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An in silico pharmacokinetic/pharmacodynamic model of agonist self‐administration behavior in rats (1053.8)
Author(s) -
Ross Alexander,
Tsibulsky Vladimir,
Norman Andrew
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1053.8
Subject(s) - agonist , pharmacodynamics , pharmacology , population , antagonist , receptor , pharmacokinetics , competitive antagonist , chemistry , medicine , environmental health
Rats trained to maintain self‐administration of dopamine (DA) receptor agonists do so with mathematically predictable regularity. The goal of this research is to model a proposed receptor‐based mechanism underlying the satiety threshold model of maintained self‐administration. MATLAB Simbiology was used to construct a multi‐compartment pharmacokinetic/pharmacodynamic model with a receptor population that exhibits mutually exclusive binding with either an agonist or a competitive antagonist according to the law of mass action. This model also incorporates drug distribution and elimination rate constants. Self‐administration events are programmed to occur only if the amount of agonist‐receptor complexes is at or below a threshold above which no further self‐administration events occur. Simulations show that the inter‐event interval is proportional to the unit dose, competitive antagonists decrease the inter‐event interval until they are eliminated from the system, and reducing the population of receptors via modeling irreversible antagonism also decreases the inter‐event interval. These simulations are consistent with maintained self‐administration behavior in rats, and suggest that the proposed receptor‐based mechanism is a viable explanation for this behavior. This model provides a useful tool for investigating the potential of antagonist‐based pharmacotherapies for drug addiction. Grant Funding Source : NIH Grant DP1DA031386