Effects of continuous administration of paroxetine on ligand binding site and expression of serotonin transporter protein in mouse brain

Hirano, Kazuyuki; Seki, Takahiro; Sakai, Norio; Kato, Yasuhiro; Hashimoto, Hisakuni; Uchida, Shinya; Yamada, Shizuo

doi:10.1016/j.brainres.2005.06.038

Cited by 22 publications

(27 citation statements)

References 31 publications

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“…Treatment post diagnosis of depression is reflective of what happens in a clinical setting. Furthermore, it is in accordance with procedures in previous studies (Hirano et al, 2005). It is possible that if the time gap between stressing ending and animal testing starting is not sufficient, the changes could not be caused only by depression, but also by the physiological reaction to recent stress.…”

Section: Discussionsupporting

confidence: 89%

miR-16 and Fluoxetine Both Reverse Autophagic and Apoptotic Change in Chronic Unpredictable Mild Stress Model Rats

Yang

et al. 2017

Front. Neurosci.

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In the clinic selective serotonin reuptake inhibitors (SSRIs), like Fluoxetine, remain the primary treatment for major depression. It has been suggested that miR-16 regulates serotonin transporters (SERT) via raphe nuclei and hippocampal responses to antidepressants. However, the underlying mechanism and regulatory pathways are still obtuse. Here, a chronic unpredicted mild stress (CUMS) depression model in rats was established, and then raphe nuclei miR-16 and intragastric Fluoxetine injections were administered for a duration of 3 weeks. An open field test and sucrose preference quantification displayed a significant decrease in the CUMS groups when compare to the control groups, however these changes were attenuated by both miR-16 and Fluoxetine treatments. A dual-luciferase reporter assay system verified that hsa-miR-16 inhibitory effects involve the targeting of 3′UTR on the 5-HTT gene. Expression levels of miR-16 and BDNF in the hippocampus were examined with RT-PCR, and it was found that increased 5-HT2a receptor expression induced by CUMS can be decreased by miR-16 and Fluoxetine administration. Immunofluorescence showed that expression levels of neuron NeuN and MAP-2 in CUMS rats were lower. Apoptosis and autophagy levels were evaluated separately through relative expression of Bcl-2, Caspase-3, Beclin-1, and LC3II. Furthermore, CUMS was found to decrease levels of hippocampal mTOR, PI3K, and AKT. These findings indicate that apoptosis and autophagy related pathways could be involved in the effectiveness of antidepressants, in which miR-16 participates in the regulation of, and is likely to help integrate rapid therapeutic strategies to alleviate depression clinically. These findings indicate that miR-16 participates in the regulation of apoptosis and autophagy and could account for some part of the therapeutic effect of SSRIs. This discovery has the potential to further the understanding of SSRIs and accelerate the development of new treatments for depression.

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Section: Discussionsupporting

confidence: 89%

miR-16 and Fluoxetine Both Reverse Autophagic and Apoptotic Change in Chronic Unpredictable Mild Stress Model Rats

Yang

et al. 2017

Front. Neurosci.

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“…We modeled chronic highdose SSRI by administering~20 mg/kg/day fluoxetine for 14 days. This abolished SERT binding of the radioligand, suggesting 100% SERT occupancy (Supplementary Figure S1), although downregulation of SERT could partly explain the finding (Hirano et al, 2005). This finding excludes the possibility that additional 5-HT Ext elevation consequent to adjunct 5-HTP SR only compensated for incomplete SERT occupancy.…”

Section: Adjunct 5-htp Sr Elevates 5-ht Ext Beyond the Maximal Ssri Ementioning

confidence: 85%

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept

Jacobsen

Rudder

Roberts

et al. 2016

Neuropsychopharmacol

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Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HT Ext ) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HT Ext beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations. In humans, adjunct treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) elevates 5-HT Ext beyond the SSRI effect. Small pilot trials suggest that adjunct 5-HTP can confer antidepressant response in treatment-resistant depression (TRD). However, sustained, stable 5-HT Ext elevation is required for antidepressant effect; therefore, the rapid absorption and elimination of standard 5-HTP immediate release (IR) likely curtail 5-HTP IR's antidepressant potential. Slow-release (SR) drug delivery can crucially improve efficacy and safety of rapidly absorbed and eliminated compounds. Here we tested in mice the hypothesis that SR delivery will substantially improve 5-HTP's drug properties, by minimizing adverse effects and securing sustained 5-HT Ext elevation beyond the SSRI effect. We modeled 5-HTP SR with minipumps, 5-HTP IR with injections, and chronic SSRI with dietary fluoxetine. We tested adjunct 5-HTP SR in wild-type mice and in mice with low brain 5-HT owing to expression of a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2. In both lines of mice, adjunct 5-HTP SR synergized with SSRI to elevate 5-HT Ext beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HT Ext spikes and marked adverse effects. Integrated with a body of clinical data, our mouse data suggest that an adjunct 5-HTP SR drug could safely and effectively elevate 5-HT Ext beyond the SSRI effect and represent a novel treatment for TRD.

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“…This interpretation is based, in part, on immunohistochemical studies showing long-lasting MDMA-induced decreases in serotonergic fiber density in both rats and monkeys (see Introduction). Chronic antidepressant treatments can also result in decreased SERT binding, but this reduction is thought to reflect a downregulation of SERT expression (Benmansour Hirano et al, 2005). It is important to acknowledge that debate continues in the literature regarding the interpretation of MDMA-induced changes in SERT (measured by radioligand binding vs immunoblotting (see Wang et al, 2004Wang et al, , 2005Xie et al, 2006)) as well as other putative measures of serotonergic neurotoxicity such as reduced levels of 5-HT and 5-HIAA (O'Callaghan and Miller, 1993).…”

Section: Discussionmentioning

confidence: 99%

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

Piper

Fraiman

Owens

et al. 2007

Neuropsychopharmacol

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High or repeated doses of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy') produce long-lasting deficits in several markers of serotonin (5-HT) system integrity and also alter behavioral function. However, it is not yet clear whether MDMA-induced serotonergic neurotoxicity is responsible for these behavioral changes or whether other mechanisms are involved. The present experiment tested the hypothesis that blocking serotonergic neurotoxicity by pretreatment with the selective 5-HT reuptake inhibitor citalopram will also prevent the behavioral and physiological consequences of an MDMA binge administration. Male, SpragueDawley rats (N ¼ 67) received MDMA (4 Â 10 mg/kg) with or without citalopram (10 mg/kg) pretreatment. Core temperature, ejaculatory response, and body weight were monitored during and immediately following drug treatments. A battery of tests assessing motor, cognitive, exploratory, anxiety, and social behaviors was completed during a 10-week period following MDMA administration. Brain tissue was collected at 1 and 10 weeks after drug treatments for measurement of regional 5-HT transporter binding and (for the 1-week samples) 5-HT and 5-HIAA concentrations. Citalopram pretreatment blocked MDMA-related reductions in aggressive and exploratory behavior measured in the social interaction and hole-board tests respectively. Such pretreatment also had the expected protective effect against MDMA-induced 5-HT neurotoxicity at 1 week following the binge. In contrast, citalopram did not prevent most of the acute effects of MDMA (eg hyperthermia and weight loss), nor did it block the decreased motor activity seen in the binge-treated animals 1 day after dosing. These results suggest that some of the behavioral and physiological consequences of a high-dose MDMA regimen in rats are mediated by mechanisms other than the drug's effects on the serotonergic system. Elucidation of these mechanisms requires further study of the influence of MDMA on other neurotransmitter systems.

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Effects of continuous administration of paroxetine on ligand binding site and expression of serotonin transporter protein in mouse brain

Cited by 22 publications

References 31 publications

miR-16 and Fluoxetine Both Reverse Autophagic and Apoptotic Change in Chronic Unpredictable Mild Stress Model Rats

miR-16 and Fluoxetine Both Reverse Autophagic and Apoptotic Change in Chronic Unpredictable Mild Stress Model Rats

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept

Dissociation of the Neurochemical and Behavioral Toxicology of MDMA (‘Ecstasy’) by Citalopram

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