Hiranita T, Soto P, Newman A, Katz JL
Assessment of Reinforcing Effects of Benztropine Analogues and Their Effects on Cocaine Self-Administration in Rats: Comparisons with Monoamine Uptake Inhibitors. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Feb 19.
Benztropine (BZT) analogues 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 analogues 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/inj) or food reinforcement under fixed-ratio 5-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/inj of cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analogue, AHN1-055, also maintained responding (0.1 mg/kg/inj), though maximal rates were less than those with cocaine. Responding was not maintained above vehicle levels by the N-allyl (AHN2-005) and N-butyl (JHW007) BZT analogues, nor with nisoxetine or citalopram. Pre-session 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 AHN1-055 (32 mg/kg) increased responding maintained by low cocaine doses, and decreased responding maintained by higher doses. A higher dose of AHN1-055 completely suppressed cocaine-maintained responding. Both AHN2-005 and JHW007 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 analogues that left food-maintained responding unchanged. During a component in which injections were not available, methylphenidate and AHN1-055, but not AHN2-005 or JHW007 increased response rates. These findings further support the low abuse liability of BZT analogues and their potential development as medications for cocaine abuse.
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