Pharmacokinetic-pharmacodynamic modelling of behavioural responses

Drug concentrations at the site of action in studies on behavioural pharmacology, are seldom constant. Therefore, observed changes in behaviour can be due to the natural time course of behavioural processes, but equally to changes in drug concentration, and it is therefore crucial to separate the former from the latter. One solution is keeping drug concentrations constant. However, one can also exploit the variation in drug concentration caused by absorption, distribution and elimination of a drug. This is done by simultaneous measurement of drug effect and concentration, while the drug enters and leaves a biologically relevant compartment, such as blood or cerebrospinal fluid. The concept of determining concentration-effect curves in individual animals, by monitoring in parallel drug effect and changes in concentration in one single experiment, has not yet found wide application in behavioural studies. The fact that behavioural processes, like any other physiological 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 assessed in every instance. Here we use PK/PD modelling to characterize fear-induced ultrasonic vocalizations and the anxiolytic effect of buspirone. This approach reduces the number of animals required to assess concentration-effect relationships. More importantly, it allows the identification of differences in individual drug response over a wide range of concentrations. Consequently, we suggest that PK/PD modelling can be used as a tool to study drug-induced changes in behavioural response. An introduction in PK/PD modelling is presented. (C) 1998 Elsevier Science B.V. All rights reserved.