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Research ArticleNEUROPHARMACOLOGY

Oral Cocaine Pharmacokinetics and Pharmacodynamics in a Cumulative-Dose Regimen: Pharmacokinetic-Pharmacodynamic Modeling of Concurrent Operant and Spontaneous Behavior within an Operant Context

Chyan E. Lau, Lei Sun, Qiao Wang, Allan Simpao and John L. Falk
Journal of Pharmacology and Experimental Therapeutics November 2000, 295 (2) 634-643;
Chyan E. Lau
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Lei Sun
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Qiao Wang
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Allan Simpao
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John L. Falk
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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

  • 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

  • ↵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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Journal of Pharmacology and Experimental Therapeutics: 295 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 2
1 Nov 2000
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Research ArticleNEUROPHARMACOLOGY

Oral Cocaine Pharmacokinetics and Pharmacodynamics in a Cumulative-Dose Regimen: Pharmacokinetic-Pharmacodynamic Modeling of Concurrent Operant and Spontaneous Behavior within an Operant Context

Chyan E. Lau, Lei Sun, Qiao Wang, Allan Simpao and John L. Falk
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 634-643;

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Research ArticleNEUROPHARMACOLOGY

Oral Cocaine Pharmacokinetics and Pharmacodynamics in a Cumulative-Dose Regimen: Pharmacokinetic-Pharmacodynamic Modeling of Concurrent Operant and Spontaneous Behavior within an Operant Context

Chyan E. Lau, Lei Sun, Qiao Wang, Allan Simpao and John L. Falk
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 634-643;
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