by Cocaine

Povlock

Schenk

1997

Journal of Neurochemistry

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Kinetic studies of dopamine transport into suspensions of nucleus accumbens (NAcc) and effects of Na + and Cl -as cosubstrates were performed using rotating disk electrode voltammetry. To mimic chemical neurotransmission, dopamine was added as a rapid pulse, and transporter-mediated clearance of dopamine was evaluated kinetically. This paradigm was shown to approximate a zero trans entry transport experiment. Dopamine was taken up with apparent Km and Vmax values of 1.3 1iM and 375 pmol/s/g wet weight, respectively.Transport exhibited apparent trans acceleration. Substitution of Nawith choline or CL with isethionate reduced dopamine transport with reaction orders of two and unity, respectively, accompanied by reductions in Vmax with no changes in Km. Apparent KNa and K~1values were 70.0 and 92.1 mM, respectively. Dopamine transport in NAcc was found to follow a partially random, sequential mechanism in which dopamine and Na~bind randomly to the transporter followed by binding of Cl -before transport. Cocaine inhibited dopamine transport and the influences of the other substrates allosterically with an overall Kõ f 0.30~sM.Thus, the general kinetic mechanism of the transport of dopamine in the NAcc is identical to that previously reported by this laboratoryfor dopamine transport in the striatum. However, the dopamine transporter in the NAcc is more tightly regulated by Na~, possesses a higher kinetic turnover rate, is four times more sensitive to cocaine than the striatal transporter, and exhibits cocaine inhibition independent of [substrate]. These findings suggest that cocaine modulates chemical signaling in NAcc differently than in striatum, providing down-regulation of function irrespective of [substrate],thereby enhancing dopaminergic signaling more robustly in the NAcc than in the striatum. Key Words: Cocaine-Dopamine-GBR 1 2909-RTI-1 20-Inhibition of transportNucleus accumbens-Rotating disk voltammetry-Kinetic mechanism of transport. J. Neurochem. 69, 1093Neurochem. 69, -1105Neurochem. 69, (1997.The effect of cocaine to produce self-administration behaviors in rodents has been correlated with its binding to the neuronal transporter for dopamine (Ritz et al., 1987). Thus, it has been hypothesized that inhibition of the reuptake of dopamine, resulting in tonically increased synaptic levels of dopamine, mediates addictive behaviors. The anatomical locus for mediating addiction could include individual or combinations of dopaminergic areas of the brain and at pre-and postsynaptic loci. However, recent evidence suggests that the behavioral influences of cocaine, via its primary effects on the dopaminergic transporter, may reside in the mesolimbic areas of the brain, most notably the nucleus accumbens (NAcc) (Koob and Bloom, 1988;Wise and Hoffman, 1992;Chang et al., 1994;Hitri et al., 1994). Although increased pre-and postsynaptic receptor occupation by dopamine in time and/or duration is the gross result of cocaine inhibition of transporter function, it has not been established whether differences ...

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Section: Comments On the Mechanism Of Inhibition Of Cocaine To Inhibimentioning

confidence: 88%

A Multisubstrate Kinetic Mechanism of Dopamine Transport in the Nucleus Accumbens and Its Inhibition by Cocaine

Povlock

Schenk

1997

Journal of Neurochemistry

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“…To this end, we substituted D-amphetamine for cocaine as the reinforcer in mice of all three genotypes. Although the reinforcing effects of D-amphetamine are also believed to depend on the DAT, its binding to the DAT molecule differs from cocaine (Wayment et al, 1998;Chen et al, 2005). Indeed, D-amphetamine increased extracellular dopamine levels in the nucleus accumbens and induced locomotor hyperactivity and conditioned place preferences in the DATki mice (Chen et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Lack of Cocaine Self-Administration in Mice Expressing a Cocaine-Insensitive Dopamine Transporter

Thomsen¹,

Han²,

Gu³

et al. 2009

J Pharmacol Exp Ther

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Cocaine addiction is a worldwide public health problem for which there are no established treatments. The dopamine transporter (DAT) is suspected as the primary target mediating cocaine's abuse-related effects based on numerous pharmacological studies. However, in a previous study, DAT knockout mice were reported to self-administer cocaine, generating much debate regarding the importance of the DAT in cocaine's abuse-related effects. Here, we show that mice expressing a "knockin" of a cocaine-insensitive but functional DAT did not self-administer cocaine intravenously despite normal food-maintained responding and normal intravenous self-administration of amphetamine and a direct dopamine agonist. Our results have three implications. First, they imply a crucial role for high-affinity DAT binding of cocaine in mediating its reinforcing effects, reconciling mouse genetic engineering approaches with data from classic pharmacological studies. Second, they demonstrate the usefulness of knockin strategies that modify specific amino acid sequences within a protein. Third, they show that it is possible to alter the DAT protein sequence in such a way as to selectively target its interaction with cocaine, while sparing other behaviors dependent on DAT function. Thus, molecular engineering technology could advance the development of highly specialized compounds such as a dopamine-sparing "cocaine antagonist."

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“…Slightly different binding sites on DAT or interactions with DAT between these classes of stimulants may explain their differing functional effects. Some studies show that the binding sites of dopamine, cocaine, and amphetamine overlap (Beuming et al, 2008), whereas others demonstrate differences between amphetamine and other psychostimulants in their binding or inhibition of DAT (Dersch et al, 1994;Wayment et al, 1998). Differences in DAT inhibition have functional implications.…”

Section: Discussionmentioning

confidence: 99%

Dopamine Uptake Inhibitors but Not Dopamine Releasers Induce Greater Increases in Motor Behavior and Extracellular Dopamine in Adolescent Rats Than in Adult Male Rats

Walker

Morris²,

Arrant³

et al. 2010

J Pharmacol Exp Ther

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Most life-long drug addiction begins during adolescence. Important structural and functional changes in brain occur during adolescence and developmental differences in forebrain dopamine systems could mediate a biologic vulnerability to drug addiction during adolescence. Studies investigating age differences in psychostimulant responses have yielded mixed results, possibly because of different mechanisms for increasing extracellular dopamine. Recent research from our laboratory suggests that adolescent dopamine systems may be most affected by selective dopamine uptake inhibitors. We investigated age-related behavioral responses to acute administration of several dopamine uptake inhibitors [methylphenidate, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR12909), and nomifensine] and releasing agents [amphetamine and methylenedioxymethamphetamine (MDMA)] in adolescent and adult male rats. Methylphenidate and amphetamine effects on stimulated dopamine efflux were determined using fast-scan cyclic voltammetry in vivo. Dopamine uptake inhibitors but not dopamine releasing agents induced more locomotion and/or stereotypy in adolescent relative to adult rats. MDMA effects were greater in adults at early time points after dosing. Methylphenidate but not amphetamine induced much greater dopamine efflux in periadolescent relative to adult rats. Periadolescent male rats are particularly sensitive to psychostimulants that are DAT inhibitors but are not internalized and do not release dopamine. Immaturity of DAT and/or DAT associated signaling systems in adolescence specifically enhances behavioral and dopaminergic responses in adolescence.

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Relationships Between the Catechol Substrate Binding Site and Amphetamine, Cocaine, and Mazindol Binding Sites in a Kinetic Model of the Striatal Transporter of Dopamine In Vitro

Cited by 40 publications

References 12 publications

A Multisubstrate Kinetic Mechanism of Dopamine Transport in the Nucleus Accumbens and Its Inhibition by Cocaine

A Multisubstrate Kinetic Mechanism of Dopamine Transport in the Nucleus Accumbens and Its Inhibition by Cocaine

Lack of Cocaine Self-Administration in Mice Expressing a Cocaine-Insensitive Dopamine Transporter

Dopamine Uptake Inhibitors but Not Dopamine Releasers Induce Greater Increases in Motor Behavior and Extracellular Dopamine in Adolescent Rats Than in Adult Male Rats

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