Alteration of 5‐HT<sub>1A</sub> receptor binding sites following chronic treatment with ipsapirone measured by quantitative autoradiography

Fanelli, Richard J.; McMonagle‐Strucko, Katheen

doi:10.1002/syn.890120109

Cited by 48 publications

(17 citation statements)

References 39 publications

(52 reference statements)

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“…It should be emphasized that both observations (change in receptor sensitivity and unchanged density) have been obtained in the same animals. Previous work with SSRIs and selective 5-HT 1A agonists is inconclusive in regards to the ability of these agents to down-regulate the density of raphe 5-HT 1A autoreceptors after chronic (2-3 weeks) treatments (Welner et al 1989;Hensler et al 1991;Fanelli and McMonagle-Strucko 1992;Casanovas et al 1999a;Le Poul et al 1999), whereas there is convincing evidence on their ability to induce a functional desensitization de Montigny 1987, 1994;Hensler et al 1991;Invernizzi et al 1994;Casanovas et al 1999a; see however Sharp et al 1993).…”

Section: Discussionmentioning

confidence: 99%

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635

Hervás

2001

Neuropsychopharmacology

100

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Using microdialysis, receptor autoradiography and in situ hybridization, we examined the effects of fluoxetine alone or with WAY-100635 on: (a) extracellular 5-HT in frontal cortex; and (b) density and sensitivity of 5-HT 1A autoreceptors in rat brain. WAY-100635 (0.3 mg/kg, s.c.) doubled the increase in extracellular 5-HT produced by fluoxetine (3 mg/kg, i.p.) (SSRI) Selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) are extensively used in the treatment of major depression. The increase in forebrain extracellular 5-HT elicited by SSRIs is limited by a negative feed-back involving raphe autoreceptors . The prevention of this inhibitory mechanism with 5-HT 1A receptor antagonists augments the neurochemical and behavioral effects of SSRIs (Gartside et al. 1995;Artigas et al. 1996;Hashimoto et al. 1997;Mitchell and Redfern 1997;Grignaschi et al. 1998;Trillat et al. 1998). At the clinical level, the ␤ -adrenoceptor/ 5-HT 1A receptor antagonist pindolol accelerates the antidepressant effects of SSRIs in open-label and placebocontrolled trials Blier and Bergeron 1995;Pérez et al. 1997;Zanardi et al. 1997Zanardi et al. , 1998Bordet et al. 1998). However, its effectiveness to potentiate antidepressant response in chronically ill or treatmentresistant patients is still controversial (Maes et al. 1996(Maes et al. , 1999Berman et al. 1997;Moreno et al. 1997;Pérez et al. 1999). Based on this rationale, selective 5-HT 1A receptor antagonists (for use with SSRIs; add-on strategy) and dual action compounds (5-HT reuptake inhibitor ϩ 5-HT 1A antagonist) are being developed for use in the treatment of major depression. The prolonged administration of SSRIs has been reported to desensitize raphe 5-HT 1A autoreceptors, as assessed by single unit recordings and brain microdialysis (Blier and de Montigny 1994;Invernizzi et al. 1994;Arborelius et al. 1995;Le Poul et al. 1995). This reduces the efficacy of the above negative feedback and increases extracellular 5-HT (Bel and Artigas 1993;Invernizzi et al. 1994;Rutter et al. 1994;Arborelius et al. 1996). Other studies, however, have failed to observe such effects even using large doses of SSRIs (Hjorth and Auerbach 1994a;Bosker et al. 1995;Invernizzi et al. 1995).To our knowledge, there are no published reports on the effects of prolonged treatments with combinations of SSRIs and 5-HT 1A receptor antagonists on these experimental paradigms, except in abstract form (Dawson et al. 1998). As with pindolol, future selective 5-HT 1A receptor antagonists would be administered for a limited period of time. Should prolonged blockade of 5-HT 1A receptor result in receptor sensitization, the withdrawal of the antagonist would increase the efficacy of the above negative feed-back and reduce the ability of the SSRI to increase extracellular 5-HT, thus increasing the possibility of a clinical relapse. Since this is crucial for the success of this therapeutic strategy, we examined the effects of two-week treatments with fluoxetine, WAY-100635 and their combination...

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Section: Discussionmentioning

confidence: 99%

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635

Hervás

2001

Neuropsychopharmacology

100

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“…Because not all of the subjects had recent exposure to antidepressant medications, it appears that the increase in serotonin-1A receptors is related to the depression and/or suicide. Furthermore, chronic treatment of rats with SSRIs, monoamine oxidase inhibitors, or novel anxiolytics with antidepressant qualities either decreases or has no effect on [ 3 H]8-OH-DPAT binding to serotonin-1A receptors in midbrain (Welner et al, 1989;Gobbi et al, 1991;Hensler et al, 1991;Fanelli et al, 1992;Burnet et al, 1994;Le Poul et al, 1995).…”

Section: The Binding Of [mentioning

confidence: 99%

Increase in Serotonin-1A Autoreceptors in the Midbrain of Suicide Victims with Major Depression—Postmortem Evidence for Decreased Serotonin Activity

Stockmeier

Shapiro²,

Dilley³

et al. 1998

J. Neurosci.

385

243

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It has been hypothesized that a deficit in serotonin may be a crucial determinant in the pathophysiology of major depression. Serotonin-1A receptors are located on serotonin cell bodies in the midbrain dorsal raphe (DR) nucleus, and the activation of these receptors inhibits the firing of serotonin neurons and diminishes the release of this neurotransmitter in the prefrontal cortex. Repeated treatment with some antidepressant medications desensitizes serotonin-1A receptors in the rat midbrain. The present study determined whether the binding of [, an agonist at serotonin-1A receptors, is altered in the midbrain of suicide victims with major depression. Radiolabeling of the serotonin-1A receptor in the DR varied significantly along the rostral-to-caudal extent of the human midbrain. The binding of [ 3 H]8-OH-DPAT to serotonin-1A receptors was increased significantly in the midbrain DR of suicide victims with major depression as compared with psychiatrically normal control subjects. In suicide victims with major depression, the increase in the binding of [ 3 H]8-OH-DPAT to serotonin-1A receptors was detected in the entire DR and specifically localized to the dorsal and ventrolateral subnuclei. Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.

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“…Based on Blier et al, 1990. Fanelli andMcMonagle-Strucko 1992), G proteins (Lesch et al 1991;Blier et al 1993), or regulatory kinases/arrestins (Lefkowitz 1993). Neuron-specihc differences in the expression and regulation of these components may also explain the differential nature of receptor desensitization, that is, that the 5-HTIA receptor desensitizes in raphe but not in hippocampal neurons.…”

Section: The Hypothesis That Antianxiety or Antidepressant Agents (Ementioning

confidence: 99%

The 5-HT1A receptor: Signaling, desensitization, and gene transcription

Albert

Lembo

Storring

et al. 1996

Neuropsychopharmacology

120

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The hypothesis that antianxiety or antidepressant agents (e.g., Serotonin uptake inhibitors (e.g., fluoxetine, paroxetine) and selective 5-HTIA receptor partial agonists (e.g., buspirone, ipsapirone) are effective in the treatment of major depression and generalized anxiety disorder but require several weeks of drug treatment to observe clinical improvement (Blier et al. 1990; Charney et al. 1990). Acting via distinct mechanisms, these compounds share the property of enhancing serotonergic neurotransmission by selectively downregulating 5-HTIA receptors located on the serotonergic cell body (Azmitia 1994). Serotonin 1A receptors act as inhibitory autoreceptors on serotonergic neurons of the raphe nuclei, whereas 5-HTIB receptors act as inhibitory presynaptic receptors at serotonergic nerve terminals. Both of these 5-HT receptors participate in a negative feedback loop to inhibit serotonergic activity (Figure 1). In experimental animals, long-term treatment with antidepressants induces selective loss of 5-HTIA autoreceptors without altering the responsiveness of postsynaptic 5-HTIA receptors (Welner et al. 1989;Blier et al. 1990; Fanelli and McMonagle-Strucko 1992). Uptake blockers may mediate this action due to chronic elevation of 5-HT levels at the synaptic deft, leading to autoreceptor downregulation. Serotonin 1A receptor agonists appear to have a direct action on the autoreceptor to induce its desensitization. Desensitization of the autoreceptor disinhibits the serotonergic neuron, enhancing the rate of action potential h_ring to augment serotonergic neurotransmission. Increase in serotonergic neurotransmission correlates with the antidepressant or antianxiety activity of these therapeutic compounds. Interestingly, chronic enhancement of serotonergic neurotransmission induced by uptake blockers is potentiated by 5-HTIA receptor agonists, suggesting the importance of autoreceptor desensitization in antidepressant action (Hjorth 1993). The cellular mechanisms involved in the longterm regulation of the 5-HTIA receptor remain uncharacterized, although the time course of therapeutic drug action suggests an effect of these compounds on gene transcription of components in the 5-HT1A receptor signaling system: either the receptor (Welner et al. 1989; 0893-133X/96/$15.00 SSDI 0893-133X(94)00044-Z

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Alteration of 5‐HT_1A receptor binding sites following chronic treatment with ipsapirone measured by quantitative autoradiography

Cited by 48 publications

References 39 publications

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635

Increase in Serotonin-1A Autoreceptors in the Midbrain of Suicide Victims with Major Depression—Postmortem Evidence for Decreased Serotonin Activity

The 5-HT1A receptor: Signaling, desensitization, and gene transcription

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Alteration of 5‐HT1A receptor binding sites following chronic treatment with ipsapirone measured by quantitative autoradiography

Cited by 48 publications

References 39 publications

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635

Desensitization of 5-HT1A Autoreceptors by a Low Chronic Fluoxetine Dose Effect of the Concurrent Administration of WAY-100635

Increase in Serotonin-1A Autoreceptors in the Midbrain of Suicide Victims with Major Depression—Postmortem Evidence for Decreased Serotonin Activity

The 5-HT1A receptor: Signaling, desensitization, and gene transcription

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Product

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Alteration of 5‐HT_1A receptor binding sites following chronic treatment with ipsapirone measured by quantitative autoradiography