Direct evidence for an important species difference in the mechanism of 8‐OH‐DPAT‐induced hypothermia

Dj, Bill; Knight, Martha; Ea, Forster; Fletcher, Allan

doi:10.1111/j.1476-5381.1991.tb12342.x

Cited by 172 publications

(96 citation statements)

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“…3c) 5-HT1A receptor function was further evaluated in awake animals by assessing the effect of 8-OH-DPAT on body temperature. Systemic administration of 8-OH-DPAT is known to elicit a sudden and profound hypothermia, an effect that in mice is thought to be mainly mediated by presynaptic 5-HT1A receptor activation (32,33). Although the hypothermic effect of a 0.5 mg͞kg dose of 8-OH-DPAT was comparable in both genotypes, the administration of a lower dose (0.16 mg͞kg) resulted in a less pronounced hypothermic effect in Ϫ͞Ϫ than in ϩ͞ϩ mice.…”

Section: Resultsmentioning

confidence: 79%

Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function

Santarelli¹

2001

Proceedings of the National Academy of Sciences

120

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Alterations in serotonin (5-hydroxytriptamine, 5-HT), norepinephrine, and ␥-aminobutyric acid have been linked to the pathophysiology of anxiety and depression, and medications that modulate these neurotransmitters are widely used to treat mood disorders. Recently, the neuropeptide substance P (SP) and its receptor, the neurokinin 1 receptor (NK1R), have been proposed as possible targets for new antidepressant and anxiolytic therapies. However, animal and human studies have so far failed to provide a clear consensus on the role of SP in the modulation of emotional states. Here we show that both genetic disruption and acute pharmacological blockade of the NK1R in mice result in a marked reduction of anxiety and stress-related responses. These behavioral changes are paralleled by an increase in the firing rate of 5-HT neurons in the dorsal raphe nucleus, a major source of serotonergic input to the forebrain. NK1R disruption also results in a selective desensitization of 5-HT1A inhibitory autoreceptors, which resembles the effect of sustained antidepressant treatment. Together these results indicate that the SP system powerfully modulates anxiety and suggest that this effect is at least in part mediated by changes in the 5-HT system. S ubstance P (SP) and its receptor, the neurokinin 1 receptor (NK1R), participate in the neural processing of a range of noxious and stressful stimuli. In the spinal cord, SP contributes to nociception, and disruption of the NK1R decreases or ablates the late-phase response to peripheral injury (1-3). In the brainstem, SP modulates emesis, which can be decreased in animals and humans by NK1R antagonists (4). Peripheral inflammation in a variety of structures including gut, joints, and cutaneous tissue also partly depends on SP release and NK1R activation (5).Recently, SP also has been implicated in the modulation of stress responses, mood, and anxiety, but its exact role remains unclear. Localized administration of SP in the central nervous system may produce anxiogenic or anxiolytic responses, depending on the animal species and location of injection (6-8). Conflicting results also have been obtained from the use of NK1R antagonists, and issues of drug access and species specificity have further clouded the roles of SP in stress-related behaviors (9). Interestingly, in humans, an NK1R antagonist has been reported to be an effective antidepressant and anxiolytic, although this result has not been replicated (10). It has been proposed that the antidepressant activity of NK1R antagonism may be independent of serotonergic and noradrenergic pathways and thus may represent an alternative therapeutic strategy for the treatment of mood disorders (10).In the present study we used genetic disruption and pharmacological blockade of the NK1R to examine the roles of SP in the generation of anxiety-related behaviors in mice. Genetic disruption of NK1R function markedly reduced anxiety-related behaviors in the elevated plus maze (EPM), novelty suppressed feeding (NSF), and maternal separation paradi...

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Section: Resultsmentioning

confidence: 79%

Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function

Santarelli¹

2001

Proceedings of the National Academy of Sciences

120

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“…Goodwin et al (1985aGoodwin et al ( , 1987a showed attenuation of the response in rats and mice both after PCPA and after injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), suggesting a presynaptic location, but it is noteworthy that the attenuation in rats was only seen when measured 14 days after the first PCPA injection and not when measured at 4 days post-PCPA. Evidence for a species difference was provided by Bill et al (1991), who showed that the response in rats was unaffected by 5,7-DHT and PCPA while that in mice was abolished. Although Hillegaart (1991) obtained a decrease in temperature on direct injection of 8-OH-DPAT into the dorsal raphe in rats, the dose of 8-OH-DPAT used was high and diffusion to postsynaptic sites may have occurred.…”

Section: Discussionmentioning

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

Neuropsychopharmacology

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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...

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“…Mianserin, which has equal affinity for the 5-HT 2A and 5-HT 2C receptor, and ketanserin, which is 100-fold selective for the 5-HT 2A versus 5-HT 2C receptor, also have high nanomolar affinity for alpha-adrenergic receptors (Leysen et al 1981). Although drugs interacting acutely with alpha-adrenergic receptors or dopaminergic receptors modulate 8-OH-DPAT-induced hypothermia in mice (Bill et al 1991;Durcan et al 1991), this has been shown not to be the case for 8-OH-DPAT-induced hypothermia in rats (Millan et al 1997). However, if mianserin or ketanserin treatment had modified 8-OH-DPATinduced hypothermia or forepaw treading in the current study, it would have been necessary to address the potential involvement of alpha-adrenergic receptors or 5-HT 2C receptors by investigating the effect of chronic administration of the alpha-1 antagonist prazosin or the selective 5-HT 2C receptor antagonist SB 206553 (Kennett et al 1996) on these 5-HT 1A receptor mediated behaviors.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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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%

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

Hensler

Truett

1998

Neuropsychopharmacology

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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...

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Direct evidence for an important species difference in the mechanism of 8‐OH‐DPAT‐induced hypothermia

Cited by 172 publications

References 19 publications

Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function

Genetic and pharmacological disruption of neurokinin 1 receptor function decreases anxiety-related behaviors and increases serotonergic function

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

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

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