Abstract
Despite wide use of cumulative-dosing procedures to evaluate dose-response relations, limited attention has been paid to investigating drug concentration-effect relations. We first characterized the pharmacokinetic (PK) parameters for i.v. (2 mg/kg) and oral cocaine (20 and 40 mg/kg) in rats. Cocaine's concentration-time profile for the escalating cumulative-dose regimen was simulated from PK parameters, dose size (1, 2, 7, 20, and 45 mg/kg by the oral route), and dosing interval (τ, 35 min) as well as validated from blood sampling at various time points. This concentration-time profile was integrated with pharmacodynamic (PD) profiles of differential reinforcement of low rate performance and spontaneous activity (large and small movements) under a differential reinforcement of low rate 45-s schedule. Effects on three behavioral measures were characterized by integrated PK-PD models using the sigmoid Emax (for increases in shorter response rate or large movements) and inhibitoryEmax (for decreases in density of reinforcement) models. But for the intrinsic differences in baseline and efficacy values among the behavioral endpoints, one set of PD parameters (i.e., potency and Hill factors) predicted concentration-effect relations for the three behavioral indices across all five doses. Concurrent monitoring of operant and spontaneous activity behavior within an operant context provides a novel behavioral paradigm to investigate drug effects on spontaneous activity under conditions where a behavioral contingency exists. Additionally, a cumulative-dosing procedure is efficient for determining the entire dose-response relation and provides an ideal mode to study phenomena such as sensitization or tolerance by varying dose size and/or τ.
Footnotes
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Send reprint requests to: Chyan E. Lau, Ph.D., Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Rd., Piscataway, NJ 08854-8020. E-mail:clau{at}rci.rutgers.edu
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↵1 This research was supported by Grants R01 DA05305 and Research Scientist Award K05 DA 00142.
- Abbreviations:
- CTP
- concentration-time profile
- DRL
- differential reinforcement of low rate
- PD
- pharmacodynamics
- PK
- pharmacokinetics
- IRT
- inter-response time
- τ
- dosing interval
- RM
- repeated measures
- AIC
- Akaike's information criterion
- Vc
- volume of distribution in the central compartment
- Cl
- clearance
- Vss
- volume of distribution at steady state
- EC50
- the concentration at half of Emax for the shorter-response rate or large movements
- Emax
- the maximal effect
- IC50
- the concentration at half ofEmax for the density of reinforcement
- lm
- large movements
- CV
- coefficient of variation
- Received April 26, 2000.
- Accepted July 10, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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