Using the self-administration of apomorphine and cocaine to measure the pharmacodynamic potencies and pharmacokinetics of competitive dopamine receptor antagonists.
Competitive dopamine receptor antagonists accelerate psychomotor stimulant self-administration. According to pharmacological theory of competitive antagonism antagonists raise the equiactive agonist concentration. In the self-administration paradigm this is assumed to be the satiety threshold or C(min). The magnitude of the proportional increase in satiety threshold (agonist concentration ratio) as a function of antagonist dose should reflect the antagonist pharmacodynamic potency. The time course of this effect should reflect the rate of change of antagonist occupancy of receptors and, therefore, antagonist concentration, i.e. pharmacokinetics. Rats self-administered apomorphine or cocaine at a stable rate and were then injected i.v. with one of four competitive D₁-like or D₂-like dopamine receptor antagonists and the session continued. The agonist concentrations at the time of each self-administration (satiety thresholds) were calculated during the session. The antagonists accelerated self-administration of both agonists with a concomitant increase in the calculated satiety thresholds. The maximum agonist concentration ratio was proportional to the dose of antagonist. The time courses of the changes in agonist concentration ratio were independent of the agonist and of the dose of antagonist. Schild analysis of the maximum agonist concentration ratio as a function of the antagonist dose allowed apparent pA₂ (or K(dose)) to be measured. Antagonist K(dose) values should provide a quantitative basis for receptor identification in behavioral pharmacology. The assay system may also measure the pharmacokinetics of antagonist elimination from the brain. Agonist self-administration represents a sensitive in vivo pharmacological assay system that provides information useful for pharmacokinetic/pharmacodynamic modeling of antagonist effects.
Norman
Andrew B
AB
Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA. andrew.norman@uc.edu
Tabet
Michael R
MR
Norman
Mantana K
MK
Tsibulsky
Vladimir L
VL
D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003216:Conditioning, Operant / Q000187:drug effects*; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration / Q000379:methods; D013997:Time Factors
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine; D001058:Apomorphine