Pharmacokinetic-pharmacodynamic modelling of behavioural responses

Drug concentrations at the site of action in studies on behavioural pharmac ology, are seldom constant. Therefore, observed changes in behaviour can be due to the natural time course of behavioural processes, but equally to ch anges in drug concentration, and it is therefore crucial to separate the fo rmer from the latter. One solution is keeping drug concentrations constant. However, one can also exploit the variation in drug concentration caused b y absorption, distribution and elimination of a drug. This is done by simul taneous measurement of drug effect and concentration, while the drug enters and leaves a biologically relevant compartment, such as blood or cerebrosp inal fluid. The concept of determining concentration-effect curves in indiv idual animals, by monitoring in parallel drug effect and changes in concent ration in one single experiment, has not yet found wide application in beha vioural studies. The fact that behavioural processes, like any other physio logical process, change over time, may have contributed to the scarcity of pharmacokinetic-pharmacodynamic (PK/PD) studies in behavioural pharmacology . However, there are now mathematical techniques that allow PK/PD modelling even if the effect parameter changes over time or cannot be properly asses sed in every instance. Here we use PK/PD modelling to characterize fear-ind uced ultrasonic vocalizations and the anxiolytic effect of buspirone. This approach reduces the number of animals required to assess concentration-eff ect relationships. More importantly, it allows the identification of differ ences in individual drug response over a wide range of concentrations. Cons equently, we suggest that PK/PD modelling can be used as a tool to study dr ug-induced changes in behavioural response. An introduction in PK/PD modell ing is presented. (C) 1998 Elsevier Science B.V. All rights reserved.