Chronic effects of antidepressants on serotonin release in rat raphe slice cultures: high potency of milnacipran in the augmentation of serotonin release

Abstract Most clinically-used antidepressants acutely increase monoamine levels in synaptic clefts, while their therapeutic effects often require several weeks of administration. Slow neuroadaptive changes in serotonergic neurons are considered to underlie this delayed onset of beneficial actions. Recently, we reported that sustained exposure of rat organotypic raphe slice cultures containing abundant serotonergic neurons to selective serotonin (5-HT) reuptake inhibitors (citalopram, fluoxetine and paroxetine) caused the augmentation of exocytotic serotonin release. However, the ability of other classes of antidepressants to evoke a similar outcome has not been clarified. In this study, we investigated the sustained actions of two tricyclic antidepressants (imipramine and desipramine), one tetracyclic antidepressant (mianserin), three 5-HT and noradrenaline reuptake inhibitors (milnacipran, duloxetine and venlafaxine) and one noradrenergic and specific serotonergic antidepressant (mirtazapine) on serotonin release in the slice cultures. For seven of nine antidepressants, sustained exposure to the agents at concentrations of 0.1–100 µm augmented the level of increase in extracellular serotonin. The rank order of their potency was as follows: milnacipran>duloxetine>citalopram>venlafaxine>imipramine>fluoxetine>desipramine. Neither mirtazapine nor mianserin caused any augmentation. The highest augmentation by sustained exposure to milnacipran was partially attenuated by an α1-adrenoceptor antagonist, benoxathian, while the duloxetine-, venlafaxine- and citalopram-mediated increases were not affected. These results suggest that inhibition of the 5-HT transporter is required for the enhancement of serotonin release. Furthermore, the potent augmentation by milnacipran is apparently due to the accompanied activation of the α1-adrenoceptor.

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Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose

The British Journal of Psychiatry ◽

10.1192/bjp.bp.109.070219 ◽

2010 ◽

Vol 196 (5) ◽

pp. 354-358 ◽

Cited By ~ 95

Author(s):

Keith Hawton ◽

Helen Bergen ◽

Sue Simkin ◽

Jayne Cooper ◽

Keith Waters ◽

...

Keyword(s):

Selective Serotonin Reuptake Inhibitors ◽

Tricyclic Antidepressants ◽

Case Fatality ◽

Relative Toxicity ◽

Toxicity Index ◽

Undetermined Intent ◽

Noradrenaline Reuptake ◽

Poisoning Deaths ◽

Rate Ratios ◽

Serotonergic Antidepressant

BackgroundSelf-poisoning is a common method of suicide and often involves ingestion of antidepressants. Information on the relative toxicity of antidepressants is therefore extremely important.AimsTo assess the relative toxicity of specific tricyclic antidepressants (TCAs), a serotonin and noradrenaline reuptake inhibitor (SNRI), a noradrenergic and specific serotonergic antidepressant (NaSSA), and selective serotonin reuptake inhibitors (SSRIs).MethodObservational study of prescriptions (UK), poisoning deaths involving single antidepressants receiving coroners' verdicts of suicide or undetermined intent (England and Wales) and non-fatal self-poisoning episodes presenting to six general hospitals (in Oxford, Manchester and Derby) between 2000 and 2006. Calculation of fatal toxicity index based on ratio of rates of deaths to prescriptions, and case fatality based on ratio of rates of deaths to non-fatal self-poisonings.ResultsFatal toxicity and case fatality indices provided very similar results (rho for relative ranking of indices 0.99). Case fatality rate ratios showed greater toxicity for TCAs (13.8, 95% CI 13.0–14.7) than the SNRI venlafaxine (2.5, 95% CI 2.0–3.1) and the NaSSA mirtazapine (1.9, 95% CI 1.1–2.9), both of which had greater toxicity than the SSRIs (0.5, 95% CI 0.4–0.7). Within the TCAs, compared with amitriptyline both dosulepin (relative toxicity index 2.7) and doxepin (2.6) were more toxic. Within the SSRIs, citalopram had a higher case fatality than the other SSRIs (1.1, 95% CI 0.8–1.4 v. 0.3, 95% CI 0.2–0.4).ConclusionsThere are wide differences in toxicity not only between classes of antidepressants, but also within classes. The findings are relevant to prescribing decisions, especially in individuals at risk, and to regulatory policy.

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New classes of antidepressant drugs

Advances in Psychiatric Treatment ◽

10.1192/apt.5.2.104 ◽

1999 ◽

Vol 5 (2) ◽

pp. 104-111 ◽

Cited By ~ 1

Author(s):

Allan I. F. Scott

Keyword(s):

Reuptake Inhibitor ◽

Selective Serotonin Reuptake Inhibitors ◽

Tricyclic Antidepressants ◽

Antidepressant Drug ◽

Antidepressant Drugs ◽

Noradrenaline Reuptake ◽

Meta Analyses ◽

Prevention Of Relapse ◽

Serotonergic Antidepressant ◽

Noradrenaline Reuptake Inhibitor

The January 1997 issue of this journal contained four reviews that compared tricyclic antidepressants with selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants in terms of their pharmacology (Palazidou, 1997), adverse effects, potential drug interactions and toxicity (Henry, 1997), efficacy in the prevention of relapse and recurrence (Edwards, 1997), and findings from meta-analyses (Anderson, 1997). In July 1997 reboxetine was promoted as the first selective noradrenaline reuptake inhibitor (NARI), and in October of the same year mirtazapine was promoted as the first noradrenergic and specific serotonergic antidepressant (NaSSA). Milnacipran is presently being registered by the manufacturers, after which it will be the second antidepressant drug promoted as a specific serotonin and noradrenaline reuptake inhibitor (SNRI).

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Evaluation of Antidepressant Effects on Recovery of Electrical Field Stimulation-Induced Contractions that have been Suppressed by Clonidine in Isolated Rat Vas Deferens

Pharmacology ◽

10.1159/000495616 ◽

2019 ◽

Vol 103 (3-4) ◽

pp. 189-201

Author(s):

Keisuke Obara ◽

Mayumi Michino ◽

Masataka Ito ◽

Lin Ao ◽

Ayano Sawada ◽

...

Keyword(s):

Receptor Antagonist ◽

Tricyclic Antidepressants ◽

Vas Deferens ◽

Electrical Field Stimulation ◽

Rat Vas Deferens ◽

Blood Levels ◽

Field Stimulation ◽

Electrical Field ◽

Tetracyclic Antidepressant ◽

Isolated Rat

Background: A report examining whether clinically available antidepressants increase urethral smooth muscle contraction via antagonistic effects on the α2-adrenoceptor (α2-AR) is lacking. Objectives: The present study was performed to evaluate the potential of clinically available antidepressants to reverse α2-AR-mediated contractile inhibition in rat vas deferens, in order to predict whether they can induce voiding impairment. Method: The effects of 18 antidepressants of different classes on electrical field stimulation (EFS)-induced contractions suppressed by 10–8 mol/L clonidine (a selective α2-AR agonist) in isolated rat vas deferens were investigated and related to their respective clinical blood concentrations. Results: The EFS-induced contractions suppressed by clonidine were recovered by amitriptyline (a tricyclic antidepressant), mirtazapine (a noradrenergic and specific serotonergic antidepressant), and trazodone (a serotonin 5-HT2A receptor antagonist) at concentrations close to the clinical blood levels. EFS-induced contractions were also recovered by trimipramine, clomipramine (tricyclic antidepressants), mianserin (a tetracyclic antidepressant), sertraline (a selective serotonin reuptake inhibitor [SSRI]), and sulpiride (a dopamine D2-receptor antagonist), albeit at concentrations that substantially exceeded their clinically-achievable blood levels. EFS-induced contractions were not significantly affected by imipramine, nortriptyline, amoxapine (tricyclic antidepressants), maprotiline (a tetracyclic antidepressant), fluvoxamine, paroxetine, escitalopram (SSRIs), milnacipran, duloxetine (serotonin and noradrenaline reuptake inhibitors), and aripiprazole (a dopamine partial agonist). Conclusions: These findings suggest that amitriptyline, mirtazapine, and trazodone induce voiding impairment caused by increased urethral resistance by enhancing sympathetic nerve activities attributed to α2-AR antagonism.

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Therapeutic effects of milnacipran, a serotonin and noradrenaline reuptake inhibitor, on post-stroke depression

International Clinical Psychopharmacology ◽

10.1097/00004850-200205000-00005 ◽

2002 ◽

Vol 17 (3) ◽

pp. 121-125 ◽

Cited By ~ 27

Author(s):

M. Kimura ◽

K. Kanetani ◽

R. Imai ◽

H. Suzuki ◽

K. Isayama ◽

...

Keyword(s):

Reuptake Inhibitor ◽

Therapeutic Effects ◽

Post Stroke ◽

Noradrenaline Reuptake ◽

Post Stroke Depression ◽

Noradrenaline Reuptake Inhibitor

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Nonexocytotic serotonin release tonically suppresses serotonergic neuron activity

The Journal of General Physiology ◽

10.1085/jgp.201411330 ◽

2015 ◽

Vol 145 (3) ◽

pp. 225-251 ◽

Cited By ~ 15

Author(s):

Boris Mlinar ◽

Alberto Montalbano ◽

Gilda Baccini ◽

Francesca Tatini ◽

Rolando Berlinguer Palmini ◽

...

Keyword(s):

Serotonin Release ◽

Raphe Nuclei ◽

Neuron Activity ◽

Release Mechanism ◽

Serotonergic Neuron ◽

Firing Activity ◽

Serotonergic Neurons ◽

Simple Diffusion ◽

Inwardly Rectifying Potassium Channels ◽

Raphé Nuclei

The firing activity of serotonergic neurons in raphe nuclei is regulated by negative feedback exerted by extracellular serotonin (5-HT)o acting through somatodendritic 5-HT1A autoreceptors. The steady-state [5-HT]o, sensed by 5-HT1A autoreceptors, is determined by the balance between the rates of 5-HT release and reuptake. Although it is well established that reuptake of 5-HTo is mediated by 5-HT transporters (SERT), the release mechanism has remained unclear. It is also unclear how selective 5-HT reuptake inhibitor (SSRI) antidepressants increase the [5-HT]o in raphe nuclei and suppress serotonergic neuron activity, thereby potentially diminishing their own therapeutic effect. Using an electrophysiological approach in a slice preparation, we show that, in the dorsal raphe nucleus (DRN), continuous nonexocytotic 5-HT release is responsible for suppression of phenylephrine-facilitated serotonergic neuron firing under basal conditions as well as for autoinhibition induced by SSRI application. By using 5-HT1A autoreceptor-activated G protein–gated inwardly rectifying potassium channels of patched serotonergic neurons as 5-HTo sensors, we show substantial nonexocytotic 5-HT release under conditions of abolished firing activity, Ca2+ influx, vesicular monoamine transporter 2–mediated vesicular accumulation of 5-HT, and SERT-mediated 5-HT transport. Our results reveal a cytosolic origin of 5-HTo in the DRN and suggest that 5-HTo may be supplied by simple diffusion across the plasma membrane, primarily from the dense network of neurites of serotonergic neurons surrounding the cell bodies. These findings indicate that the serotonergic system does not function as a sum of independently acting neurons but as a highly interdependent neuronal network, characterized by a shared neurotransmitter pool and the regulation of firing activity by an interneuronal, yet activity-independent, nonexocytotic mechanism.

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Chronic Pain Treatment: The Influence of Tricyclic Antidepressants on Serotonin Release and Uptake in Mast Cells

Mediators of Inflammation ◽

10.1155/2013/340473 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 9

Author(s):

Ilonka Ferjan ◽

Metoda Lipnik-Štangelj

Keyword(s):

Chronic Pain ◽

Mast Cells ◽

Tricyclic Antidepressants ◽

Cell Function ◽

Pain Treatment ◽

Serotonin Release ◽

Experimental Conditions ◽

Pain Mechanisms ◽

Chronic Pain Treatment ◽

5 Ht Uptake

The involvement of serotonin (5-HT) in chronic pain mechanisms is established. 5-HT inhibits central painful stimuli, but recent data suggests that 5-HT could also enhance pain stimulus from the periphery, where mast cells play an important role. We aimed in our study to clarify the influence of selected tricyclic antidepressants (TCAs) on mast cell function: secretion, uptake, and reuptake of 5-HT, that could interfere with 5-HT levels and in this way contribute to the generation of pain. As an experimental model, we used isolated rat peritoneal mast cells and incubated them with selected TCAs (clomipramine, amitriptyline, doxepin, and imipramine) under different experimental conditions. 5-HT release, uptake, and reuptake were determined spectrofluorometrically. We showed that TCAs were able to inhibit 5-HT secretion from mast cells, as well as uptake of exogenous 5-HT and reuptake of secreted 5-HT back into mast cells. The effects of TCAs were concentration dependent; higher concentrations of TCAs inhibited the secretion of 5-HT induced by compound 48/80, whereas lower concentrations of TCAs inhibited 5-HT uptake. The most effective TCA was halogenated clomipramine. As TCAs are well introduced in chronic pain treatment, the insight into mechanisms of action is important for an understanding of their effect in various pain conditions.

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Somatodendritic serotonin release and re-uptake in mouse embryonic stem cell-derived serotonergic neurons

Neurochemistry International ◽

10.1016/j.neuint.2010.10.003 ◽

2010 ◽

Vol 57 (8) ◽

pp. 969-978 ◽

Cited By ~ 14

Author(s):

Thorsten Lau ◽

Tatjana Schneidt ◽

Felix Heimann ◽

Eckart D. Gundelfinger ◽

Patrick Schloss

Keyword(s):

Stem Cell ◽

Embryonic Stem Cell ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cell ◽

Serotonin Release ◽

Serotonergic Neurons

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Gender differences in the endothelial regulation of α2-adrenoceptor-mediated contraction in the rat aorta

Clinical Science ◽

10.1042/cs0970019 ◽

1999 ◽

Vol 97 (1) ◽

pp. 19-25 ◽

Cited By ~ 11

Author(s):

Nuria TEJERA ◽

Gloria BALFAGÓN ◽

Jesús MARÍN ◽

Mercedes FERRER

Keyword(s):

Rank Order ◽

Rat Aorta ◽

Ovariectomized Rats ◽

Maximal Response ◽

Nitric Oxide Synthase Inhibitor ◽

Adrenoceptor Antagonist ◽

Α2 Adrenoceptor ◽

No Release ◽

Synthase Inhibitor ◽

Oxide Synthase

The aim of this study was to determine the possible influence of sex hormones on the contractile responses induced by clonidine, an agonist of α2-adrenoceptors, as well as the endothelial modulation of these responses. For this purpose, thoracic aorta segments from male (control and castrated) and female (in oestrous phase and ovariectomized) rats were used. In intact segments from the four groups of rats, clonidine (0.01-10 µmol/l) induced concentration-dependent contractions, which were increased by the nitric oxide synthase inhibitor Nω-nitro-⌊-arginine methyl ester (0.1 mmol/l) or by endothelium removal, but were reduced by 1 µmol/l yohimbine (an α2-adrenoceptor antagonist) in all animals and by 1 µmol/l indomethacin (a cyclo-oxygenase inhibitor) in control males only. The rank order of the magnitude of the maximal response was: oestrous females > ovariectomized females > control males > castrated males, whereas the sensitivity to clonidine (EC50 value) was similar in all animals. In endothelium-denuded segments, the rank order was: oestrous females = control males > ovariectomized females = castrated males. These results suggest that: (1) the presence of oestrogen or androgen increases the contraction caused by α2-adrenoceptor activation with clonidine; (2) endothelium negatively modulates the response to this agonist in the four groups of rats, due to endothelial NO release (entirely in females and in part in males); (3) androgen also seems to modulate the response by stimulating the release of an endothelial contracting factor, probably a prostanoid; and (4) the endothelium of males has a greater capacity than that of comparable females for negative regulation of the tension generated by the underlying vascular smooth muscle.

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