RESUMO
Foraging theory prescribes when optimal foragers should leave the current option for more rewarding alternatives. Actual foragers often exploit options longer than prescribed by the theory, but it is unclear how this foraging suboptimality arises. We investigated whether the upregulation of cholinergic, noradrenergic, and dopaminergic systems increases foraging optimality. In a double-blind, between-subject design, participants (N = 160) received placebo, the nicotinic acetylcholine receptor agonist nicotine, a noradrenaline reuptake inhibitor reboxetine, or a preferential dopamine reuptake inhibitor methylphenidate, and played the role of a farmer who collected milk from patches with different yield. Across all groups, participants on average overharvested. While methylphenidate had no effects on this bias, nicotine, and to some extent also reboxetine, significantly reduced deviation from foraging optimality, which resulted in better performance compared to placebo. Concurring with amplified goal-directedness and excluding heuristic explanations, nicotine independently also improved trial initiation and time perception. Our findings elucidate the neurochemical basis of behavioral flexibility and decision optimality and open unique perspectives on psychiatric disorders affecting these functions.
Assuntos
Acetilcolina , Metilfenidato , Humanos , Nicotina/farmacologia , Norepinefrina , Reboxetina , Método Duplo-CegoRESUMO
Reboxetine, the first selective norepinephrine (NA) reuptake inhibitor used in the treatment of depression, mainly acts by binding to the NA transporter and blocking reuptake of extracellular NA. Recently, some other pharmacological targets beyond the NA transporter are being demonstrated for reboxetine. Peroxisome proliferator activated receptor α (PPARα) is a member of the nuclear hormone receptor family of ligand-dependent transcription factors. Previous reports have demonstrated the role of hippocampal PPARα in the pathophysiology of depression. Here we assume that hippocampal PPARα may participate in the antidepressant mechanism of reboxetine. Therefore, the chronic social defeat stress (CSDS) model of depression, various behavioral tests, the western blotting and adenovirus associated virus (AAV)-mediated genetic knockdown methods were used together in the present study. Our results showed that repeated reboxetine treatment markedly restored the decreasing effects of CSDS on the expression of hippocampal PPARα, brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (pCREB). Pharmacological blockade of PPARα notably prevented the antidepressant-like effects of reboxetine in the CSDS model. Furthermore, genetic knockdown of hippocampal PPARα also fully abolished the antidepressant-like effects of reboxetine in the CSDS model. Taken together, promoting the hippocampal PPARα expression participates in the antidepressant mechanism of reboxetine.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Depressão/tratamento farmacológico , Hipocampo/metabolismo , PPAR alfa/metabolismo , Reboxetina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, α1adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of α1-ARs, namely, α1A-, α1B- and α1DARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at α1A-AR (IMI < DMI < CIT < MIA < REB) and α1DAR (IMI = DMI < CIT < MIA), while the α1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Receptores Adrenérgicos alfa 1/genética , Animais , Antidepressivos/classificação , Citalopram/farmacologia , Depressão/etiologia , Depressão/genética , Depressão/patologia , Desipramina/farmacologia , Fluoxetina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imipramina/farmacologia , Mianserina/farmacologia , Camundongos , Células PC12 , Ratos , Reboxetina/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Armillaria mellea, also known as Hazel mushroom, is a delicious food material and traditional herbal medicine in East Asia. Protoilludane sesquiterpenoid aromatic esters from A. mellea (PSAM) are the main active components with antibacterial and anticancer activities. This study explored the antidepressant-like activities of PSAM and its possible mechanisms of action using the open field test (OFT), tail suspension test (TST) and forced swimming test (FST) in mice for the first time. The results revealed that PSAM (1 mg/kg, i.p.) exhibited markedly antidepressant-like activity, which could be reversed by pretreatment with haloperidol (a non-selective D2 receptor antagonist), bicuculline (a competitive GABA antagonist), NMDA (an agonist at the glutamate site). Meanwhile, PSAM also effectively increased the hippocampus dopamine (DA) and γ-aminobutyric acid (GABA) and decreased the hippocampus glutamate (Glu) levels of mice, indicating that the antidepressant-like effect of PSAM might be mediated by the DAergic, GABAergic and Gluergic systems.
Assuntos
Antidepressivos/uso terapêutico , Armillaria/química , Ésteres/uso terapêutico , Sesquiterpenos Policíclicos/uso terapêutico , Sesquiterpenos/uso terapêutico , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Dopamina/metabolismo , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Ácido Glutâmico/metabolismo , Elevação dos Membros Posteriores , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Teste de Campo Aberto , Sesquiterpenos Policíclicos/farmacologia , Reboxetina/farmacologia , Reboxetina/uso terapêutico , Natação , Ácido gama-Aminobutírico/metabolismoRESUMO
BACKGROUND: Vasovagal syncope (VVS) significantly reduces quality of life, yet lacks effective medical therapies. Pharmacological norepinephrine transporter (NET) inhibition increases synaptic norepinephrine reuptake, which may be able to prevent hypotension, bradycardia, and syncope. OBJECTIVE: The objective of this systematic review was to evaluate the ability of 3 NET inhibitors-reboxetine, sibutramine, and atomoxetine-to prevent head-up tilt-induced vasovagal outcomes in healthy participants and patients with VVS. METHODS: Relevant studies were identified from Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature without language restriction from database inception to August 2019. All randomized controlled trials comparing the benefit of a NET inhibitor vs placebo in adult populations were selected for review and meta-analysis. RESULTS: Four studies (101 participants) met inclusion criteria. The mean study size was 25 (range 11-56) participants. NET inhibition reduced the likelihood of vasovagal reactions marked by hypotension and bradycardia in healthy participants during head-up tilt testing (relative risk 0.15; 95% confidence interval 0.04-0.52; P = .003). This relative risk reduction also occurred in patients with VVS during head-up tilt when given atomoxetine (relative risk 0.49; 95% confidence interval 0.28-0.86; P = .01). This was achieved through heart rate compensation with NET inhibition toward the end of tilt testing (106 ± 32 beats/min vs 60 ± 22 beats/min; P < .001), which in turn preserved cardiac output and mean arterial pressure (71 ± 20 mm Hg vs 43 ± 13 mm Hg; P < .001) in the absence of significantly increased systemic vascular resistance. CONCLUSION: NET inhibition prevents severe vasovagal reactions and syncope induced by head-up tilt testing in both healthy participants and patients with VVS. Pharmacological NET inhibition is a promising potential treatment of recurrent syncope.
Assuntos
Débito Cardíaco/fisiologia , Frequência Cardíaca/fisiologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Reboxetina/uso terapêutico , Síncope Vasovagal/tratamento farmacológico , Adulto , Débito Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Qualidade de Vida , Síncope Vasovagal/fisiopatologia , Adulto JovemRESUMO
The aim of the present study was to investigate and compare the ability of three novel 5-HT6 and/or 5-HT7 receptor antagonists as follows: PZ-668-a preferential 5-HT6 antagonist; PZ-1433-a preferential 5-HT7 antagonist; and ADN-1184-a monoaminergic ligand with potent 5HT6/7 antagonist properties, to augment the effect of antidepressant drugs with different mechanisms of action (escitalopram, reboxetine, and bupropion) in the forced swim test in rats. In neurochemical ex vivo experiments, the influence of the tested compounds on levels of monoamines and their metabolites were determined in the rat frontal cortex, in addition to behavioral experiments. The results of our investigations revealed the differences in action of the tested compounds. PZ-668 strongly affected dopaminergic and faintly noradrenergic system, PZ-1433 induced a significant elevation in dopamine, noradrenaline, serotonin, and their metabolite levels, while ADN-1184 appeared to act mostly through dopaminergic transmission. The agent with 5-HT6 antagonistic properties (PZ-668) revealed an anti-immobility action of bupropion (primarily) and reboxetine in interaction studies. PZ-1433, the 5-HT7 preferential antagonist facilitated antidepressant effects of escitalopram and, to a lesser extent, bupropion, while ADN-1184, a multireceptor ligand, potentiated the effectiveness of escitalopram, reboxetine, and bupropion. The presented findings may contribute to further investigations of more effective and safer antidepressant drugs, and may help selecting optimal augmentation therapy in treatment-resistant depression.
Assuntos
Antidepressivos/farmacologia , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Atividade Motora/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Animais , Encéfalo/metabolismo , Bupropiona/farmacologia , Citalopram/farmacologia , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Isoxazóis/farmacologia , Masculino , Atividade Motora/fisiologia , Ratos Wistar , Reboxetina/farmacologia , Receptores de Serotonina/metabolismo , Sulfonamidas/farmacologiaRESUMO
The main goal of the present study was to evaluate the influence of the adenosine A1 receptor (A1R) antagonist - DPCPX - on depressive-like behavior in mice, as well as the effect of DPCPX on the activity of imipramine, escitalopram, and reboxetine, each at non-effective doses. The influence of DPCPX on behavior and its influence on the activity of selected antidepressants was evaluated in the forced swim test (FST) and the tail suspension test (TST) in mice. Locomotor activity was measured to verify and exclude false-positive data obtained in the FST and TST. Moreover, serum and brain concentrations of tested antidepressants were determined using HPLC. DPCPX, at doses of 2 and 4 mg/kg, exhibited antidepressant activity in the FST and TST, which was not related to changes in the spontaneous locomotor activity. Co-administration of DPCPX with imipramine, escitalopram, or reboxetine, each at non-active doses, significantly reduced the immobilization period in the FST and TST in mice, which was not due to the increase in locomotor activity. Both antagonists of 5-HT receptors (WAY 100635 and ritanserin) completely antagonized the effect elicited by DPCPX in the behavioral tests. Results of assessment of the nature of the interaction between DPCPX and test drugs show that in the case of DPCPX and imipramine or reboxetine, there were pharmacodynamic interactions, whereas the DPCPX-escitalopram interaction is at least partially pharmacokinetic in nature. Presented outcomes indicate that an inhibition of A1Rs and an increase of monoaminergic transduction in the CNS may offer a novel strategy for the development of antidepressant drugs.
Assuntos
Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Imipramina/uso terapêutico , Reboxetina/uso terapêutico , Xantinas/uso terapêutico , Animais , Antidepressivos/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Citalopram/farmacocinética , Depressão/metabolismo , Interações Medicamentosas , Quimioterapia Combinada , Elevação dos Membros Posteriores , Imipramina/farmacocinética , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Reboxetina/farmacocinética , Antagonistas da Serotonina/farmacologiaRESUMO
RATIONALE: Antidepressant action has been linked to increased synaptic plasticity in which epigenetic mechanisms such as histone posttranslational acetylation could be involved. Interestingly, the histone deacetylases HDAC5 and SIRT2 are oppositely regulated by stress and antidepressants in mice prefrontal cortex (PFC). Besides, the neuroblastoma SH-SY5Y line is an in vitro neuronal model reliable to study drug effects with clear advantages over animals. OBJECTIVES: We aimed to characterize in vitro the role of HDAC5 and SIRT2 in antidepressant regulation of neuroplasticity. METHODS: SH-SY5Y cultures were incubated with imipramine, fluoxetine, and reboxetine (10 µM, 2 and 24 h) as well as the selective HDAC5 (MC3822, 5 µM, 24 h) or SIRT2 (33i, 5 µM, 24 h) inhibitors. The regulation of the brain-derived neurotrophic factor (BDNF), the vesicular glutamate transporter 1 (VGLUT1), the acetylated histones 3 (AcH3) and 4 (AcH4), HDAC5, and SIRT2 was studied. Comparatively, the long-term effects of these antidepressants (21 days, i.p.) in the mice (C57BL6, 8 weeks) PFC were studied. RESULTS: Antidepressants increased both in vitro and in vivo expression of BDNF, VGLUT1, AcH3, and AcH4. Moreover, imipramine and reboxetine increased the phosphorylated form of HDAC5 (P-HDAC5), mediating its cytoplasmic export. Further, SIRT2 was downregulated by all antidepressants. Finally, specific inhibition of HDAC5 and SIRT2 increased neuroplasticity markers. CONCLUSIONS: This study supports the validity of the SH-SY5Y model for studying epigenetic changes linked to synaptic plasticity induced by antidepressants as well as the effect of selective HDAC inhibitors. Particularly, nucleocytoplasmic export of HDAC5 and SIRT2 downregulation mediated by antidepressants could enhance synaptic plasticity markers leading to antidepressant action.
Assuntos
Antidepressivos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Histona Desacetilases/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Sirtuína 2/metabolismo , Animais , Regulação para Baixo/fisiologia , Epigênese Genética/fisiologia , Fluoxetina/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Imipramina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Distribuição Aleatória , Reboxetina/farmacologiaRESUMO
Inflammation plays a role in the pathophysiology of depression. The purpose of this study is to examine whether the selective serotonin reuptake inhibitor (SSRI) escitalopram, its inactive enantiomer R-citalopram, and selective noradrenaline reuptake inhibitor (NRI) reboxetine, show anti-inflammatory and antidepressant effects in an inflammation-induced model of depression. Pretreatment with escitalopram (1, 3, or 10mg/kg, i.p.) markedly blocked an increase in the serum levels of pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), after a single administration of lipopolysaccharide (LPS; 0.5mg/kg). Furthermore, escitalopram (3 or 10mg/kg) significantly increased the serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) by a single administration of LPS. In contrast, pretreatment with R-citalopram (10mg/kg, i.p.) or reboxetine (10mg/kg, i.p.) did not affect the alterations in serum levels of TNF-α and IL-10 after LPS administration. Co-administration of reboxetine with escitalopram did not show anti-inflammatory effects. Pretreatment with escitalopram (10mg/kg) significantly attenuated LPS-induced increase of the immobility time in the tail-suspension test (TST) and forced swimming test (FST). In contrast, pretreatment with R-citalopram (10mg/kg), or reboxetine (10mg/kg) did not alter LPS-induced increase of immobility time of TST and FST. Interestingly, co-administration of reboxetine with escitalopram did not show antidepressant effect in this model. These findings suggest that escitalopram, but not R-citalopram and reboxetine, has anti-inflammatory and antidepressant effects in LPS-treated model of depression, and that reboxetine can antagonize the effects of escitalopram in the inflammation model. Therefore, it is likely that serotonergic system plays a key role in the pathophysiology of inflammation-induced depression.
Assuntos
Citalopram/farmacologia , Depressão/tratamento farmacológico , Interleucina-10/sangue , Lipopolissacarídeos/administração & dosagem , Morfolinas/farmacologia , Fator de Necrose Tumoral alfa/sangue , Animais , Comportamento Animal/efeitos dos fármacos , Depressão/psicologia , Camundongos , Camundongos Endogâmicos C57BL , ReboxetinaRESUMO
Vasovagal or neurocardiogenic syncope is a common clinical situation and, as with other entities associated with orthostatic intolerance, the underlying condition is a dysfunction of the autonomic nervous system. This article reviews various aspects of vasovagal syncope, including its relationship with orthostatic intolerance and the role of the autonomic nervous system in it. A brief history of the problem is given, as well as a description of how the names and associated concepts have evolved. The response of the sympathetic system to orthostatic stress, the physiology of the baroreflex system and the neurohumoral changes that occur with standing are analyzed. Evidence is presented of the involvement of the autonomic nervous system, including studies of heart rate variability, microneurography, cardiac innervation, and molecular genetic studies. Finally, we describe different studies on the use of beta-blockers and norepinephrine transporter inhibitors (sibutramine, reboxetine) and the rationality of their use to prevent this type of syncope.
El síncope vasovagal o neurocardiogénico es una situación clínica común, y así como en otras entidades asociadas con la intolerancia ortostática, la condición de base es una disfunción del sistema nervioso autónomo. En este artículo se revisan diversos aspectos sobre el síncope vasovagal, incluyendo su relación con la intolerancia ortostática y el papel que juega el sistema nervioso autónomo. Se da una breve reseña histórica del problema, así como una descripción de la forma en que han evolucionado los términos y conceptos asociados al mismo. Se hace un análisis sobre la respuesta del sistema nervioso simpático al estrés ortostático, la fisiología del sistema barorreflejo y los cambios neurohumorales que ocurren. Se muestra evidencia sobre el papel del sistema nervioso autónomo, incluyendo estudios sobre variabilidad de la frecuencia cardiaca, microneurografía, inervación cardiaca y estudios genéticos moleculares. Finalmente, se describen diferentes estudios sobre el uso de betabloqueadores e inhibidores del transportador de noradrenalina (sibutramina, reboxetina) y la justificación de su uso en la prevención de este tipo de síncope.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Sistema Nervoso Simpático/fisiopatologia , Síncope Vasovagal/fisiopatologia , Barorreflexo , Ciclobutanos/farmacologia , Ciclobutanos/uso terapêutico , Frequência Cardíaca/fisiologia , Humanos , Biologia Molecular , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Reboxetina , Síncope Vasovagal/tratamento farmacológicoRESUMO
Adult Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition associated with high disability and frequent comorbidity. Current standard pharmacotherapy (methylphenidate and atomoxetine) improves ADHD symptoms in the short-term, but poor data were published about long-term treatment. In addition a number of patients present partial or no response to methylphenidate and atomoxetine. Research into the main database sources has been conducted to obtain an overview of alternative pharmacological approaches in adult ADHD patients. Among alternative compounds, amphetamines (mixed amphetamine salts and lisdexamfetamine) have the most robust evidence of efficacy, but they may be associated with serious side effects (e.g. psychotic symptoms or hypertension). Antidepressants, particularly those acting as noradrenaline or dopamine enhancers, have evidence of efficacy, but they should be avoided in patients with comorbid bipolar disorder. Finally metadoxine and lithium may be particularly suitable in case of comorbid alcohol misuse or bipolar disorder.
Assuntos
Antidepressivos/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Dopaminérgicos/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Agonistas alfa-Adrenérgicos/uso terapêutico , Adulto , Anfetaminas/uso terapêutico , Compostos Benzidrílicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Bupropiona/uso terapêutico , Desipramina/uso terapêutico , Droxidopa/uso terapêutico , Combinação de Medicamentos , Cloridrato de Duloxetina/uso terapêutico , Guanfacina/uso terapêutico , Histamínicos/uso terapêutico , Humanos , Dimesilato de Lisdexanfetamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Lobelina/uso terapêutico , Mecamilamina/uso terapêutico , Memantina/uso terapêutico , Modafinila , Morfolinas/uso terapêutico , Antagonistas Nicotínicos/uso terapêutico , Nomifensina/uso terapêutico , Paroxetina/uso terapêutico , Piridinas/uso terapêutico , Piridoxina/uso terapêutico , Ácido Pirrolidonocarboxílico/uso terapêutico , Quinazolinonas/uso terapêutico , Reboxetina , Cloridrato de Venlafaxina/uso terapêutico , Promotores da Vigília/uso terapêuticoRESUMO
BACKGROUND: The GPR39-Zn(2+)-sensing receptor seems to be involved in the pathophysiology of depression. GPR39 knockout animals show depressive- and anxiety-like behavior. Chronic treatment with selective antidepressants (ADs) up-regulates GPR39. OBJECTIVE AND METHODS: In the present study we investigated whether acute or chronic treatment with imipramine, escitalopram, reboxetine and bupropion would cause changes in CREB, BDNF, TrkB and GPR39-Zn(2+) receptor proteins (measured by Western Blot) in the frontal cortex of mice fed with a low-zinc diet. RESULTS: The administration of acute antidepressants induced diverse effects in the proteins that were examined (namely, GPR39 down-regulation and a reduction in CREB protein after administration of all ADs; a decrease in BDNF after administration of imipramine and escitalopram; an increase in BDNF after administration of reboxetine; no change in BDNF following administration of bupropion; and a decrease in TrkB following the administration of all ADs except bupropion). On the other hand, chronic treatment (which is required for depression relief) with all antidepressants increased the levels of all these proteins. CONCLUSIONS: The present study for the first time demonstrates the up-regulation of GPR39 (and CREB, BDNF, and TrkB) protein when induced by chronic treatment with antidepressants (with different pharmacological profiles) in a zinc-deficiency model in mice. These data further indicate that the GPR39 receptor may be an important target in the antidepressant response.
Assuntos
Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Lobo Frontal/efeitos dos fármacos , Receptor trkB/metabolismo , Receptores Acoplados a Proteínas G/biossíntese , Zinco/deficiência , Animais , Antidepressivos/administração & dosagem , Bupropiona/administração & dosagem , Bupropiona/farmacologia , Citalopram/administração & dosagem , Citalopram/farmacologia , Regulação para Baixo , Esquema de Medicação , Lobo Frontal/metabolismo , Imipramina/administração & dosagem , Imipramina/farmacologia , Masculino , Camundongos , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Reboxetina , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
Evidence suggests that lobeline, a nicotinic acetylcholine receptor ligand, has antidepressant-like properties in mice. The present study investigated the possible additive or synergistic effects of lobeline in combination with commonly used antidepressants, such as reboxetine, fluoxetine, or bupropion, using the tail suspension test (TST) and the forced swim test (FST) in C57BL/6J mice. Reboxetine (5 or 10 mg/kg, i.p.), fluoxetine (5 or 10 mg/kg, i.p.), or bupropion (2 or 4 mg/kg, i.p.) were administered 30 min before TST or FST. A fixed dose of lobeline (1 mg/kg, i.p.) was injected 15 min prior to tests. Co-administration of lobeline and reboxetine, fluoxetine, or bupropion significantly reduced immobility time in the TST and FST in comparison to the antidepressants used alone. The results suggest that lobeline enhanced the effects of reboxetine, fluoxetine, or bupropion in mice. Therefore, lobeline or similar nicotinic receptor ligand may have therapeutic potential as an adjunct for the treatment of major depression.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Bupropiona/farmacologia , Depressão/tratamento farmacológico , Fluoxetina/farmacologia , Lobelina/farmacologia , Morfolinas/farmacologia , Animais , Antidepressivos/uso terapêutico , Bupropiona/uso terapêutico , Depressão/fisiopatologia , Depressão/psicologia , Sinergismo Farmacológico , Quimioterapia Combinada , Fluoxetina/uso terapêutico , Resposta de Imobilidade Tônica/efeitos dos fármacos , Lobelina/uso terapêutico , Masculino , Camundongos , Morfolinas/uso terapêutico , ReboxetinaRESUMO
BACKGROUND: The studied compound: 3-chloro-5-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-9H-xanthen-9-one dihydrochloride (HBK-6) is a new xanthone derivative. In this study we investigated its antidepressant-like properties and possible mechanism of action. METHODS: Antidepressant-like activity was evaluated in the forced swim test (FST) in mice. The influence on locomotor activity in mice was analyzed to determine whether the observed in FST effect is specific. Rotarod test was used to determine neurotoxic properties. RESULTS: HBK-6 reduced immobility time in mice in FST at the doses 5 and 10mg/kg, whereas fluoxetine (FX) at 15 mg/kg, reboxetine (RX) at 10mg/kg and bupropion (BPR) at 5mg/kg. Joint administration of sub-effective doses of HBK-6 and FX, but not RX or BPR, reduced immobility in mice in FST. HBK-6 at the dose 5mg/kg did not show activity in FST after pretreatment with p-chlorophenylalanine. The studied xanthone derivative at the doses 5 and 10mg/kg did not impair motor coordination in mice. CONCLUSIONS: We demonstrated that HBK-6 has a potent antidepressant-like activity in FST, stronger than that of FX and RX, and seems to mediate its effect through serotonergic system. Moreover, at antidepressant-like doses it does not show neurotoxic properties. Given the promising results, HBK-6 may have potential in the treatment of depression, but this needs extended studies.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/psicologia , Piperazinas/farmacologia , Serotonina/fisiologia , Natação/psicologia , Xantonas/farmacologia , Animais , Bupropiona/farmacologia , Fenclonina/farmacologia , Fluoxetina/farmacologia , Masculino , Camundongos , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Reboxetina , Serotoninérgicos/farmacologia , Xantonas/síntese químicaRESUMO
Depression is the leading psychiatric disorder with a high risk of morbidity and mortality. Clinical studies report lower serum zinc in depressed patients, suggesting a strong link between zinc and mood disorders. Also copper as an antagonistic element to zinc seems to play a role in depression, where elevated concentration is observed. In the present study we investigated serum copper and zinc concentration after acute or chronic antidepressant (AD) treatment under pathological/zinc-deficient conditions. Zinc deficiency in mice was induced by a special diet administered for 6 weeks (zinc adequate diet - ZnA, contains 33.5 mgZn/kg; zinc deficient diet - ZnD, contains 0.2 mgZn/kg). Animals received acute or chronically saline (control), imipramine, escitalopram, reboxetine or bupropion. To evaluate changes in serum copper and zinc concentrations the total reflection X-ray fluorescence (TXRF) and flame atomic absorption spectrometry (FAAS) was performed. In ZnD animals serum zinc level was reduced after acute ADs treatment (similarly to vehicle treatment), however, as demonstrated in the previous study after chronic ADs administration no differences between both ZnA and ZnD groups were observed. Acute ADs in ZnD animals caused different changes in serum copper concentration with no changes after chronic ADs treatment. The calculated serum Zn/Cu ratio is reduced in ZnD animals (compared to ZnA subjects) treated with saline (acutely or chronically) and in animals treated acutely with ADs. However, chronic treatment with ADs normalized (by escitalopram, reboxetine or bupropion) or increased (by imipramine) this Zn/Cu ratio. Observed in this study normalization of serum Zn/Cu ratio in depression-like conditions by chronic (but not acute) antidepressants suggest that this ratio may be consider as a marker of depression or treatment efficacy.
Assuntos
Antidepressivos/farmacologia , Cobre/sangue , Depressão/sangue , Zinco/sangue , Zinco/deficiência , Animais , Bupropiona/farmacologia , Citalopram/farmacologia , Modelos Animais de Doenças , Imipramina/farmacologia , Masculino , Camundongos , Morfolinas/farmacologia , Reboxetina , Cloreto de Sódio/farmacologiaRESUMO
RATIONALE: Antidepressants include a relatively wide spectrum of drugs that increase the synaptic concentration of monoamines, mostly through neurotransmitter reuptake blockade. The bed nucleus of stria teminalis (BNST) is considered a relay station in mediating the activation of stress response but also in the acquisition and expression of emotions. BNST is richly innervated by monoamines and sends back projections to the nucleus of origin. We previously showed that the administration of selective blockers of norepinephrine transporter (NET) increases the extracellular concentration (output) of dopamine, suggesting that dopamine could be captured by NET in the BNST. OBJECTIVES: The aim of this study, carried out by means of in vivo microdialysis, was to ascertain the acute effects that antidepressants with varying mechanisms of action have on dopamine and norepinephrine output in the BNST. RESULTS: We observed that all the antidepressants tested (5-20 mg/kg i.p.) increased the output of catecholamines, dose dependently. In particular, the maximum increases (as a percent of basal) for norepinephrine and dopamine respectively, were as follows: desipramine, 239 and 137; reboxetine, 185 and 128; imipramine, 512 and 359; citalopram, 95 and 122; fluoxetine, 122 and 68; bupropion, 255 and 164. CONCLUSIONS: These results suggest that catecholamine transmission in the BNST may be part of a common downstream pathway that is involved in the action mechanism of antidepressants. Consequently, it is hypothesized that a dysfunction of neuronal transmission in this brain area may have a role in the etiology of affective disorders.
Assuntos
Antidepressivos/farmacologia , Dopamina/metabolismo , Norepinefrina/metabolismo , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/metabolismo , Animais , Antidepressivos de Segunda Geração/farmacologia , Antidepressivos Tricíclicos/farmacologia , Bupropiona/farmacologia , Citalopram/farmacologia , Desipramina/farmacologia , Relação Dose-Resposta a Droga , Fluoxetina/farmacologia , Imipramina/farmacologia , Masculino , Morfolinas/farmacologia , Ratos Sprague-Dawley , Reboxetina , Fatores de TempoRESUMO
Recent studies indicated that zinc activates neural transmission via the GPR39 Zn²âº-sensing receptor. Preclinical and clinical studies demonstrated the antidepressant properties of zinc. To investigate whether the GPR39 receptor is involved in the mechanism of antidepressant action, we measured the expression of the GPR39 receptor (Western Blot) in the frontal cortex of mice treated intraperitoneally with imipramine (30 mg/kg), escitalopram (4 mg/kg), reboxetine (10 mg/kg) or bupropion (15 mg/kg) for 14 days. The present study shows the up-regulation of the GPR39 receptor protein level after escitalopram (by 290%), reboxetine (by 816%) and bupropion (by 272%), but not imipramine treatment. This is the first report to indicate the involvement of the GPR39 Zn²âº-sensing receptor in the antidepressant effect of selective monoamine reuptake inhibitors.
Assuntos
Antidepressivos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Bupropiona/farmacologia , Citalopram/farmacologia , Imipramina/farmacologia , Masculino , Camundongos , Morfolinas/farmacologia , Reboxetina , Zinco/metabolismoRESUMO
The interaction of the selective norepinephrine reuptake inhibitor (-)-reboxetine with the human α4ß2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca(2+)-influx results indicate that (-)-reboxetine does not activate hα4ß2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced hα4ß2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiology-based functional approach suggest that (-)-reboxetine may act via open channel block; therefore, it is capable of producing a use-dependent type of inhibition of the hα4ß2 nAChR function. We tested whether (-)-reboxetine binds to the luminal [(3)H]imipramine site. The results indicate that, although (-)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized hα4ß2 nAChR ion channels. Patch-clamp results also indicate that (-)-reboxetine progressively inhibits the hα4ß2 nAChR with two-fold higher potency at the end of one-second application of agonist, compared with the peak current. The molecular docking studies show that (-)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 6' and 14'. In addition, we found a (-)-reboxetine conformer that docks in the helix bundle of the α4 subunit, near the middle region. According to molecular dynamics simulations, (-)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (-)-reboxetine may be produced (at least partially) by its inhibitory action on hα4ß2 nAChRs.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Morfolinas/farmacologia , Receptores Nicotínicos/metabolismo , Inibidores da Captação Adrenérgica/química , Alcaloides/metabolismo , Animais , Azocinas/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/antagonistas & inibidores , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Fenômenos Eletrofisiológicos , Células Epiteliais/efeitos dos fármacos , Células HEK293 , Humanos , Imipramina/metabolismo , Modelos Moleculares , Conformação Molecular , Morfolinas/química , Agonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Piridinas/antagonistas & inibidores , Piridinas/farmacologia , Quinolizinas/metabolismo , Ensaio Radioligante , Reboxetina , Receptores Nicotínicos/química , Receptores Nicotínicos/efeitos dos fármacos , TorpedoRESUMO
RATIONALE: Pupillometry can be used to characterize autonomic drug effects. OBJECTIVE: This study was conducted to determine the autonomic effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), administered alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin, on pupillary function. METHODS: Infrared pupillometry was performed in five placebo-controlled randomized studies. Each study included 16 healthy subjects (eight men, eight women) who received placebo-MDMA (125 mg), placebo-placebo, pretreatment-placebo, or pretreatment-MDMA using a crossover design. RESULTS: MDMA produced mydriasis, prolonged the latency, reduced the response to light, and shortened the recovery time. The impaired reflex response was associated with subjective, cardiostimulant, and hyperthermic drug effects and returned to normal within 6 h after MDMA administration when plasma MDMA levels were still high. Mydriasis was associated with changes in plasma MDMA concentration over time and longer-lasting. Both reboxetine and duloxetine interacted with the effects of MDMA on pupillary function. Clonidine did not significantly reduce the mydriatic effects of MDMA, although it produced miosis when administered alone. Carvedilol and doxazosin did not alter the effects of MDMA on pupillary function. CONCLUSIONS: The MDMA-induced prolongation of the latency to and reduction of light-induced miosis indicate indirect central parasympathetic inhibition, and the faster recovery time reflects an increased sympathomimetic action. Both norepinephrine and serotonin mediate the effects of MDMA on pupillary function. Although mydriasis is lasting and mirrors the plasma concentration-time curve of MDMA, the impairment in the reaction to light is associated with the subjective and other autonomic effects of MDMA and exhibits acute tolerance.
Assuntos
Fármacos do Sistema Nervoso Autônomo/farmacologia , Carbazóis/farmacologia , Clonidina/farmacologia , Doxazossina/farmacologia , Morfolinas/farmacologia , Midriáticos/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Propanolaminas/farmacologia , Reflexo Pupilar/efeitos dos fármacos , Tiofenos/farmacologia , Agonistas Adrenérgicos/farmacologia , Inibidores da Captação Adrenérgica/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Adulto , Afeto/efeitos dos fármacos , Fármacos do Sistema Nervoso Autônomo/sangue , Fármacos do Sistema Nervoso Autônomo/farmacocinética , Regulação da Temperatura Corporal/efeitos dos fármacos , Carvedilol , Estudos Cross-Over , Inibidores da Captação de Dopamina/farmacologia , Cloridrato de Duloxetina , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Luz , Masculino , Miose/fisiopatologia , Miose/prevenção & controle , Midríase/induzido quimicamente , Midríase/fisiopatologia , Midriáticos/sangue , Midriáticos/farmacocinética , N-Metil-3,4-Metilenodioxianfetamina/sangue , N-Metil-3,4-Metilenodioxianfetamina/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Tempo de Reação/efeitos dos fármacos , Reboxetina , Recuperação de Função Fisiológica , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fatores de Tempo , Adulto JovemRESUMO
Most antidepressant treatments, based on serotonin (5-HT) and/or norepinephrine (NE) transporter blockade, show limited efficacy and slow onset of action, requiring the use of augmentation strategies. Here we report on a novel antidepressant strategy to selectively increase DA function in prefrontal cortex (PFC) without the potential tolerance problems associated to DA transporter blockade. This approach is based on previous observations indicating that extracellular DA in rat medial PFC (mPFC) - but not in nucleus accumbens (NAc) - arises from noradrenergic terminals and is sensitive to noradrenergic drugs. A low dose of reboxetine (3 mg/kg i.p.; NE reuptake inhibitor) non-significantly increased extracellular DA in mPFC. Interestingly, its combined administration with 5 mg/kg s.c. mirtazapine (non-selective α2-adrenoceptor antagonist) increased extracellular DA in mPFC (264 ± 28%), but not in NAc. Extracellular NE (but not 5-HT) in mPFC was also enhanced by the combined treatment (472 ± 70%). Repeated (×3) reboxetine + mirtazapine administration produced a moderate additional increase in mPFC DA and markedly reduced the immobility time (-51%) in the forced-swim test. Neurochemical and behavioral effects of the reboxetine + mirtazapine combination persisted in rats pretreated with citalopram (3 mg/kg, s.c.), suggesting its potential usefulness to augment SSRI effects. In situ hybridization c-fos studies were performed to examine the brain areas involved in the above antidepressant-like effects, showing changes in c-fos expression in hippocampal and cortical areas. BDNF expression was also increased in the hippocampal formation. Overall, these results indicate a synergistic effect of the reboxetine + mirtazapine combination to increase DA and NE function in mPFC and to evoke robust antidepressant-like responses.