Abstract
Rationale and objectives
Benztropine (BZT) analogs and other atypical dopamine uptake inhibitors selectively decrease cocaine self-administration at doses that do not affect responding maintained by other reinforcers. Those effects were further characterized in the current study using a behavioral economic assessment of how response requirement (price) affects reinforcers obtained (consumption) in rats.
Methods
Two groups of rats were trained to press levers with food (45-mg pellet) or cocaine (0.32 mg/kg/injection) reinforcement under fixed-ratio (FR) 5-response schedules. In selected sessions, the FR requirement was increased (5–80) during successive 20-min components to determine demand curves, which plot consumption against price. An exponential function was fitted to the data to derive the consumption at zero price (Q 0) and the rate of decrease in consumption (essential value, EV) with increased price. The BZT analogs, AHN1-055, AHN2-005, JHW007 (3.2–10 or 17.8 mg/kg, each), vehicle, or comparison drugs (methylphenidate, ketamine), were administered i.p. before selected demand-curve determinations.
Results
Consumption of cocaine or food decreased with increased FR requirement. Each drug shifted the demand curve rightward at the lowest doses and leftward/downward at higher doses. The effects on EV and Q 0 were greater for cocaine than for food-reinforced responding. Additionally, the effects of the BZT analogs on EV and Q 0 were greater than those obtained with a standard dopamine transport inhibitor, methylphenidate, and the NMDA antagonist, ketamine (1.0–10.0 mg/kg, each). With these latter drugs, the demand-curve parameters were affected similarly with cocaine and food-maintained responding.
Conclusions
The current findings, obtained using a behavioral economic assessment, suggest that BZT analogs selectively decrease the reinforcing effectiveness of cocaine.
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Acknowledgements
We thank Maryann Carrigan for administrative assistance and Li Jing for occasional help with the conduct of experiments. We thank Jianjing Cao and Amy H. Newman, of the Medicinal Chemistry Section of the NIDA Intramural Research Program, for synthesis of the BZT analogs reported herein.
Funding
The current studies were supported by funding from the National Institute on Drug Abuse (NIDA) Intramural Research Program (IRP).
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Zanettini, C., Wilkinson, D.S. & Katz, J.L. Behavioral economic analysis of the effects of N-substituted benztropine analogs on cocaine self-administration in rats. Psychopharmacology 235, 47–58 (2018). https://doi.org/10.1007/s00213-017-4739-x
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DOI: https://doi.org/10.1007/s00213-017-4739-x