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

doi:10.1016/S0014-2999(96)00779-0

European Journal of Pharmacology

Volume 316, Issue 1, 28 November 1996, Pages 43-47

https://doi.org/10.1016/S0014-2999(96)00779-0 Get rights and content

Abstract

In vivo microdialysis in rat ventral hippocampus was used (i) to verify the importance of 5-HT_1A autoreceptors in the raphe as targets for drugs that enhance the citalopram-induced elevation of forebrain 5-hydroxytryptamine (5-HT), and (ii) to further examine the specificity of (−)-penbutolol in this regard. The selective 5-HT_1A receptor antagonist WAY100635 (s.c., or intra-raphe) or the mixed $5-HT_{1A1B} β- adrenoceptor$ antagonist (−)-penbutolol (s.c.), potentiated the citalopram-induced 5-HT rise, whereas local ‘reverse’ dialysis of WAY100635 into the ventral hippocampus did not. Furthermore, the (−)-penbutolol-induced augmentation proved stereoselective and not mediated by β-adrenoceptors (no effect of s.c. (+)-penbutolol, or β₁- and β₂-adrenoceptor blockers (betaxolol, ICI118.551)). These data provide direct evidence that increased stimulation of 5-HT_1A autoreceptors in the midbrain raphe impedes the effect of citalopram on forebrain extracellular 5-HT, whereas neither postsynaptic 5-HT_1A receptors nor β-adrenoceptors appear to be involved.

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Maternal separation induces changes in TREK-1 and 5HT<inf>1A</inf> expression in brain areas involved in the stress response in a sex-dependent way
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Despite many studies approached the 5HT1A role in depression, it is still unsettled how it participates in depression pathophysiology, as it can play different roles depending on the brain region. For instance, 5HT1A expression is upregulated in raphe nuclei of depressed patients [31] and it has to be desensitized or inhibited by antidepressant drugs at these nuclei in order to achieve an antidepressant effect [32], while a decrease in 5HT1A expression is observed on temporal and cortical areas in both men and women with depression [33,34]. In general, these studies lead to a revision in the monoaminergic hypothesis for depression, stating that activation of presynaptic 5HT1A in raphe nuclei would be detrimental to mood balance as it reduces the serotonergic tone in the brain, while activation of postsynaptic 5HT1A in cortical areas is expected to be beneficial for mood and stress regulation [35,36].
Depression is a prevalent disease in modern society, and has been linked to stressful events at early ages. Women are more susceptible to depression, and the neural basis for this are still under investigation. Serotonin is known to be involved in depression, and a decrease in 5HT_1A expression is observed on temporal and cortical areas in both men and women with depression. As knockout animals for TREK-1 are resilient to depression, this channel has emerged as a new potential pharmacological target for depression treatment. In this study, maternal separation (MS) was used to emulate early-life stress, and evaluate behaviour, as well as TREK-1 and 5HT_1A expression in the brain using immunohistochemistry. In juvenile females, 5HT_1A reduction coupled to increased TREK-1 in the dentate gyrus (DG) was associated with behavioural despair, as well as increased TREK-1 expression in basolateral amygdala (BLA) and prelimbic cortex (PL). In juvenile males, MS induced an increase in 5HT_1A in the BLA, and in TREK-1 in the PL, while no behavioural despair was observed. Anhedonia and anxiety-like behaviour were not induced by MS. We conclude stress-induced increase in TREK-1 in PL and GD is associated to depression, while 5HT_1A changes coupled to TREK-1 changes may be necessary to induce depression, with females being more vulnerable to MS effects than males. Thus, TREK-1 and 5HT_1A may be potential pharmacological targets for antidepressants development.
Differential environmental regulation of neurogenesis along the septo-temporal axis of the hippocampus
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These two pathways have also been described as anatomically, electrophysically and functionally distinct (Hensler, 2006). In particular the serotonin transporter SERT and the 5-HT1A presynaptic autoreceptor, which desensitization is thought to be critical for SSRIs to enhance 5-HT transmission in limbic structures (Blier et al., 1987; Blier and de, 1983; Chaput et al., 1991; Gartside et al., 1997; Hjorth et al., 1996; Rutter et al., 1994) have been reported to be more expressed or to display higher binding affinity in the dorsal than in the median raphe nucleus (Adams and van den Buuse, 2011; Khawaja, 1995). Additionally, 5-HT1A autoreceptors in the dorsal raphe seem more readily desensitized following chronic agonist treatment than those of the median raphe nucleus (Kreiss and Lucki, 1997; Romero and Artigas, 1997).
The hippocampus is involved in both cognitive and emotional processing; these different functions are topographically distributed along its septo-temporal axis, the dorsal (septal) hippocampus being preferentially involved in cognitive processes such as learning and memory while the ventral (temporal) hippocampus participates in emotional regulation and anxiety-related behaviors. Newborn hippocampal neurons become functionally integrated into hippocampal networks and are likely to contribute to hippocampal functions, but whether their regulation and function are homogenous throughout this axis is not clear. Here we investigate changes in cell proliferation and neurogenesis along the septo-temporal axis of the hippocampus induced by the Unpredictable Chronic Mild Stress model of depression (UCMS), chronic fluoxetine treatment and enriched environment.
Mice were either subjected to UCMS, standard housing or enriched environment. Stress-exposed mice were treated daily with fluoxetine (10 mg/kg) or vehicle. Effects of UCMS regimen, fluoxetine treatment and enrichment were assessed by physical measures and behavioral testing. Quantitative changes in cell proliferation and neurogenesis were assessed by immunohistochemistry using BrdU labeling.
Results indicate that UCMS decreased cell proliferation and neurogenesis preferentially in the ventral hippocampus, an effect that was reversed by fluoxetine treatment. Environmental enrichment on the other hand increased cell proliferation in both divisions but promoted neurogenesis only in the dorsal hippocampus. These results indicate that environmental factors can differentially regulate neurogenesis in a region-specific manner. This may possibly underlie heterogeneous function of newborn neurons along the septo-temporal axis of the hippocampus and have functional significance as to their implication in stress related disorders and memory processes.
Serotonin-1A receptors in the dorsal periaqueductal gray matter mediate the panicolytic-like effect of pindolol and paroxetine combination in the elevated T-maze
2011, Neuroscience Letters
The β-adrenergic blocker and 5-HT_1A receptor antagonist pindolol has been combined with selective serotonin reuptake inhibitors (SSRIs) in patients with depressive and anxiety disorders to shorten the onset of the clinical action and/or increase the proportion of responders. The results of a previous study have shown that pindolol potentiates the panicolytic effect of paroxetine in rats submitted to the elevated T-maze (ETM). Since reported evidence has implicated the 5-HT_1A receptors of the dorsal periaqueductal gray matter (DPAG) in the panicolytic effect of antidepressants, rats treated with pindolol (5.0 mg/kg, i.p.) and paroxetine (1.5 mg/kg, i.p.) received a previous intra-DPAG injection of the selective 5-HT_1A antagonist, WAY-100635 (0.4 μg) and were submitted to the ETM. Pretreatment with WAY-100635 reversed the increase in escape latency, a panicolytic effect, determined by the pindolol-paroxetine combination. These results implicate the 5-HT_1A receptors of the DPAG in the panicolytic effect of the pindolol-paroxetine combination administered systemically. They also give further preclinical support for the use of this drug combination in the treatment of panic disorder.
Effect of xanthone from Kielmeyera coriacea stems on serotonergic neurons of the median raphe nucleus
2010, Phytomedicine
Kielmeyera coriacea Mart. (Clusiaceae), known as “Pau Santo”, is used to treat several tropical diseases. The hydroethanolic extract (HE) of Kielmeyera coriacea stems and its semi-pure dichloromethane constituent (DCM) produced an anti-immobility effect in rats submitted to the forced swimming test (FST), suggesting a antidepressant-like profile. This study evaluated the effect of intra-median raphe nucleus (MRN) microinjection of 1,3,7-trihydroxy-2-(3-methylbut-2-enyl)-xanthone, present in large quantity in the HE from Kielmeyera coriacea stems, on immobility behaviour in the FST in rats. The effects of xanthone were compared with intra-MRN microinjections of Way100635 (5-HT1A antagonist) or (+) 8-OH-DPAT (5-HT1A agonist).
Locomotor activity in the open-field test (OFT) was evaluated as a complementary measure. Xanthone (0.3 ng) or Way100635 (2.5 μg) reduced, whereas (+) 8-OH-DPAT (5.0 μg) increased immobility time in the FST. Way100635 (2.5 or 5.0 μg) completely reversed the effects of (+) 8-OHDPAT (5.0 μg), and potentiated the anti-immobility effect of the ineffective dose of xanthone (0.2 ng) in the FST. The association of effective doses of (+) 8-OH-DPAT (5.0 μg) and xanthone (0.3 ng) annulled the effect of each compound on immobility time. These results suggest that xanthone acts as an antagonist at 5-HT1A autoreceptors in MRN and increases serotonin (5-HT) availability in projection regions, proving to be a prototype drug that may be useful in mood isorders such as depression, or indeed be a beneficial adjunctive treatment improving the efficacy and/or accelerating the effects of antidepressant drugs in patients with major depression.
Acute effects of combining citalopram and pindolol on regional brain serotonin synthesis in sham operated and olfactory bulbectomized rats
2009, Neurochemistry International
The olfactory bulbectomized (OBX) rat is considered to be a good model of the pathology of human depression and also of the functional actions of antidepressant drug therapy. It has been proposed that antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) can be accelerated by blocking 5-HT_1A/B autoreceptors with pindolol. The underlying mechanism is thought to involve acute unrestricting of 5-HT release and, consequently, relatively enhanced 5-HT turnover throughout the forebrain serotonergic networks. The effect of this combination on 5-HT turnover in sham operated or OBX rats can be assessed at the level of 5-HT synthesis, a very important presynaptic step in serotonergic neurotransmission, using the α-[¹⁴C]methyl-l-tryptophan autoradiography method. In sham rats, acute citalopram (20 mg/kg) treatment increased synthesis at almost all serotonergic terminal regions but slightly decreased synthesis at serotonergic cell body regions (i.e. dorsal and median (not significant) raphe; ∼16%). Combining pindolol (10 mg/kg) with citalopram further increased synthesis at many regions in sham rats (relative to treatment with only citalopram). In OBX rats, citalopram decreased synthesis at a few terminal regions and greatly decreased synthesis at the dorsal and median raphe (∼45%; relative to OBX rats treated with saline). Combining pindolol with citalopram greatly increased synthesis at almost all regions in OBX rats (relative to treatment with only citalopram). These results suggest that acute citalopram effects result in elevated terminal 5-HT synthesis, but these effects are restrained by 5-HT_1A/B autoreceptor feedback to different degrees in sham and OBX rats. Moreover, 5-HT_1A/B autoreceptor feedback is stronger in OBX rats and may underlie the delay of SSRI effects in OBX rats and, correspondingly, in human depression. Pindolol acceleration and augmentation of SSRI antidepressant therapy for human depression may be mediated by attenuation of 5-HT_1A/B autoreceptor feedback, permitting unhindered SSRI effects on serotonergic terminals.
Glucocorticoid Receptor Antagonists Hasten and Augment Neurochemical Responses to a Selective Serotonin Reuptake Inhibitor Antidepressant
2007, Biological Psychiatry
Citation Excerpt :
The fall in dialysate 5-HT is thought to reflect the SSRI-induced inhibition of 5-HT neuronal firing and hence terminal release. Evidence from electrophysiological and microdialysis studies indicates that the effects of systemic SSRIs on 5-HT firing and release are mediated by somatodendritic 5-HT1A receptors and are not contributed to by postsynaptic feedback loops (45,46). These data indicate that the decrease in dialysate 5-HT after systemic administration of fluoxetine is principally mediated by somatodendritic 5-HT1A receptors.
Selective serotonin reuptake inhibitor (SSRI) antidepressant drugs have a delayed onset and commonly produce an incomplete therapeutic response. The therapeutic actions of SSRIs are thought to depend on increased forebrain extracellular serotonin (5-HT), after desensitization of somatodendritic 5-HT_1A autoreceptors. Here we determined whether concurrent glucocorticoid receptor (GR) blockade enhances these neurochemical responses to the SSRI fluoxetine.
Male rats were treated (3, 7, or 14 days) with either fluoxetine (10 mg/kg IP) or vehicle once daily, in combination with either a GR antagonist (Org 34850 15 mg/kg SC or Org 34517 25 mg/kg SC) or vehicle twice daily. After treatment, 5-HT in the medial prefrontal cortex was measured by microdialysis.
Chronic fluoxetine treatment (14 days) raised basal 5-HT and also attenuated the fall in 5-HT after acute systemic administration of fluoxetine (10 mg/kg IP), indicating desensitization of 5-HT_1A autoreceptors. Concurrent chronic administration (14 days) of Org 34850 or Org 34517 enhanced the fluoxetine-induced increase in basal 5-HT. Org 34850 also hastened the 5-HT_1A autoreceptor desensitization induced by chronic fluoxetine treatment. Org 34850 alone (14 days) failed to alter basal 5-HT or 5-HT_1A autoreceptor desensitization.
Antidepressant response is proposed to depend on 5-HT_1A autoreceptor desensitization and elevation of forebrain 5-HT. These data suggest adjunctive GR antagonists might both hasten and enhance antidepressant responses to SSRIs.

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

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Regional distribution of extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the brain of freely moving rats

J. Neurochem.

Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors

Arch. Gen. Psychiatry

Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression

J. Clin. Psychopharmacol.

Modifications of the serotonin system by antidepressant treatments: implications for the therapeutic response in major depression

J. Clin. Psychopharmacol.

Presynaptic and post-synaptic modifications of the serotonin system by long-term administration of antidepressant treatments - an in vivo electrophysiologic study in the rat

Neuropsychopharmacology

Short communication
Raphe 5-HT_1A autoreceptors, but not postsynaptic 5-HT_1A receptors or β-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo