Therapeutic doses of amphetamine and methylphenidate selectively redistribute the vesicular monoamine transporter-2

Riddle, Evan L.; Hanson, Glen R.; Fleckenstein, Annette E.

doi:10.1016/j.ejphar.2007.05.044

Cited by 42 publications

(34 citation statements)

References 16 publications

(15 reference statements)

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“…of six independent determinations, and an asterisk indicates a statistical difference, p Ͻ 0.05 via a two-tailed t test, between DA content in saline-and MPDtreated animals. Riddle et al, 2007) to increase the velocity (Fig. 8A) and magnitude (Fig.…”

Section: Resultsmentioning

confidence: 90%

“…QUIN hydrochloride and SCOP hydrobromide were purchased from Tocris Bioscience (Ellisville, MO). All drugs were administered at doses previously used to investigate receptor-mediated effects in rat brain (Herná ndez-López et al, 1992;Keefe and Adams, 1998;Casas et al, 1999;Forster and Blaha, 2000;Ichikawa et al, 2002;Sandoval et al, 2002;Kilbourn et al, 2004;Truong et al, 2004;Riddle et al, 2007;Volz et al, 2007a). Drug doses were calculated as the free base and were dissolved in 0.9% (w/v) saline before being administered at 1 ml/kg as indicated in the figure legends.…”

Section: Methodsmentioning

confidence: 99%

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Methylphenidate-Induced Increases in Vesicular Dopamine Sequestration and Dopamine Release in the Striatum: The Role of Muscarinic and Dopamine D2 Receptors

Volz

Farnsworth

Rowley

et al. 2008

J Pharmacol Exp Ther

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Methylphenidate (MPD) administration alters the subcellular distribution of vesicular monoamine transporter-2 (VMAT-2)-containing vesicles in rat striatum. This report reveals previously undescribed pharmacological features of MPD by elucidating its receptor-mediated effects on VMAT-2-containing vesicles that cofractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles) and on striatal dopamine (DA) release. MPD administration increased DA transport into, and decreased the VMAT-2 immunoreactivity of, the membrane-associated vesicle subcellular fraction. These effects were mimicked by the D2 receptor agonist quinpirole and blocked by the D2 receptor antagonist eticlopride. Both MPD and quinpirole increased vesicular DA content. However, MPD increased, whereas quinpirole decreased, K ϩ -stimulated DA release from striatal suspensions. Like MPD, the muscarinic receptor agonist, oxotremorine, increased K ϩ -stimulated DA release. Both eticlopride and the muscarinic receptor antagonist scopolamine blocked MPD-induced increases in K ϩ -stimulated DA release, whereas the N-methyl-D-aspartate receptor antagonist (Ϫ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) was without effect. This suggests that D2 receptors mediate both the MPD-induced redistribution of vesicles away from synaptosomal membranes and the MPD-induced up-regulation of vesicles remaining at the membrane. This results in a redistribution of DA within the striatum from the cytoplasm into vesicles, leading to increased DA release. However, D2 receptor activation alone is not sufficient to mediate the MPD-induced increases in striatal DA release because muscarinic receptor activation is also required. These novel findings provide insight into the mechanism of action of MPD, regulation of DA sequestration/release, and treatment of disorders affecting DA disposition, including attention-deficit hyperactivity disorder, substance abuse, and Parkinson's disease.The ritalinic acid psychostimulant methylphenidate (MPD) is frequently used to treat attention-deficit hyperactivity disorder. It is well established that MPD prevents the clearance of dopamine (DA) from the synaptic cleft by binding to the neuronal DA transporter (DAT) (Wayment et al., 1999;. In addition, MPD also indirectly affects the vesicular monoamine transporter (VMAT)-2, a protein that sequesters cytoplasmic DA inside the synaptic vesicles of nerve terminals. A single MPD treatment increases DA transport, VMAT-2 immunoreactivity, and binding of the VMAT-2 ligand [ 3 H]dihydrotetrabenazine in cytoplasmic vesicles purified from osmotic lysates of rat striatal synaptosomes (Sandoval et al., 2002(Sandoval et al., , 2003Volz et al., 2007a). These effects on cytoplasmic vesicles are D2 receptor-mediated, because the D2 receptor antagonist eticlopride (ETIC) attenuates or blocks these effects, and the D2 receptor agonist quinpirole (QUIN) mimics the effects of MPD (Sandoval et al., 2002;Truong et al., 2004).In co...

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Section: Resultsmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Methylphenidate-Induced Increases in Vesicular Dopamine Sequestration and Dopamine Release in the Striatum: The Role of Muscarinic and Dopamine D2 Receptors

Volz

Farnsworth

Rowley

et al. 2008

J Pharmacol Exp Ther

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“…The impact of cocaine is strikingly different from the pharmacological effects of another DAT inhibitor, methylphenidate (MPD), despite the fact that these agents: 1) have a similar binding site on the DAT (Schweri et al, 1985;Schenk, 2002), 2) block the inward transport of DA via the plasmalemmal DAT (Ritz et al, 1987;Wayment et al, 1999), and 3) redistribute VMAT-2 and associated vesicles away from synaptosomal membranes and into the cytoplasm (Riddle et al, , 2007Sandoval et al, 2002;Volz et al, 2007a,b). In particular, cocaine and MPD differentially affect the transport of DA into vesicles that remain associated with the synaptosomal membranes in that cocaine decreases DA transport because of vesicle trafficking, whereas MPD kinetically up-regulates the activity of the VMAT-2 protein per se in this subcellular fraction (Volz et al, 2007a,b).…”

Section: Discussionmentioning

confidence: 99%

“…Eticlopride hydrochloride and SCH-23390 were purchased from Sigma-Aldrich (St. Louis, MO). All drugs were administered at doses and times previously used to investigate receptor-mediated effects of psychostimulants in rat brain (Brown et al, 2001;Sandoval et al, 2002;Truong et al, 2004;Riddle et al, 2007). Drug doses were calculated as the free base, dissolved in 0.9% (w/v) saline, and administered at 1 ml/kg as stated in the figure legends.…”

Section: Methodsmentioning

confidence: 99%

“…After DA transport velocities were measured with RDE, SDS-polyacrylamide gel electrophoresis and Western blot analysis were completed on the membrane-associated vesicle samples as described previously (Riddle et al, , 2007Volz et al, 2007a). Forty micrograms of protein (as determined with a Bradford protein assay) from each membrane-associated vesicle sample was loaded onto the 10% gel.…”

Section: Methodsmentioning

confidence: 99%

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Cocaine Alters Vesicular Dopamine Sequestration and Potassium-Stimulated Dopamine Release: The Role of D2 Receptor Activation

Farnsworth¹,

Volz²,

Hanson³

et al. 2008

J Pharmacol Exp Ther

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Cocaine is a psychostimulant that inhibits the inward transport of dopamine (DA) via the neuronal DA transporter, thereby increasing DA concentrations in the synaptic cleft. Cocaine administration also causes a redistribution of striatal vesicular monoamine transporter (VMAT)-2-containing vesicles that cofractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles) to a nonmembrane-associated, cytoplasmic subcellular fraction. Although previous studies from our laboratory have focused on the impact of cocaine on cytoplasmic vesicles, the present report describes the pharmacological effects of cocaine on the membrane-associated vesicle population. Results revealed that the redistribution of VMAT-2 and associated vesicles away from synaptosomal membranes is associated with a decrease in total DA transport and DA content in the membrane-associated VMAT-2-containing subcellular fraction. Cocaine also decreases the velocity and magnitude of K ϩ -stimulated exocytotic DA release from whole striatal suspensions. The cocaineinduced VMAT-2 redistribution, decrease in DA release, and decrease in total DA transport are mediated by D2 receptors as these events were prevented by pretreatment with the D2 re-. These data suggest that after cocaine administration, D2 receptors are activated because of increased synaptic DA, resulting in a redistribution of DAcontaining vesicles away from synaptosomal membranes, thus leading to less DA released after a depolarizing stimulus. These findings provide insight into not only the mechanism of action of cocaine but also mechanisms underlying the regulation of dopaminergic neurons.Synaptic vesicles sequester neurotransmitters for storage and subsequent release. The transport of catecholamines into vesicles is solely mediated by the vesicular monoamine transporter (VMAT)-2, so any alterations in VMAT-2 function can affect intra-and extra-neuronal dopamine (DA) concentrations. There are probably several different populations of VMAT-2-associated vesicles, including those that cofractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles) and those that do not (referred to herein as cytoplasmic vesicles). These vesicle populations differ in that DA transport into cytoplasmic vesicles obeys Michaelis-Menten kinetics, whereas the DA transport profile of membrane-associated VMAT-2 is sigmoidal (Volz et al., 2007a). In addition, the membrane-associated vesicles are able to transport, in aggregate, 5-to 9-fold more DA in total capacity than cytoplasmic vesicles (Volz et al., 2007a); thus, they may have greater bearing on cytosolic DA concentrations than cytoplasmic vesicles.Several investigators have assessed the impact of cocaine on stimulated dopamine release. For example, Wightman and coworkers demonstrated that cocaine increases DA release caused by electrical stimuli that mobilize vesicles from the reserve vesicular pool (Venton et al., 2006). However, others have reported decrease...

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Comparative pharmacology and abuse potential of oral dexamphetamine and lisdexamfetamine—A literature review

Kämmerer

2024

Human Psychopharmacology

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ObjectiveTo compare the pharmacology and abuse potential of oral dexamphetamine and lisdexamfetamine (LDX).MethodsA search of Medline and Embase was conducted to identify relevant articles for this literature review.ResultsDexamphetamine and LDX, a prodrug of dexamphetamine, are indicated for the treatment of attention‐deficit/hyperactivity disorder. It has been suggested that LDX may have a reduced potential for oral abuse compared to immediate‐release dexamphetamine. As a prodrug, LDX has the same pharmacodynamic properties as dexamphetamine. A study in healthy adults showed that the pharmacokinetic profile of dexamphetamine following oral administration of LDX is essentially identical to that of an equimolar dose of dexamphetamine administered 1 h later. In addition, dexamphetamine produced subjective drug liking effects comparable to those produced by LDX. LDX showed linear dose proportional pharmacokinetics up to a dose of 250 mg, indicating a lack of overdose protection at supratherapeutic doses. Furthermore, the exposure to dexamphetamine released from LDX may be prolonged by the consumption of alkalizing agents.ConclusionsThe available evidence from pharmacodynamic, pharmacokinetic and abuse liability studies suggests a comparable potential for oral abuse of dexamphetamine and LDX.

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Therapeutic doses of amphetamine and methylphenidate selectively redistribute the vesicular monoamine transporter-2

Cited by 42 publications

References 16 publications

Methylphenidate-Induced Increases in Vesicular Dopamine Sequestration and Dopamine Release in the Striatum: The Role of Muscarinic and Dopamine D2 Receptors

Methylphenidate-Induced Increases in Vesicular Dopamine Sequestration and Dopamine Release in the Striatum: The Role of Muscarinic and Dopamine D2 Receptors

Cocaine Alters Vesicular Dopamine Sequestration and Potassium-Stimulated Dopamine Release: The Role of D2 Receptor Activation

Comparative pharmacology and abuse potential of oral dexamphetamine and lisdexamfetamine—A literature review

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