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Research ArticleNEUROPHARMACOLOGY

In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain

Vishakantha Murthy, Thomas J. Martin, Susy Kim, Huw M. L. Davies and Steven R. Childers
Journal of Pharmacology and Experimental Therapeutics August 2008, 326 (2) 587-595; DOI: https://doi.org/10.1124/jpet.108.138842
Vishakantha Murthy
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Thomas J. Martin
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Susy Kim
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Huw M. L. Davies
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Steven R. Childers
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Abstract

Previous studies have shown that the phenylisothiocyanate tropane analog 2-β-propanoyl-3-β-(2-naphthyl)-8-[4-isothiocyanato)benzyl]nortropane (HD-205) binds covalently to dopamine and serotonin transporters (DAT and SERT, respectively) in rat brain membranes (Biochem Pharmacol74:336–344, 2007). The present study evaluated the irreversible effects of HD-205 in vivo in rats after intracranial injection. Rats were implanted with unilateral cannulae in rat striatum, and HD-205 (0.001–3 nmol) was administered by intrastriatal injection. In vitro autoradiography of DAT binding with [125I]2-carbomethoxy-3-(4-iodophenyl)tropane (RTI-55) on brain sections obtained 24 h after injection showed a highly localized blockade of binding in striatum, with maximal blockade of binding by 1 to 3 nmol HD-205. Similar blockade of SERT binding (using [3H]-citalopram) was observed in the same area. No blockade of DAT or SERT binding was observed after intrastriatal injections of the reversible analog 2-β-propanoyl-3-β-(2-naphthyl)-8-benzyl nortropane (HD-206), and HD-205 treatment had no effect on D2- and μ-opioid-stimulated guanosine 5′-O-(3-[35S]thio)-triphosphate binding in sections from the same animals. In a time course study, rats administered with 1 nmol HD-205 showed recovery of 50% DAT binding after 3 to 4 days postinjection, and full recovery after 6 weeks. Rats implanted with bilateral cannulae were tested for cocaine-induced locomotor activity. Two days after intrastriatal injection of 1 nmol of HD-205, systemic (20 mg/kg i.p.) cocaine-induced locomotor activity was not affected; however, locomotor activity induced by intrastriatal administration of cocaine (6 nmol) was eliminated. This strategy of site-specific chemical blockade of transporters could serve as a valuable tool to evaluate the neuroanatomical basis of DAT-mediated cocaine effects.

Footnotes

  • This research was supported by Grant DA-06634 from the National Institute on Drug Abuse.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.138842.

  • ABBREVIATIONS: DAT, dopamine transporter; SERT, serotonin transporter; NET, norepinephrine transporter; WF-23, 2-propanoyl-3-(2-naphthyl)-tropane; AD-96-129, 4-(2-(diphenylmethoxy)ethyl)-1-benzyl piperidine; GA-II-34, N-(n-butyl)-4-(4‴-azido-3‴-iodophenyl)-4′,4″-difluoro-3α-(diphenylmethoxy)tropane; RTI-82, 3-(4-chlorophenyl)-tropane-2-carboxylate; MFZ-2-24, N-(4-(4-azido-3-[125I]iodophenyl)butyl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropane; TM, transmembrane; DEEP, 1-[2-(diphenylmethoxy)ethyl]-4-[2-(4-azido-3-iodophenyl)ethyl]piperazine; RTI-76, 3-(p-chlorophenyl)tropan-2-carboxylic acid p-isothiocyanatophenylethyl ester hydrochloride; GTPγS, guanosine 5′-O-(3-thio)triphosphate; DAMGO, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; DPCPX, 8-cyclopentyl-1,3-dihydroxylxanthine; NPA, R-(–)-propylnorapomorphine; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance; 5-HT, 5-hydroxytryptamine; OD, optical density; HD-205, 2-β-propanoyl-3-β-(2-naphthyl)-8-[4-isothiocyanato)benzyl]nortropane; HD-206, 2-β-propanoyl-3-β-(2-naphthyl)-8-benzyl nortropane.

    • Received March 7, 2008.
    • Accepted May 20, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 326 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 326, Issue 2
1 Aug 2008
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Research ArticleNEUROPHARMACOLOGY

In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain

Vishakantha Murthy, Thomas J. Martin, Susy Kim, Huw M. L. Davies and Steven R. Childers
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 587-595; DOI: https://doi.org/10.1124/jpet.108.138842

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Research ArticleNEUROPHARMACOLOGY

In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain

Vishakantha Murthy, Thomas J. Martin, Susy Kim, Huw M. L. Davies and Steven R. Childers
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 587-595; DOI: https://doi.org/10.1124/jpet.108.138842
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