Serotonergic mechanisms in the hypothalamus mediate thermoregulatory responses in rats

Lin, Mao Tsun; Wu, Jionn-Jong; Tsay, B. L.

doi:10.1007/bf00508342

Cited by 58 publications

(21 citation statements)

References 27 publications

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“…Indeed, the neurons ultimately responsible for the decrease in body temperature are probably located in the medial preoptic region of the hypothalamus. This is based, in part, on the observations that increasing 5-HT in the medial preoptic region, either by stimulating the raphe nuclei or directly injecting 5-HT into this region, induces a decrease in core temperature in the rat (Lin et al 1983). Nevertheless, the possibility that the 8-OH-DPAT-induced hypothermia could in fact be mediated by somatodendritic 5-HT 1A autoreceptors of 5-HT neurons in the median raphe has to be considered.…”

Section: Discussionmentioning

confidence: 99%

Serotonin 1A Receptor Activation and Hypothermia in Humans Lack of Evidence for a Presynaptic Mediation

Blier

Seletti

Gilbert

et al. 2002

Neuropsychopharmacology

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The hypothermia produced by 5-HT 1A 1A receptors are located both on the cell body of 5-HT neurons and on postsynaptic neurons throughout the central nervous system. On 5-HT neurons, 5-HT 1A receptors mediate a negative feedback influence on firing activity. When overactivated by an excess amount of 5-HT, or by an exogenous agonist, they slow down the pacemaker activity leading to a decreased firing rate of 5-HT neurons (Aghajanian and Lakoski 1984;Blier and de Montigny 1987). As 5-HT release is proportional to firing rate, the excess activation of these 5-HT 1A autoreceptors generally results in a decrease of 5-HT release in projecting structures (see Rueter et al. Gainesville, FL 32610, Tel.: 352-392-3681, Fax : 352-392-2579, E-mail : blier@psych.med.ufl.edu Received May 11, 2001 revised January 16, 2002; accepted February 20, 2002. Online publication: 2/27/02 at www.acnp.org/citations/ Npp022702253. 302 P. Blier et al. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 2 1997). The postsynaptic 5-HT 1A receptors, particularly abundant in the limbic system, commonly exert an inhibitory function on neuronal activity as well. Therefore, the net effect of the systemic administration of a 5-HT 1A receptor agonist on 5-HT 1A signal transfer in postsynaptic areas represents a composite of decreased 5-HT release, resulting from 5-HT 1A autoreceptor activation, and direct occupation of the postsynaptic 5-HT 1A receptors.Although it is well established that neuroendocrine responses, such as growth hormone and adenocorticotropic hormone release, produced by systemic administration of 5-HT 1A agonists are mediated by postsynaptic 5-HT 1A receptors (Van de Kar et al. 1985;Gilbert et al. 1988;Pan and Gilbert 1992), there has been controversy with respect to the hypothermia resulting from this pharmacological challenge. The very first study examining the pre-versus postsynaptic mediation of the hypothermia clearly indicated that this response was produced by postsynaptic 5-HT 1A receptors (Hjörth 1985). Indeed, this initial study clearly showed that the hypothermic response to the prototypical 5-HT 1A agonist 8-OH-DPAT was not attenuated, but even enhanced in rats pretreated daily for 3 days with the 5-HT synthesis inhibitor parachlorophenylalanine (PCPA). Subsequently, identical results were obtained by another group of investigators using 2-day injections of a higher dose of PCPA (Goodwin et al. 1987). When their PCPA treatment was prolonged, however, for 14 days, despite producing its maximal effect on 5-HT levels after the first 3 days, the 8-OH-DPATinduced hypothermia was dampened and the conclusion of a presynaptic mediation of this phenomenon was made. From then on, several studies carried out in laboratory animals and humans used the 5-HT 1A -induced hypothermia to assess the responsiveness of the 5-HT 1A autoreceptor in different disease states and following administration of various types of psychotropic drugs. Although the majority of studies (Hutson et al. 1987;O'Connell et al. 1992;Hillegaart 1991;Mill...

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Section: Discussionmentioning

confidence: 99%

Serotonin 1A Receptor Activation and Hypothermia in Humans Lack of Evidence for a Presynaptic Mediation

Blier

Seletti

Gilbert

et al. 2002

Neuropsychopharmacology

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“…This model is considered physiological and accurately reflects the mechanism of R-8-OH-DPAT-induced hypothermia. It is well established that the 5-HT 1A receptors play a role in maintaining the body's set-point temperature (Bligh, 1979;Lin et al, 1983;Zeisberger, 1990;1998;Jessen, 1996;Schwartz et al, 1998). Numerous reports suggest this set point is regulated though an interplay between the 5-HT 1A (hypothermia) and 5-HT 2A/C (hyperthermia) receptor system (Gudelsky et al, 1986;Abdel-fattah et al, 1995;Schwartz et al, 1995;1998); Salmi and Ahlenius, 1998).…”

Section: Discussionmentioning

confidence: 99%

A Competitive Interaction Model Predicts the Effect of WAY-100,635 on the Time Course of R -(+)-8-Hydroxy-2-(di-n-propylamino)tetralin-Induced Hypothermia

Zuideveld¹,

Treijtel²,

Maas³

et al. 2002

J Pharmacol Exp Ther

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The objective of this investigation was to characterize quantitatively the pharmacodynamic interaction between N-[2-[4-(2-The 8-OH-DPATinduced change in body temperature was used as a pharmacodynamic endpoint. Four groups of rats each received 1 mg/kg 8-OH-DPAT in 5 min during computer-controlled infusions of physiological saline or WAY-100,635, targeted at steady-state concentrations of 20, 85, and 170 ng/ml. Body temperature was monitored continuously with a telemetric system, and frequent blood samples were obtained to determine the pharmacokinetics of both drugs. Large differences in pharmacokinetics were observed between WAY-100,635 and R-8-OH-DPAT, reflected in values of the terminal elimination half-life of 33 and 143 min, respectively. Infusion of WAY-100,635 had no influence on the pharmacokinetics of R-8-OH-DPAT. With regard to the pharmacodynamics, clear antagonism of the R-8-OH-DPAT-induced hypothermia was observed. The complex pharmacological effect versus time profiles of R-8-OH-DPAT were analyzed on the basis of an indirect physiological response model with set point control coupled to a competitive interaction model for an agonist and antagonist acting at a common receptor. This model converged, yielding precise estimates of the pharmacodynamic parameters of both WAY-100,635 and R-8-OH-DPAT, which were independent of the infusion rate of WAY-100,635. The estimated in vivo binding constant of WAY-100,635 was 0.98 ng/ml (2.3 nM), which is very similar to the reported value from in vitro receptor binding assays. The findings of this investigation show that, in contrast to earlier reports in the literature, WAY 100,635 behaves as a pure competitive antagonist at the 5-hydroxytryptamine 1A receptor in vivo.Over the years, several, more or less, stable agonists at the 5-HT 1A receptor have been developed that differ in both affinity and intrinsic efficacy. Of these 5-HT 1A ligands,

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“…The PK-PD model itself combines an indirect physiological response model (Dayneka et al, 1993) with a set-point control. It is believed that the 5-HT 1A receptors play a role in maintaining the body's set-point temperature (Lin et al, 1983;Schwartz et al, 1998;Zeisberger, 1998). In addition numerous reports suggest that this set-point is regulated through an interplay between the 5-HT 1A (hypothermia) and the 5-HT 2A/C (hyperthermia) receptor system (Gudelsky et al, 1986;Salmi and Ahlenius, 1998).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

Zuideveld

Rusiç-Pavletiç

Maas

et al. 2002

J Pharmacol Exp Ther

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The objective of this investigation was to compare the in vivo potency and intrinsic activity of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in rats by pharmacokineticpharmacodynamic modeling. Following intravenous administration of buspirone (5 or 15 mg/kg in 15 min) or 1-PP (10 mg/kg in 15 min), the time course of the concentrations in blood were determined in conjunction with the effect on body temperature. The pharmacokinetics of buspirone and 1-PP were analyzed based on a two-compartment model with metabolite formation. Differences in the pharmacokinetics of buspirone and 1-PP were observed with values for clearance of 13.1 and 8.2 ml/min and for terminal elimination half-life of 25 and 79 min, respectively. At least 26% of the administered dose of buspirone was converted into 1-PP. Complex hypothermic effects versus time profiles were observed, which were successfully analyzed on the basis of a physiological indirect response model with setpoint control. Both buspirone and 1-PP behaved as partial agonists relative to R-(ϩ)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) with values of the intrinsic activity of 0.465 and 0.312, respectively. Differences in the potency were observed with values of 17.6 and 304 ng/ml for buspirone and 1-PP, respectively. The results of this analysis show that buspirone and 1-PP behave as partial 5-hydroxytryptamine 1A agonists in vivo and that following intravenous administration the amount of 1-PP formed is too small to contribute to the hypothermic effect.Buspirone is a selective 5-HT 1A agonist that is used clinically as an anxiolytic drug (for reviews on its pharmacological properties, see New, 1990 andFulton and Brogdon, 1997). In vivo buspirone is metabolized into 1-(2-pyrimidinyl)-piperazine (1-PP), which also possesses affinity to the 5-HT 1A receptor. This metabolite could therefore contribute to the effect of buspirone (Bianchi et al., 1988;Manahan-Vaughan et al., 1995;Cao and Rodgers, 1997). At present there is limited quantitative information on the magnitude of this effect. In theory the contribution of the metabolite to the effect is determined by the relative concentrations of buspirone and 1-PP, their relative in vivo potency and intrinsic activity, and the nature of the pharmacodynamic interaction between the two.Recently we have developed a physiological pharmacokinetic-pharmacodynamic (PK-PD) model to quantitatively characterize the pharmacodynamics of 5-HT 1A receptor agonists in vivo using the hypothermic effect as a pharmacodynamic endpoint (Zuideveld et al., 2001(Zuideveld et al., , 2002a. The hypothermic response is considered a robust marker of 5-HT 1A activity (Millan et al., 1993;Cryan et al., 1999). It has been shown that the PK-PD model allows for the estimation of the in vivo potency and intrinsic activity of a wide array of different 5-HT 1A agonists such as R-8- -100,635), and Flesinoxan (Zuideveld et al., 2001, 2002a, 2002b. In the present investigation we apply this model to determine the relative in vivo po...

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Serotonergic mechanisms in the hypothalamus mediate thermoregulatory responses in rats

Cited by 58 publications

References 27 publications

Serotonin 1A Receptor Activation and Hypothermia in Humans Lack of Evidence for a Presynaptic Mediation

Serotonin 1A Receptor Activation and Hypothermia in Humans Lack of Evidence for a Presynaptic Mediation

A Competitive Interaction Model Predicts the Effect of WAY-100,635 on the Time Course of R -(+)-8-Hydroxy-2-(di-n-propylamino)tetralin-Induced Hypothermia

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

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