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Am J Physiol Regul Integr Comp Physiol 281: R2059-R2071, 2001;
0363-6119/01 $5.00
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Vol. 281, Issue 6, R2059-R2071, December 2001

A set-point model with oscillatory behavior predicts the time course of 8-OH-DPAT-induced hypothermia

Klaas P. Zuideveld1, Hugo J. Maas1, Nicoline Treijtel1, Joost Hulshof2, Piet H. van der Graaf1, Lambertus A. Peletier3, and Meindert Danhof1

1 Sylvius Laboratory, Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, 2300 RA Leiden; 2 Department of Mathematics, Free University of Amsterdam, 1081 HV Amsterdam; and 3 Mathematical Institute, Leiden University, 2300 RA Leiden, The Netherlands

Agonists for the 5-hydroxytryptamine (HT)1A receptor induce a hypothermic response that is believed to occur by lowering of the body's set-point temperature. We have developed a physiological model that can be used to predict the complex time course of the hypothermic response after administration of 5-HT1A agonists to rats. In the model, 5-HT1A agonists exert their effect by changing heat loss through a control mechanism with a thermostat signal that is proportional to the difference between measured and set-point temperature. Agonists exert their effect in a direct concentration-dependent manner, with saturation occurring at higher concentrations. On the basis of simulations, it is shown that, depending on the concentration and the intrinsic efficacy of a 5-HT1A agonist, the model shows oscillatory behavior. The model was successfully applied to characterize the complex hypothermic response profiles after administration of the reference 5-HT1A agonists R-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) and S-8-OH-DPAT. This analysis revealed that the observed difference in effect vs. time profile for these two reference agonists could be explained by a difference in in vivo intrinsic efficacy.

pharmacokinetic-pharmacodynamic modeling; 5-hydroxytryptamine1A receptor; R-8-hydroxy-2-(di-n-propylamino)tetralin; S-8-hydroxy-2-(di-n-propylamino)tetralin


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