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Research ArticleArticle

Pharmacokinetic-Pharmacodynamic Modeling of the Psychomotor Stimulant Effect of Cocaine after Intravenous Administration: Timing Performance Deficits

Chyan E. Lau, Fang Ma, David M. Foster and John L. Falk
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 535-543;
Chyan E. Lau
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Fang Ma
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David M. Foster
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John L. Falk
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Abstract

We investigated dose-response cocaine pharmacokinetic and metabolite profiles in a within-subject design after intravenous bolus cocaine administration (1–4 mg/kg) in rats under a food-limited regimen. Cocaine was rapidly distributed (T1/2β = 1.09 min) and eliminated (T1/2α = 14.93 min). Norcocaine was not detected. The free fraction of cocaine was 31.3–33.1% for serum cocaine concentrations of 0.5 to 1 μg/ml. Parallel pharmacodynamics was studied using performance on a contingency-controlled timing behavior, a differential reinforcement of low rate schedule (45 s) in 3-h sessions. Cocaine increased the shorter-response rate and decreased the density of reinforcement in a dose- and time-related fashion. The increased shorter-response rate is the stimulatory effect herein reported. The changes in shorter-response rate and the density of reinforcement were directly interpretable as functions of cocaine concentrations in the respective hypothetical effect compartments by using sigmoidal Emaxand inhibitory Emax models, respectively. Because the concentration at half of Emaxfor the shorter-response rate (EC50 = 0.467 μg/ml) was greater than that for density of reinforcement (IC50 = 0.070 μg/ml), the former began to return toward baseline sooner than the latter. Only as cocaine concentration decreased to values smaller than the EC50 did the density of reinforcement begin to return toward baseline. Thus, the density of reinforcement is an index for evaluating the deficit in timing performance. The concentration-effect plot confirmed that the intensity of the effects of cocaine depends solely on concentration regardless of the dose. These results demonstrated that the pharmacokinetic-pharmacodynamic analysis allows the identification of the stimulant action of cocaine, which in turn delineates its consequence on timing performance.

Footnotes

  • Send reprint requests to: Chyan E. Lau, Ph.D., Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Road, 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-DA00142.

  • Abbreviations:
    AIC
    Akaike’s Information Criterion
    AUC
    area under the curve
    ANOVA
    analysis of variance
    AUMC
    area under the first moment curve
    HPLC
    high-performance liquid chromatography
    Cl
    clearance
    Cpt
    compartment
    DRL
    differential reinforcement of low rate
    E0
    the effect when cocaine concentration is zero
    Emax
    the maximal effect
    EC50
    the concentration at half ofEmax for the short-response rate
    IC50
    the concentration at half ofEmax for the density of reinforcement
    FSD
    fractional standard deviation
    IRT
    interresponse time
    MRT
    mean residence time
    PK
    pharmacokinetics
    PD
    pharmacodynamics
    Vc
    volume of distribution at the central compartment
    Vss
    volume of distribution at steady state
    • Received October 28, 1998.
    • Accepted August 10, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
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Research ArticleArticle

Pharmacokinetic-Pharmacodynamic Modeling of the Psychomotor Stimulant Effect of Cocaine after Intravenous Administration: Timing Performance Deficits

Chyan E. Lau, Fang Ma, David M. Foster and John L. Falk
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 535-543;

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Research ArticleArticle

Pharmacokinetic-Pharmacodynamic Modeling of the Psychomotor Stimulant Effect of Cocaine after Intravenous Administration: Timing Performance Deficits

Chyan E. Lau, Fang Ma, David M. Foster and John L. Falk
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 535-543;
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