Evidence for postsynaptic mediation of the hypothermic effect of 5‐HT 1A receptor activation

Serotonergic receptors of the 5-HT 1A subtype have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, including specific serotonin reuptake inhibitors (SSRIs). We examined the effect of clinical doses of the SSRI, fluoxetine, on 5-HTThere is considerable interest in the role of serotonergic (5-HT) receptors of the 5-HT 1A subtype in the therapeutic action of antidepressant drugs. 5-HT 1A receptors are located presynaptically on serotonergic cell bodies in the raphe nuclei where they serve as autoreceptors which inhibit cell firing and reduce 5-HT release by a negative feedback mechanism, and post-synaptically in the hippocampus, cortex and other brain areas, including the hypothalamus. Based on electrophysiological studies in rats, De Montigny and colleagues Mongeau et al. 1997) proposed that each major class of antidepressants increases 5-HT neurotransmission by a distinct mechanism involving either From the Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center (BL, YG, MEN) and the Laboratory of Applied Statistics, Hebrew University (MG), Jerusalem, Israel; the Endocrine Laboratory, Department of Medicine (BA) and Department of Psychiatry (KPL), University of Wuerzburg, Wuerzburg, Germany.Address correspondence to: Prof. Bernard Lerer, Biological Psychiatry Laboratory, Dept. of Psychiatry, Hadassah-Hebrew University Medical Center, Ein Karem, Jerusalem 91120, Israel.Received May 15, 1998; accepted August 25, 1998. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 20 , NO . 6 Ipsapirone Challenge in Normal Subjects on Fluoxetine 629pre-or post-synaptic 5-HT 1A receptors. The selective serotonin re-uptake inhibitors (SSRIs), which raise 5-HT synaptic levels when given acutely, were proposed to increase 5-HT transmission on repeated administration by inducing desensitization of somatodendritic 5-HT 1A autoreceptors in the raphe nuclei and nerve terminal 5-HT 1B autoreceptors, which also mediate feedback inhibition of 5-HT release. These effects would lead to a slow increase in 5-HT levels which corresponds to the delayed clinical effect of the drugs. Evidence for subsensitivity of somatodendritic 5-HT 1A autoreceptors after chronic administration of SSRIs has been provided by microdialysis experiments in which 5-HT levels are measured in vivo in response to a challenge dose of the 5-HT 1A receptor agonist, 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) (Rutter et al. 1994, Kreiss andLucki 1995;Invernizzi et al. 1994). However, other studies using SSRIs (Hjorth and Auerbach 1994; Bosker et al. 1995a,b;Invernizzi et al. 1995Invernizzi et al. , 1996 or clomipramine (Gur et al. 1999) failed to show any change in 5-HT 1A autoreceptor subsensitivity by this method. An increase in basal 5-HT levels after chronic SSRI administration, taken to be due to pre-synaptic 5-HT 1A and 5-HT 1B receptor desensitization, has been observed in cortex (Bel and Artigas 1993), hippocampus (Auerbach and Hjorth 1995) diencephalon (Rutter et al. 1994) an...

Section: Discussionmentioning

confidence: 88%

Section: Serotonergic Receptors Of the 5-ht 1a Subtype Have Been Suggmentioning

confidence: 99%

5-HT1A Receptor Function in Normal Subjects on Clinical Doses of Fluoxetine Blunted Temperature and Hormone Responses to Ipsapirone Challenge

Lerer¹,

Gelfin²,

Gorfine

et al. 1999

“…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;Millan et al 1993;Blier and Bouchard 1992;Stockmeier et al 1992) now indicate that this response in rats results from the activation of postsynaptic 5-HT 1A receptors, it is still claimed that it is presynaptically mediated in mice (Goodwin et al 1985). In humans, this issue had not been addressed.…”

mentioning

confidence: 99%

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

Blier

Seletti

Gilbert

et al. 2002

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...

“…The pharmacology of this response has been well characterized, demonstrating that 8-OH-DPAT-induced hypothermia is mediated by activation of 5-HT 1A receptors (Millan et al 1997;Scott et al 1994;Thielen et al 1996). Although it has been suggested that 8-OH-DPAT-induced hypothermia in rats is mediated by presynaptic receptors (Goodwin et al 1987b), the majority of evidence supports the view that in rats, the hypothermic response elicited by 5-HT 1A receptor agonists is mediated by postsynaptic receptors (Bill et al 1991;O'Connell et al 1992;Millan et al 1997 and discussion therein). 5-HT 1A receptor-mediated hypothermia has been used to assess the sensitivity of 5-HT 1A receptors following a variety of antidepressant treatments (Goodwin et al 1987a;Hensler et al 1991), and has been proposed as a model to screen and identify novel 5-HT 1A receptor agonists and antagonists (Millan et al 1997).…”

Section: Discussionmentioning

confidence: 97%

“…The effectiveness of these drug treatment paradigms was confirmed by measuring the binding of [ 3 H]-ketanserin to 5-HT 2A receptor sites in cortical homogenates, because all of these drug treatments have been shown to result in downregulation of 5-HT 2A receptor sites. The sensitivity of postsynaptic 5-HT 1A receptors was assessed in vivo by two behavioral measures, forepaw treading (Tricklebank et al 1984;Scott et al 1994;Thielen et al 1996) or hypothermia (Bill et al 1991;O'Connell et al 1992;Millan et al 1997) induced by acute injection of the 5-HT 1A receptor agonist 8-OH-DPAT. Because changes in 5-HT 1A receptor second messenger function have not been consistently reported to follow administration of antidepressants or 5-HT 1A receptor agonists (Sleight et al 1988;Varrault et al 1991;Newman et al 1992), we chose not to measure second messenger responses associated with 5-HT 1A receptor activation following 5-HT 2 receptor agonist or antagonist treatment.…”

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confidence: 99%

Effect of Chronic Serotonin-2 Receptor Agonist or Antagonist Administration on Serotonin-1A Receptor Sensitivity

Hensler

Truett

1998

We have investigated the effect of 5-HT 2 receptor agonist or antagonist administration on postsynaptic 5-HT 1A receptor sensitivity assessed by two behavioral measures, reciprocal forepaw treading or hypothermia induced by acute injection of the 5-HT 1A receptor agonist 8-OH-DPAT. The effectiveness of these drug treatments to downregulate 5-HT 2A receptors was confirmed by measuring the binding of [ 3 H]-ketanserin in cortical homogenates, because all of these drug treatments have been shown to result in the downregulation of 5-HTOf some 14 subtypes of receptor for the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) (see Hoyer et al. 1994), a tremendous amount of attention has been focused on the serotonin 1A (5-HT 1A ) receptor subtype. Drugs that act as agonists at this receptor have proved useful clinically as antidepressants (see Murphy et al. 1995) and anxiolytics (Coplan et al. 1995). The unique distribution of this serotonin receptor subtype in brain is consistent with its potential involvement in cognitive or integrative functions, as well as in emotional states. In terminal field areas of serotonergic innervation, the 5-HT 1A receptor is located postsynaptically and is present in high density in cortical and limbic structures (i.e., hippocampus, entorhinal cortex, septum, amygdala, frontal cortex) (Vergé et al. 1986;Hensler et al. 1991;Khawaja 1995). The 5-HT 1A receptor is also found in high density in serotonin cell body areas, such as the dorsal and median raphé, where it is believed to function as the somatodendritic autoreceptor modulating the activity of serotonergic neurons (see Aghajanian et al. 1990).The sensitivity of behavioral (Goodwin et al. 1987;Hensler et al. 1991;Wieland et al. 1993;Maj et al. 1996) and electrophysiological (Blier and deMontigny 1983, Received June 16, 1997; revised December 15, 1997; accepted February 16, 1998. N EUROPSYCHOPHARMACOLOGY 1998 -VOL . 19 , NO . 5 Modulation of 5-HT 1A Receptor Sensitivity 355 1985 responses mediated by the 5-HT 1A receptor is decreased after chronic administration of 5-HT 1A receptor agonists or antidepressants drugs. The desensitization of 5-HT 1A receptor-mediated responses has also been reported to occur after acute or short-term agonist administration (Kennett et al. 1987;Larsson et al. 1990). Although some investigators have reported changes in 5-HT 1A receptor number following agonist or antidepressant treatments (Welner et al. 1989;Fanelli and McMonagle-Strucko 1992), in many cases desensitization of 5-HT 1A receptor-mediated responses has not been found to be accompanied by a decrease 5-HT 1A receptor number (Larsson et al. 1990;Schecter et al. 1990;Hensler et al. 1991;Wieland et al. 1993). Changes in 5-HT 1A receptor second messenger function have not been consistently reported to follow administration of antidepressants or 5-HT 1A receptor agonists (Sleight et al. 1988;Varrault et al. 1991;Newman et al. 1992).Interactions between serotonin receptor subtypes have been observed in behavioral studies. For example, 5...