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 pretreatment 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.
Footnotes
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This work was supported by the Intramural Research program of the National Institutes of Health National Institute on Drug Abuse.
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Parts of this work were previously presented at the following conference: Hiranita T, Newman AH, and Katz JL (2008) Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats: comparisons with monoamine uptake inhibitors; 2008 Annual Meeting of the American Society for Pharmacology and Experimental Therapeutics; 2008 Apr 5–9; San Diego, CA. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.145813.
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ABBREVIATIONS: DAT, dopamine transporter; SERT, serotonin transporter; NET, norepinephrine transporter; BZT, benztropine; AHN 1-055, 3α-[bis(4′-fluorophenyl)methoxy]-tropane; AHN 2-005, N-allyl-3α-[bis(4′-fluorophenyl)methoxy]-tropane; JHW 007, N-(n-butyl)-3α-[bis(4′-fluorophenyl)methoxy]-tropane; LED, light-emitting diode; FR, fixed ratio; inj, injection; ANOVA, analysis of variance; GBR 12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; WIN 35,428, (-)-carbomethoxy-3β-(4-fluorophenyl)tropane.
- Received September 5, 2008.
- Accepted February 18, 2009.
- U.S. Government work not protected by U.S. copyright
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