Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or β-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo

Stephan, Holger; Bengtsson, Henrik; Milano, Stéphane

doi:10.1016/s0014-2999(96)00779-0

Cited by 56 publications

(32 citation statements)

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“…Previous studies have shown that the blockade of the somatodendritic 5-HT 1A autoreceptors potentiates the elevation of extracellular levels of 5-HT in terminal areas induced by 5-HT reuptake inhibitors (Hjorth 1993;Hjorth et al 1996;Gartside et al 1995;Dreshfield et al 1996;Romero and Artigas 1997). This contention has also been verified with venlafaxine in a recent report published during the preparation of this manuscript (Gur et al 1999).…”

Section: Discussionsupporting

confidence: 65%

“…Although microdialysis studies cannot assess the postsynaptic impact, several such studies have corroborated the above by showing that the acute coadministration of (-)pindolol and an SSRI produces a greater elevation of extracellular levels of 5-HT in terminal regions than that achieved with the reuptake inhibitor alone (Dreshfield et al 1996;Hjorth et al 1996;Romero et al 1996).…”

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confidence: 92%

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Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Béı̈que

Blier

Montigny

et al. 2000

Neuropsychopharmacology

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The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT 1A autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre-and postsynaptic 5-HT 1A receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA 3 pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective ␤ -adrenoceptor antagonist metoprolol (15 mg/kg, i.p .). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT 1A receptors was suggested by its complete reversal by the 5-HT 1Aantagonist WAY 100635 (100 g/kg, i.v It is becoming increasingly clear that the therapeutic efficacy of antidepressant treatments such as selective serotonin reuptake inhibitors (SSRI's) finds its substrate in an enhanced serotonergic (5-HT) neurotransmission . At least in the rat, this occurs only in the midst of long-term administration of antidepressant treatments, which is necessary for the development of specific adaptative changes. Indeed, acute administration of SSRI's induces a reduction of firing activity of the 5-HT neurons of the raphe nuclei due to an increased activation of the somatodendritic 5-HT 1A autoreceptors, resulting from the increased extracellular 5-HT (de Montigny et al. 1981;Blier et al. 1984;Chaput et al. 1986;Hajós et al. 1995;Béïque et al. 1999). However, in the course of a long-term administration of SSRI's, 5-HT neurons recover their normal firing activity as a consequence of the desensitization of these autoreceptors . .). A short-term treatment with VLX (20 mg/kg/day ϫ 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day ϫ 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HTA way by which the action of the somatodendritic 5-HT 1A autoreceptors can be circumvented has been Activation of Postsynaptic 5-HT 1A Receptors 295 delineated by the electrophysiological observation that a 2-day administration of the mixed ␤ -adrenergic/5-HT 1A receptors antagonist (-)pindolol prevents the suppressant effects of paroxetine and of the 5-HT autoreceptor agonist LSD on the firing activity of dorsal raphe 5-HT (Romero et al. 1996). Although microdialysis studies cannot assess the postsynaptic impact, several such studies have corroborated the above by showing that the acute coadministration of (-)pindolol and an SSRI produces a greater elevation of extracellular levels of 5-HT in terminal regions than that achieved with the reuptake inhibitor alon...

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 92%

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Béı̈que

Blier

Montigny

et al. 2000

Neuropsychopharmacology

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“…Among the 14 different mammalian 5-HT receptors, the 5-HT1A receptor is one of the most abundant, being expressed as a postsynaptic heteroreceptor in cortex, limbic areas (septum, hippocampus, amygdala), hypothalamus and other areas, where it is implicated in a diversity of physiological, cognitive and affective functions [57][58][59][60][61][62]. In addition, the 5-HT1A receptor is expressed presynaptically on the cell body and dendrites of 5-HT neurons in the raphe nuclei, where it functions as an inhibitory autoreceptor [63,64], acting as a key negative regulator of the activity of serotonergic neurons by mediating inhibitory feedback of 5-HT release [65][66][67][68][69][70]. The inhibitory effects of both the 5-HT1A auto-and heteroreceptors occur through activation of G-protein inward rectifying potassium channels [53] to reduce neuronal firing rate, inhibition of voltage-gated calcium channels to reduce calcium entry, and inhibition of adenylyl cyclase.…”

Section: The Serotonin System and 5-ht1a Receptorsmentioning

confidence: 99%

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Albert¹,

Fiori

2014

CPD

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The etiology of major depression remains unclear, but reduced activity of the serotonin (5-HT) system remains implicated and treatments that increase 5-HT neurotransmission can ameliorate depressive symptoms. 5-HT1A receptors are critical regulators of the 5-HT system. They are expressed as both presynaptic autoreceptors that negatively regulate 5-HT neurons, and as postsynaptic heteroreceptors on non-serotonergic neurons in the hippocampus, cortex, and limbic system that are critical to mediate the antidepressant actions of 5-HT. Thus, 5-HT1A auto-and heteroreceptors have opposite actions on serotonergic neurotransmission. Because most 5-HT1A ligands target both auto-and heteroreceptors their efficacy has been limited, resulting in weak or unclear responses. We propose that by understanding the transcriptional regulation of the 5-HT1A receptor it may be possible to regulate its expression differentially in raphe and projection regions. Here we review the transcriptional architecture of the 5-HT1A gene (HTR1A) with a focus on specific DNA elements and transcription factors that have been shown to regulate 5-HT1A receptor expression in the brain. Association studies with the functional HTR1A promoter polymorphism rs6295 suggest a new model for the role of the 5-HT1A receptor in susceptibility to depression involving early deficits in cognitive, fear and stress reactivity as stressors that may ultimately lead to depression. We present evidence that by targeting specific transcription factors it may be possible to oppositely regulate 5-HT1A auto-and heteroreceptor expression, synergistically increasing serotonergic neurotransmission for the treatment of depression. KeywordsSerotonin; repressor; enhancer; antidepressant; raphe; autoreceptor SEROTONIN AND MAJOR DEPRESSIONDepression continues to grow as a major health challenge with a lifetime prevalence for major depressive disorder (MDD) estimated at 16 % [1, 2] (Box 1). In developed countries, MDD currently accounts for the second highest lifetime burden of disease, and is predicted

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“…Together, the direct and indirect 5-HT 1A -mediated feedback mechanisms negatively regulate the activity of the 5-HT system. Release of 5-HT 1A -mediated autoinhibition by receptor desensitization appears to play a key role in the efficacy of antidepressant treatments, especially 5-HT-SSRIs [13,[33][34][35]. Acute treatment with SSRI leads to a local increase in 5-HT levels in the raphe nuclei [36,37], activating 5-HT 1A -mediated autoinhibition to inhibit firing of 5-HT neurons.…”

Section: -Ht 1a Autoreceptors As Brakes For 5-ht Neurotransmissionmentioning

confidence: 99%

Transcriptional regulation of the 5-HT_1Areceptor: implications for mental illness

Albert

2012

Phil. Trans. R. Soc. B

115

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The serotonin-1A (5-HT 1A ) receptor is an abundant post-synaptic 5-HT receptor (heteroreceptor) implicated in regulation of mood, emotion and stress responses and is the major somatodendritic autoreceptor that negatively regulates 5-HT neuronal activity. Based on animal models, an integrated model for opposing roles of pre-and post-synaptic 5-HT 1A receptors in anxiety and depression phenotypes and response to antidepressants is proposed. Understanding differential transcriptional regulation of pre-versus post-synaptic 5-HT 1A receptors could provide better tools for their selective regulation. This review examines the transcription factors that regulate brain region-specific basal and stress-induced expression of the 5-HT 1A receptor gene (Htr1a). A functional polymorphism, rs6295 in the Htr1a promoter region, blocks the function of specific repressors Hes1, Hes5 and Deaf1, resulting in increased 5-HT 1A autoreceptor expression in animal models and humans. Its association with altered 5-HT 1A expression, depression, anxiety and antidepressant response are related to genotype frequency in different populations, sample homogeneity, disease outcome measures and severity. Preliminary evidence from gene Â environment studies suggests the potential for synergistic interaction of stress-mediated repression of 5-HT 1A heteroreceptors, and rs6295-induced upregulation of 5-HT 1A autoreceptors. Targeted therapeutics to inhibit 5-HT 1A autoreceptor expression and induce 5-HT 1A heteroreceptor expression may ameliorate treatment of anxiety and major depression.

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Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or β-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo

Cited by 56 publications

References 11 publications

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Transcriptional regulation of the 5-HT_1Areceptor: implications for mental illness

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Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or β-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo

Cited by 56 publications

References 11 publications

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Transcriptional regulation of the 5-HT1Areceptor: implications for mental illness

Contact Info

Product

Resources

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Transcriptional regulation of the 5-HT_1Areceptor: implications for mental illness