New, potent cocaine analogs: ligand binding and transport studies in rat striatum

Boja, John W.; Carroll, F. Ivy; Rahman, Mostafizur; Abraham, Philip; Lewin, Anita H.; Kuhar, Michael J.

doi:10.1016/0014-2999(90)90627-i

Cited by 73 publications

(34 citation statements)

References 5 publications

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“…Reactions were terminated by the addition of ice-cold buffered solutions. Membrane-associated ligand was assessed after rapid filtration using Whatman GF͞B filters and a Brandel apparatus (26). Protein concentrations were determined by the Bradford method (Bio-Rad) and results analyzed by using MACLIGAND.…”

Section: Methodsmentioning

confidence: 99%

Cocaine reward models: Conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice

Sora

Wichems

Takahashi

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

436

387

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Cocaine and methylphenidate block uptake by neuronal plasma membrane transporters for dopamine, serotonin, and norepinephrine. Cocaine also blocks voltagegated sodium channels, a property not shared by methylphenidate. Several lines of evidence have suggested that cocaine blockade of the dopamine transporter (DAT), perhaps with additional contributions from serotonin transporter (5-HTT) recognition, was key to its rewarding actions. We now report that knockout mice without DAT and mice without 5-HTT establish cocaine-conditioned place preferences. Each strain displays cocaine-conditioned place preference in this major mouse model for assessing drug reward, while methylphenidate-conditioned place preference is also maintained in DAT knockout mice. These results have substantial implications for understanding cocaine actions and for strategies to produce anticocaine medications.Cocaine use is a principal drug abuse problem in the United States and other countries, contributing to substantial morbidity and mortality among the millions of individuals who use it each year (1). No current medication provides effective treatment for cocaine dependence (2). These facts give particular importance to defining the sites for cocaine reward in the brain so that they can be more accurately targeted by potential therapeutic agents.Several lines of evidence have provided support for a role of the dopamine transporter (DAT) as a primary site for cocaine reward. Structure-activity studies document good correlations between psychostimulant properties in tests of reward and their abilities to block DAT; poorer correlations are noted with their potencies in blocking other transporters (3, 4). Dopaminergic lesions blunt cocaine influences in model systems that test reward (5-7). Psychostimulants enhance dopamine release from dopaminergic circuits (8). Transgenic mice that overexpress DAT display enhanced cocaine-conditioned place preference (G.R.U., et al., unpublished observations). Finally, ''indifference'' to cocaine has been inferred from the reduced cocaine-stimulated locomotion recently described in mice that lack DAT (9, 10).There are also limitations to postulated direct relationships between DAT blockade and psychostimulant-induced reward. Among these are the failure of several compounds that potently inhibit dopamine uptake, including mazindol, to display substantial abuse liability in humans or animal model studies (11-13). Because mazindol potently inhibits dopamine and norepinephrine transport, but only weakly inhibits serotonin transport, this difference from cocaine could conceivably contribute to a distinct profile on tests of reward (14-16). These and other more indirect lines of evidence support the idea that cocaine's inhibition of serotonin uptake could also provide an alternative and plausible molecular site for contributions to cocaine reward (17)(18)(19).To test the dopamine-or serotonin-transporter dependence of cocaine reward, we have constructed DAT knockout mice and assessed cocaine-conditioned plac...

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Section: Methodsmentioning

confidence: 99%

Cocaine reward models: Conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice

Sora

Wichems

Takahashi

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

436

387

View full text Add to dashboard Cite

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“…Washed membranes were prepared from brain regions and were incubated with tritiated ligands as described (23)(24)(25)(26)(27)(28)(29)(30). Reactions were terminated by the addition of ice-cold buffered solutions as described (23)(24)(25)(26)(27)(28)(29)(30), and membrane-associated ligand estimated after rapid filtration over Whatman GF͞B filters using a Brandel apparatus. VMAT2, serotonin transporter, norepinephrine transporter, dopamine transporter, dopamine D 1 and D 2 receptor, serotonin 5HT 1 Measurement of Blood Pressure and Heart Rates.…”

Section: Methodsmentioning

confidence: 99%

VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

Takahashi

Miner

Sora

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

379

312

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The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP ؉ ) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP ؉ each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP ؉ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion.

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“…As an alternative, many laboratories have developed metabolically stable compounds based on the structure of cocaine [3][4][5][6][7][8][9][10]. Development of novel cocaine analogs has two purposes: first, as potential therapeutic agents to treat cocaine abuse; second, as ligands to probe the structure of cocaine binding site on monoamine transporters.…”

Section: Introductionmentioning

confidence: 99%

Irreversible binding of a novel phenylisothiocyanate tropane analog to monoamine transporters in rat brain

Murthy

Davies

Hedley

et al. 2007

Biochemical Pharmacology

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Irreversible tropane analogs have been useful in identifying binding sites of cocaine on biogenic amine transporters, including transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET). The present study characterizes the properties of the novel phenylisothiocyanate tropane HD-205, synthesized from the highly potent 2-napthyl tropane analog WF-23. [ 125 I]HD-244 was synthesized with chloramine-T, purified on HPLC, reacted with rat striatal membranes, and proteins were separated by SDS-PAGE. Results showed several non-specific labeled bands, but only a single specific band of radioactivity co-migrating with an immunoreactive DAT band at approx. 80 kDa was detected, suggesting that [ 125 I]HD-244 covalently labeled DAT protein in striatal membranes. These results demonstrate that phenylisothiocyanate analogs of WF-23 can be used as potential ligands to map distinct binding sites of cocaine analogs at DAT.

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New, potent cocaine analogs: ligand binding and transport studies in rat striatum

Cited by 73 publications

References 5 publications

Cocaine reward models: Conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice

Cocaine reward models: Conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice

VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

Irreversible binding of a novel phenylisothiocyanate tropane analog to monoamine transporters in rat brain

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