<i>N‐n</i>‐alkylnicotinium and <i>N‐n</i>‐alkylpyridinium analogs inhibit the dopamine transporter: Selectivity as nicotinic receptor antagonists

Zhu, Jun; Crooks, Peter A.; Ayers, Joshua T.; Sumithran, Sangeetha P.; Dwoskin, Linda P.

doi:10.1002/ddr.10328

Cited by 4 publications

(5 citation statements)

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“…Although in vivo nicotine administration results in an increase in striatal dopamine transporter function as demonstrated using in vivo voltammetry and in vitro synaptosomal [ 3 H]dopamine uptake, previous results show that when striatum is exposed to nicotine in vitro, there is no effect on [ 3 H]dopamine uptake (Carr et al, 1989;Zhu et al, 2003). These contrasting findings may be due to the effect of nicotine at the dopaminergic cell body or upon the neuronal circuitry, which has been interrupted during the preparation of striatal slices or synaptosomes.…”

Section: Discussionmentioning

confidence: 99%

“…(Corrigall et al, 1992;Koob, 1992;Stolerman and Jarvis, 1995). Previous results show that in vitro exposure to nicotine does not alter [ 3 H]dopamine uptake into striatal synaptosomes (Carr et al, 1989;Zhu et al, 2003); however, the effect of systemic nicotine administration on [ 3 H] dopamine uptake into striatal synaptosomes and on dopamine transporter trafficking has not been determined.…”

Section: Introductionmentioning

confidence: 93%

“…[ 3 H]Dopamine uptake assays were conducted using a previously published method (Zhu et al 2003). Separate groups of rats were injected with nicotine (0.32 mg/kg, free base weight, s.c.) or saline.…”

Section: Synaptosomal [ 3 H]dopamine Uptakementioning

confidence: 99%

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Nicotine increases dopamine transporter function in rat striatum through a trafficking-independent mechanism

Middleton

Apparsundaram

King-Pospisil

et al. 2007

European Journal of Pharmacology

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In previous in vivo voltammetry studies, acute nicotine administration increased striatal dopamine clearance. The current study aimed to determine whether nicotine also increases [ 3 H]dopamine uptake across the time course of the previous voltammetry studies and whether dopamine transporter trafficking to the cell surface mediates the nicotine-induced augmentation of dopamine clearance in striatum. Rats were administered nicotine (0.32 mg/kg, s.c.); striatal synaptosomes were obtained 5, 10, 40 or 60 min later. Nicotine increased (25%) the V max of [ 3 H]dopamine uptake at 10 and 40 min. To determine whether the increase in V max was due to an increase in dopamine transporter density, [ 3 H]GBR 12935 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride) binding was performed using rat striatal membranes; no differences were found between nicotine and saline control groups at 5, 10 or 40 min post-injection, indicating that nicotine did not increase striatal dopamine transporter density; however, [ 3 H]GBR 12935 binding assays determine both cell surface and intracellular dopamine transporter. Changes in cellular dopamine transporter localization in striatum were determined using biotinylation and subfractionation approaches; no differences between nicotine and saline control groups were observed at 10 and 40 min post-injection. These results suggest that the nicotine-induced increase in dopamine uptake and clearance in striatum may occur via a trafficking-independent mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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Nicotine increases dopamine transporter function in rat striatum through a trafficking-independent mechanism

Middleton

Apparsundaram

King-Pospisil

et al. 2007

European Journal of Pharmacology

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“…26 In vitro striatal VMAT2 and DAT function were assessed using saturation analysis of [ 3 H]dopamine uptake into vesicles 27 and synaptosomes, 28 respectively. To evaluate methamphetamine-induced DAT reverse transport, methamphetamine-evoked [ 3 H]dopamine overflow was determined using superfused striatal slices.…”

Section: Methodsmentioning

confidence: 99%

Diet-induced obesity: dopamine transporter function, impulsivity and motivation

et al. 2012

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OBJECTIVE A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. DESIGN To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. METHODS Striatal D2-receptor density was determined by in vitro kinetic analysis of [3H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [3H]dopamine uptake, methamphetamine-evoked [3H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. RESULTS Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [3H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. CONCLUSION Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that motivation for high-fat food, but not impulsive behavior, predicts the development of obesity, whereas decreases in striatal DAT function are exhibited only after the development of obesity.

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“…Potential interaction of the analogs with DAT was determined by evaluating the ability of the analogs to inhibit [ 3 H]DA uptake into striatal synaptosomes using a published method. 104 For each experiment, striata from an individual rat were homogenized in 20 mL of ice-cold 0.32 M sucrose containing 5 mM NaHCO 3 (pH 7.4) with 16 up and down strokes of a Teflon pestle homogenizer (clearance ~0.003 inches). Homogenates were centrifuged (2000g for 10 minutes at 4°C) and the resulting supernatants were again centrifuged (20 000g for 17 minutes at 4°C).…”

Section: [ 3 H]da Uptake Assaymentioning

confidence: 99%

Introduction of unsaturation into theN-n-alkyl chain of the nicotinic receptor antagonists, NONI and NDNI: Effect on affinity and selectivity

Sumithran

Crooks

et al. 2005

AAPS J

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.M., standard error of the mean; * indicates putative nAChR subtype assignment.ABSTRACT N-n-Octylnicotinium iodide (NONI) and N-n-decylnicotinium iodide (NDNI) are selective nicotinic receptor (nAChR) antagonists mediating nicotine-evoked striatal dopamine (DA) release, and inhibiting [ 3 H]nicotine binding, respectively. This study evaluated effects of introducing unsaturation into the N-n-alkyl chains of NONI and NDNI on inhibition of [ 3 H]nicotine and [ 3 H]methyllycaconitine binding (α4β2* and α7* nAChRs, respectively), 86 Rb + efflux and [ 3 H]DA release (agonist or antagonist effects at α4β2* and α6β2*-containing nAChRs, respectively). In the NONI series, introduction of a C 3 -cis-(NONB3c), C 3 -trans-(NONB3t), C 7 -double-bond (NONB7e), or C 3 -triple-bond (NONB3y) afforded a 4-fold to 250-fold increased affinity for [ 3 H]nicotine binding sites compared with NONI. NONB7e and NONB3y inhibited nicotine-evoked 86 Rb + efflux, indicating α4β2* antagonism. NONI analogs exhibited a 3-fold to 8-fold greater potency inhibiting nicotineevoked [ 3 H]DA overflow compared with NONI (IC 50 = 0.62 µM; Imax = 89%), with no change in Imax, except for NONB3y (Imax = 50%). In the NDNI series, introduction of a C 4 -cis-(NDNB4c), C 4 -trans-double-bond (NDNB4t), or C 3 -triple-bond (NDNB3y) afforded a 4-fold to 80-fold decreased affinity for [ 3 H]nicotine binding sites compared with NDNI, whereas introduction of a C 9 double-bond (NDNB9e) did not alter affinity. NDNB3y and NDNB4t inhibited nicotine-evoked 86 Rb + efflux, indicating antagonism at α4β2* nAChRs. Although NDNI had no effect, NDNB4t and NDNB9e potently inhibited nicotine-evoked [ 3 H]DA overflow (IC 50 = 0.02-0.14 µM, Imax = 90%), as did NDNB4c (IC 50 = 0.08 µM; Imax = 50%), whereas NDNB3y showed no inhibition. None of the analogs had significant affinity for α7* nAChRs. Thus, unsaturated NONI analogs had enhanced affinity at α4β2*-and α6β2*-containing nAChRs, however a general reduction of affinity at α4β2* and an uncovering of antagonist effects at α6β2*-containing nAChRs were observed with unsaturated NDNI analogs.

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N‐n‐alkylnicotinium and N‐n‐alkylpyridinium analogs inhibit the dopamine transporter: Selectivity as nicotinic receptor antagonists

Cited by 4 publications

References 46 publications

Nicotine increases dopamine transporter function in rat striatum through a trafficking-independent mechanism

Nicotine increases dopamine transporter function in rat striatum through a trafficking-independent mechanism

Diet-induced obesity: dopamine transporter function, impulsivity and motivation

Introduction of unsaturation into theN-n-alkyl chain of the nicotinic receptor antagonists, NONI and NDNI: Effect on affinity and selectivity

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