RESUMO
1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT(1B) receptor agonist [EC(50) = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT(3) receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.
Assuntos
Ansiolíticos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Piperazinas/uso terapêutico , Sulfetos/uso terapêutico , Animais , Monoaminas Biogênicas/análise , Citalopram/farmacologia , Humanos , Masculino , Ondansetron/farmacologia , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1B de Serotonina/metabolismo , Receptores de Serotonina/metabolismo , Reflexo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Sulfetos/farmacocinética , Sulfetos/farmacologia , Vocalização Animal/efeitos dos fármacos , VortioxetinaRESUMO
RATIONALE: Ketamine has rapid antidepressant effects that represent a significant advance in treating depression, but its poor safety and tolerability limit its clinical utility. Accreting evidence suggests that serotonergic neurotransmission participates in the rapid antidepressant effects of ketamine and hallucinogens. Thus, understanding how serotonin contributes to these effects may allow identification of novel rapid antidepressant mechanisms with improved tolerability. OBJECTIVE: The goal of this paper is to understand how serotonergic mechanisms participate in rapid antidepressant mechanisms. METHODS: We review the relevance of serotonergic neurotransmission for rapid antidepressant effects and evaluate the role of 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors in synaptic plasticity, BDNF signaling, and GSK-3ß activity. Subsequently, we develop hypotheses on the relationship of these receptor systems to rapid antidepressant effects. RESULTS: We found that 5-HT1A and 5-HT1B receptors may participate in ketamine's rapid antidepressant mechanisms, while agonists at 5-HT2A and 5-HT4 receptors may independently behave as rapid antidepressants. 5-HT1A, 5-HT2A, and 5-HT4 receptors increase synaptic plasticity in the cortex or hippocampus but do not consistently increase BDNF signaling. We found that 5-HT1A and 5-HT1B receptors may participate in rapid antidepressant mechanisms as a consequence of increased BDNF signaling, rather than a cause. 5-HT2A and 5-HT4 receptor agonists may increase BDNF signaling, but these relationships are tenuous and need more study. Finally, we found that ketamine and several serotonergic receptor systems may mechanistically converge on reduced GSK-3ß activity. CONCLUSIONS: We find it plausible that serotonergic neurotransmission participates in rapid antidepressant mechanisms by increasing synaptic plasticity, perhaps through GSK-3ß inhibition.
Assuntos
Ketamina , Serotonina , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo , Glicogênio Sintase Quinase 3 beta , Ketamina/farmacologia , Ketamina/uso terapêutico , Transmissão SinápticaRESUMO
The aim of this study was to investigate the antidepressant activity of vortioxetine in a tryptophan (TRP) depletion female rat model of depression and compare it to that of paroxetine using doses that fully occupy the serotonin transporter (SERT). We evaluated the effects of vortioxetine on potential biomarkers associated with TRP depletion including serum aldosterone, corticosterone and IL-6 levels together with indirect indicators of glutamate neurotransmission. Female Sprague-Dawley rats were randomized to control, low TRP, low TRP/paroxetine or low TRP/vortioxetine groups. Vortioxetine and paroxetine were administered via diet (10mg/kg/day) and drinking water (10mg/kg/day) respectively for 14days. Vortioxetine but not paroxetine reversed TRP depletion-induced depressive-like behavior. Vortioxetine reduced TRP depletion-induced increases of serum corticosterone, aldosterone, IL-6 and N-methyl-d-aspartate and α7-nicotinic acetylcholine receptor expression in the amygdala and hippocampus, respectively. Paroxetine demonstrated little effect except a reduction of aldosterone. Vortioxetine but not paroxetine reversed TRP depletion-induced reductions of serum and brain kynurenic acid. In conclusion, vortioxetine, but not paroxetine, enabled reversals of TRP depletion-induced changes of depression-like behavior and markers of glutamatergic activity. These observations support the hypothesis that vortioxetine's antidepressant activity may involve mechanisms beyond SERT inhibition.
Assuntos
Transtorno Depressivo/sangue , Transtorno Depressivo/tratamento farmacológico , Ácido Glutâmico/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Vortioxetina/farmacologia , Administração Oral , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Feminino , Paroxetina/farmacologia , Distribuição Aleatória , Ratos Sprague-DawleyRESUMO
More effective treatments for major depression are needed. We studied if the selective 5-HT3 receptor antagonist ondansetron can potentiate the antidepressant potential of the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine using behavioral, neurochemical and electrophysiological methods. Flinders Sensitive Line (FSL) rats, treated with ondansetron, and/or a sub-effective dose of paroxetine, were assessed in the forced swim test. The effects of an acute intravenous administration of each compound alone and in combination were evaluated with respect to 5-HT neuronal firing rate in the dorsal raphe nucleus (DRN). Effects of s.c. administration of the compounds alone and in combination on extracellular levels of 5-HT were assessed in the ventral hippocampus of freely moving rats by microdialysis. The results showed that ondansetron enhanced the antidepressant activity of paroxetine in the forced swim test. It partially prevented the suppressant effect of paroxetine on DRN 5-HT neuronal firing and enhanced the paroxetine-induced increase of hippocampal extracellular 5-HT release. These findings indicate that 5-HT3 receptor blockade potentiates the antidepressant effects of SSRIs. Since both paroxetine and ondansetron are used clinically, it might be possible to validate this augmentation strategy in depressed patients.
Assuntos
Depressão/tratamento farmacológico , Ondansetron/farmacologia , Paroxetina/agonistas , Inibidores Seletivos de Recaptação de Serotonina/agonistas , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Animais , Depressão/fisiopatologia , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/fisiologia , Sinergismo Farmacológico , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Hipocampo/química , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Microdiálise , Ratos , Ratos Sprague-Dawley , Serotonina/análise , Serotonina/fisiologiaRESUMO
BACKGROUND AND PURPOSE: EEG studies show that 5-HT is involved in regulation of sleep-wake state and modulates cortical oscillations. Vortioxetine is a 5-HT3 , 5-HT7 , and 5-HT1D receptor antagonist, 5-HT1B partial agonist, 5-HT1A agonist, and 5-HT transporter inhibitor. Preclinical (animal) and clinical studies with vortioxetine show positive impact on cognitive metrics involving cortical function. Here we assess vortioxetine's effect on cortical neuronal oscillations in actively awake rats. EXPERIMENTAL APPROACH: Telemetric EEG recordings were obtained with the following treatments (mg·kg(-1) , s.c.): vehicle, vortioxetine (0.1, 1.0, 3.0, 10), 5-HT1A agonist flesinoxan (2.5), 5-HT3 antagonist ondansetron (0.30), 5-HT7 antagonist SB-269970-A (10), escitalopram (2.0), duloxetine (10) and vortioxetine plus flesinoxan. Target occupancies were determined by ex vivo autoradiography. KEY RESULTS: Vortioxetine dose-dependently increased wakefulness. Flesinoxan, duloxetine, ondansetron, but not escitalopram or SB-269970-A increased wakefulness. Quantitative spectral analyses showed vortioxetine alone and with flesinoxan increased θ (4-8 Hz), α (8-12 Hz) and γ (30-50 Hz) power. Duloxetine had no effect on θ and γ, but decreased α power, while escitalopram produced no changes. Ondansetron and SB-269970 (≈31-35% occupancy) increased θ power. Flesinoxan (≈41% occupancy) increased θ and γ power. CONCLUSIONS AND IMPLICATIONS: Vortioxetine increased wakefulness and increased frontal cortical activity, most likely because of its 5-HT7 and 5-HT3 antagonism and 5-HT1A agonism. Vortioxetine differs from escitalopram and duloxetine by increasing cortical θ, α and γ oscillations. These preclinical findings suggest a role of vortioxetine in modulating cortical circuits known to be recruited during cognitive behaviours and warrant further investigation as to their clinical impact.
Assuntos
Antidepressivos/farmacologia , Lobo Frontal/efeitos dos fármacos , Piperazinas/farmacologia , Sulfetos/farmacologia , Animais , Citalopram/farmacologia , Cloridrato de Duloxetina , Eletroencefalografia , Lobo Frontal/fisiologia , Masculino , Proteínas de Ligação a RNA/fisiologia , Ratos Sprague-Dawley , Receptores de Serotonina/fisiologia , Tiofenos/farmacologia , Vortioxetina , Vigília/efeitos dos fármacosRESUMO
The prototypical atypical antipsychotic drug (APD) clozapine (CLZ) elicits a discriminative cue that appears to be similar to the stimulus properties elicited by atypical, but not typical, antipsychotic drugs in two-choice drug discrimination procedures. However, the ability of CLZ to generalize to atypical APDs depends on the training dose, since several atypical APDs (e.g. sertindole, risperidone) do not substitute for a 5.0 mg/kg CLZ training dose in rats, but do so for a 1.25 mg/kg CLZ training dose. Yet, a 1.25 mg/kg CLZ discriminative stimulus has not generalized to all atypical APDs either (e.g. quetiapine); thus, both 1.25 mg/kg and 5.0 mg/kg CLZ discriminative stimuli may be necessary to provide a better screen for atypical APDs. The present study sought to determine whether a three-choice 1.25 mg/kg CLZ versus 5.0 mg/kg CLZ versus vehicle drug discrimination task in rats might better distinguish atypical from typical APDs. Adult male Sprague-Dawley rats were trained in this three-choice drug discrimination task with a fixed ratio 30 reinforcement schedule for food. Clozapine produced full substitution (>or=80% condition-appropriate responding) for both the 1.25 mg/kg CLZ dose (ED50=0.09 mg/kg) and the 5.0 mg/kg CLZ dose (ED50=2.71 mg/kg). The atypical APD olanzapine produced full substitution for the 5.0 mg/kg CLZ dose, but not for the 1.25 mg/kg CLZ dose (ED50=1.55 mg/kg). In contrast, the atypical APD quetiapine produced full substitution for the 1.25 mg/kg CLZ dose (ED50=0.13 mg/kg), but not for the 5.0 mg/kg CLZ dose. Similarly, the atypical APD sertindole produced full substitution for only the 1.25 mg/kg CLZ dose (ED50=0.94 mg/kg). Risperidone, another atypical APD, produced partial substitution (>or=60% and Assuntos
Antipsicóticos/administração & dosagem
, Antipsicóticos/farmacologia
, Clozapina/administração & dosagem
, Clozapina/farmacologia
, Aprendizagem por Discriminação/efeitos dos fármacos
, Discriminação Psicológica/efeitos dos fármacos
, Generalização do Estímulo/efeitos dos fármacos
, Animais
, Condicionamento Operante/efeitos dos fármacos
, Relação Dose-Resposta a Droga
, Masculino
, Ratos
, Ratos Sprague-Dawley
, Esquema de Reforço