A set-point model with oscillatory behavior predicts the time course of 8-OH-DPAT-induced hypothermia.
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-HT(1A) agonists to rats. In the model, 5-HT(1A) 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-HT(1A) agonist, the model shows oscillatory behavior. The model was successfully applied to characterize the complex hypothermic response profiles after administration of the reference 5-HT(1A) 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.
Zuideveld
K P
KP
Sylvius Laboratory, Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, 2300 RA Leiden, The Netherlands.
Maas
H J
HJ
Treijtel
N
N
Hulshof
J
J
van der Graaf
P H
PH
Peletier
L A
LA
Danhof
M
M
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D007035:Hypothermia / Q000139:chemically induced* / Q000503:physiopathology; D007700:Kinetics; D008954:Models, Biological; D009991:Oscillometry; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013237:Stereoisomerism; D013997:Time Factors
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin