Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats

Comparisons with monoamine uptake inhibitors

Takato Hiranita, Paul L. Soto, Amy H. Newman, Jonathan L. Katz

Research output: Contribution to journalArticle

Abstract

Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producing behavioral effects predicting abuse liability. The present study compared reinforcing effects of intravenous BZT analogs with those of standard monoamine uptake inhibitors and the effects of their oral pre-treatment on cocaine self-administration. Responding of rats was maintained by cocaine [0.032-1.0 mg/kg/injection (inj)] or food reinforcement under fixed-ratio five-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analog, AHN 1-055 (3α-[bis(4′-fluorophenyl)methoxy]-tropane), also maintained responding (0.1 mg/kg/inj), although maximal rates were less than those with cocaine. Responding was not maintained above vehicle levels by the N-allyl, AHN 2-005 (N-allyl-3α-[bis(4′-fluorophenyl)methoxy]-tropane), and N-butyl, JHW 007 [N-(n-butyl)-3α-[bis(4′-fluorophenyl)methoxy]- tropane], BZT analogs, and it was not maintained with nisoxetine or citalopram. Presession treatment with methylphenidate (3.2-32 mg/kg) dose-dependently shifted the cocaine self-administration dose-effect curve leftward, whereas nisoxetine and citalopram effects were not significant. An intermediate dose of AHN 1-055 (32 mg/kg) increased responding maintained by low cocaine doses and decreased responding maintained by higher doses. A higher dose of AHN 1-055 completely suppressed cocaine-maintained responding. Both AHN 2-005 and JHW 007 dose-dependently (10-32 mg/kg) decreased cocaine self-administration, shifting its dose-effect curve down. Decreases in cocaine-maintained responding occurred at doses of methylphenidate and BZT analogs that left food-maintained responding unchanged. During a component in which injections were not available, methylphenidate and AHN 1-055, but not AHN 2-005 or JHW 007, increased response rates. These findings further support the low abuse liability of BZT analogs and their potential development as medications for cocaine abuse.

Original languageEnglish (US)
Pages (from-to)677-686
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume329
Issue number2
DOIs
StatePublished - May 2009
Externally publishedYes

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Benztropine
Self Administration
Cocaine
Methylphenidate
nisoxetine
Tropanes
Citalopram
Injections
Food
Cocaine-Related Disorders
Dopamine
Appointments and Schedules

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats : Comparisons with monoamine uptake inhibitors. / Hiranita, Takato; Soto, Paul L.; Newman, Amy H.; Katz, Jonathan L.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 329, No. 2, 05.2009, p. 677-686.

Research output: Contribution to journalArticle

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