RESUMO
ABSTRACTKetamine, an N-methyl-D-aspartate receptor antagonist, produces rapid antidepressant effects in patients with treatment-resistant depression. However, owing to the undesirable adverse effects of ketamine, there is an urgent need for developing safer and more effective prophylactic and therapeutic interventions for depression. Preclinical studies have demonstrated that activation of the mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC) mediates the rapid antidepressant effects of ketamine. The steroidal alkaloid tomatidine and its glycoside α-tomatine (tomatine) can activate mTORC1 signaling in peripheral tissues/cells. We examined whether tomatidine and tomatine exerted prophylactic and therapeutic antidepressant-like actions via mPFC mTORC1 activation using a mouse model of lipopolysaccharide (LPS)-induced depression. Male mice were intraperitoneally (i.p.) administered tomatidine/tomatine before and after the LPS challenge to test their prophylactic and therapeutic effects, respectively. LPS-induced depression-like behaviors in the tail suspension test (TST) and forced swim test (FST) were significantly reversed by prophylactic and therapeutic tomatidine/tomatine administration. LPS-induced anhedonia in the female urine sniffing test was reversed by prophylactic, but not therapeutic, injection of tomatidine, and by prophylactic and therapeutic administration of tomatine. Intra-mPFC infusion of rapamycin, an mTORC1 inhibitor, blocked the prophylactic and therapeutic antidepressant-like effects of tomatidine/tomatine in TST and FST. Moreover, both tomatidine and tomatine produced antidepressant-like effects in ovariectomized female mice, a model of menopause-associated depression. These results indicate that tomatidine and tomatine exert prophylactic and therapeutic antidepressant-like effects via mTORC1 activation in the mPFC and suggest these compounds as promising candidates for novel prophylactic and therapeutic agents for depression.
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The pathophysiology and treatment of depression have been the focus of intense research and while there is much that remains unknown, modern neurobiological approaches are making progress. This work demonstrates that stress and depression are associated with atrophy of neurons and reduced synaptic connectivity in brain regions such as the hippocampus and prefrontal cortex that contribute to depressive behaviors, and conversely that antidepressant treatment can reverse these deficits. The role of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), has been of particular interest as these factors play a key role in activity-dependent regulation of synaptic plasticity. Here, we review the literature demonstrating that exposure to stress and depression decreases BDNF expression in the hippocampus and PFC and conversely that antidepressant treatment can up-regulate BDNF in the adult brain and reverse the effects of stress. We then focus on rapid-acting antidepressants, particularly the NMDA receptor antagonist ketamine, which produces rapid synaptic and antidepressant behavioral actions that are dependent on activity-dependent release of BDNF. This rapid release of BDNF differs from typical monoaminergic agents that require chronic administration to produce a slow induction of BDNF expression, consistent with the time lag for the therapeutic action of these agents. We review evidence that other classes of rapid-acting agents also require BDNF release, demonstrating that this is a common, convergent downstream mechanism. Finally, we discuss evidence that the actions of ketamine are also dependent on another growth factor, vascular endothelial growth factor (VEGF) and its complex interplay with BDNF.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Ketamina , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Fator A de Crescimento do Endotélio VascularRESUMO
In contrast with the delayed onset of therapeutic responses and relatively low efficacy of currently available monoamine-based antidepressants, a single subanesthetic dose of ketamine, an N-methyl-D-aspartate receptor antagonist, produces rapid and sustained antidepressant actions even in patients with treatment-resistant depression. However, since the clinical use of ketamine as an antidepressant is limited owing to its adverse effects, such as psychotomimetic/dissociative effects and abuse potential, there is an unmet need for novel rapid-acting antidepressants with fewer side effects. Preclinical studies have revealed that the antidepressant actions of ketamine are mediated via the release of brain-derived neurotrophic factor and vascular endothelial growth factor, with the subsequent activation of mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex. Recently, we demonstrated that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), endogenous lipid mediators generated from n-3 polyunsaturated fatty acids (docosahexaenoic and eicosapentaenoic acids), exert antidepressant effects in a rodent model of depression, and that the antidepressant effects of RvD1, RvD2, and RvE1 necessitate mTORC1 activation. In this review, we first provide an overview of the mechanisms underlying the antidepressant effects of ketamine and other rapid-acting agents. We then discuss the possibility of using resolvins as novel therapeutic candidates for depression.
Assuntos
Antidepressivos , Transtorno Depressivo Maior/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/farmacologia , Animais , Modelos Animais de Doenças , Ácido Eicosapentaenoico/uso terapêutico , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Córtex Pré-Frontal/metabolismoRESUMO
Nicotine administration enhances object recognition memory. However, target brain regions and cellular mechanisms underlying the nicotine effects remain unclear. In mice, the novel object recognition test revealed that systemic nicotine administration before training enhanced object recognition memory. Moreover, this effect was inhibited by infusion of retigabine, a selective voltage-dependent potassium 7 (Kv7) channel opener, into the medial prefrontal cortex (mPFC) before nicotine administration. Additionally, infusion of XE-991, a selective Kv7 channel blocker, into the mPFC before training enhanced object recognition memory. Therefore, Kv7 channels in the mPFC may be at least partly involved in nicotine-induced enhancement of object recognition memory.
Assuntos
Memória/efeitos dos fármacos , Nicotina/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Córtex Pré-Frontal/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Antracenos/farmacologia , Carbamatos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Fenilenodiaminas/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Estimulação QuímicaRESUMO
Nicotine enhances attention, working memory and recognition. One of the brain regions associated with these effects of nicotine is the medial prefrontal cortex (mPFC). However, cellular mechanisms that induce the enhancing effects of nicotine remain unclear. To address this issue, we performed whole-cell patch-clamp recordings from mPFC layer 5 pyramidal neurons in slices of C57BL/6J mice. Shortly (approx. 2 min) after bath application of nicotine, the number of action potentials, which were elicited by depolarizing current injection, was increased, and this increase persisted for over 5 min. The effect of nicotine was blocked by the α4ß2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-ß-erythroidine, α7 nAChR antagonist methyllycaconitine, or intracellular perfusion with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Additionally, the voltage-dependent potassium 7 (Kv7) channel blocker, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE-991), as well as nicotine, shortened the spike threshold latency and increased the spike numbers. By contrast, the Kv7 channel opener, retigabine reduced the number of firings, and the addition of nicotine did not increase the spike numbers. These results indicate that nicotine induces long-lasting enhancement of firing activity in mPFC layer 5 pyramidal neurons, which is mediated by the stimulation of the α4ß2 and α7 nAChRs and subsequent increase in intracellular Ca2+ levels followed by the suppression of the Kv7 channels. The novel effect of nicotine might underlie the nicotine-induced enhancement of attention, working memory and recognition.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Nicotina/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Animais , Antracenos/farmacologia , Células Cultivadas , Feminino , Masculino , Camundongos , Antagonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Cultura Primária de Células , Células Piramidais/metabolismo , Receptores Nicotínicos/metabolismoRESUMO
Nicotine has been known to enhance recognition memory in various species. However, the brain region where nicotine acts and exerts its effect remains unclear. Since the medial prefrontal cortex (mPFC) is associated with memory, we examined the role of the mPFC in nicotine-induced enhancement of recognition memory using the novel object recognition test in male C57BL/6J mice. Systemic nicotine administration 10 min before training session significantly enhanced object recognition memory in test session that was performed 24 h after the training. Intra-mPFC infusion of mecamylamine, a non-selective nicotinic acetylcholine receptor (nAChR) antagonist, 5 min before nicotine administration blocked the effect of nicotine. Additionally, intra-mPFC infusion of dihydro-ß-erythroidine, a selective α4ß2 nAChR antagonist, or methyllycaconitine, a selective α7 nAChR antagonist, significantly suppressed the nicotine-induced object recognition memory enhancement. Finally, intra-mPFC infusion of nicotine 1 min before the training session augmented object recognition memory in a dose-dependent manner. These findings suggest that mPFC α4ß2 and α7 nAChRs mediate the nicotine-induced object recognition memory enhancement.
Assuntos
Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptores Nicotínicos/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/fisiologia , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Di-Hidro-beta-Eritroidina/farmacologia , Masculino , Mecamilamina/farmacologia , Camundongos Endogâmicos C57BL , Antagonistas Nicotínicos/farmacologia , Córtex Pré-Frontal/fisiologia , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidoresRESUMO
The antidepressant effect of eicosapentaenoic acid-derived bioactive lipid, resolvin E1 (RvE1), was examined in a murine model of chronic pain-induced depression using a tail suspension test. Because RvE1 reportedly possesses agonistic activity on a chemerin receptor ChemR23, we also examined the antidepressant effect of chemerin. Two weeks after surgery for unilateral spared nerve injury to prepare neuropathic pain model mice, immobility time was measured in a tail suspension test. Chronic pain significantly increased immobility time, and this depression-like behavior was attenuated by intracerebroventricular injection of RvE1 (1 ng) or chemerin (500 ng). These results demonstrate that RvE1 exerts an antidepressant effect in a murine model of chronic pain-induced depression, which is likely to be via ChemR23. RvE1 and its receptor may be promising targets to develop novel antidepressants.
Assuntos
Antidepressivos/administração & dosagem , Dor Crônica/complicações , Depressão/tratamento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Receptores de Quimiocinas/agonistas , Animais , Quimiocinas/administração & dosagem , Quimiocinas/metabolismo , Dor Crônica/psicologia , Depressão/etiologia , Depressão/psicologia , Modelos Animais de Doenças , Ácido Eicosapentaenoico/administração & dosagem , Humanos , Injeções Intraventriculares , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Camundongos , Receptores de Quimiocinas/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
In drug addiction, environmental stimuli previously associated with cocaine use readily elicit cocaine-associated memories, which persist long after abstinence and trigger cocaine craving and consumption. Although previous studies suggest that the medial prefrontal cortex (mPFC) is involved in the expression of cocaine-addictive behaviors, it remains unclear whether excitatory and inhibitory neurons in the mPFC are causally related to the formation and retrieval of cocaine-associated memories. To address this issue, we used the designer receptors exclusively activated by designer drugs (DREADD) technology combined with a cocaine-induced conditioned place preference (CPP) paradigm. We suppressed mPFC neuronal activity in a cell-type- and timing-dependent manner. C57BL/6J wild-type mice received bilateral intra-mPFC infusion of an adeno-associated virus (AAV) expressing inhibitory DREADD (hM4Di) under the control of CaMKII promotor to selectively suppress mPFC pyramidal neurons. GAD67-Cre mice received bilateral intra-mPFC infusion of a Cre-dependent AAV expressing hM4Di to specifically silence GABAergic neurons. Chemogenetic suppression of mPFC pyramidal neurons significantly attenuated both the acquisition and expression of cocaine CPP, while suppression of mPFC GABAergic neurons affected neither the acquisition nor expression of cocaine CPP. Moreover, chemogenetic inhibition of mPFC glutamatergic neurons did not affect the acquisition and expression of lithium chloride-induced conditioned place aversion. These results suggest that the activation of glutamatergic, but not GABAergic, neurons in the mPFC mediates both the formation and retrieval of cocaine-associated memories.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Memória/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Animais , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/farmacologia , Eletrofisiologia , Imunofluorescência , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The medial prefrontal cortex (mPFC) plays critical roles in the development of cocaine addiction. Numerous studies have reported about the effects of cocaine on neuronal and synaptic activities in the nucleus accumbens and ventral tegmental area, which are brain regions associated with cocaine addiction; however, a limited number of studies have reported the effect of cocaine on mPFC neuronal activity. In this study, using whole-cell patch-clamp recordings in brain slices, we present that under the condition where synaptic transmission is enhanced by increasing extracellular K+ concentration, cocaine significantly reduced the frequency but not amplitude of spontaneous excitatory postsynaptic currents. These findings suggest that cocaine exposure could be a trigger to induce hypofrontality, which is related to the compulsive craving for cocaine use.
Assuntos
Cocaína/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Animais , Feminino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Transmissão Sináptica/efeitos dos fármacosRESUMO
Pain is a complex experience with both sensory and affective components. Clinical and preclinical studies have shown that the affective component of pain can be reduced by doses of morphine lower than those necessary to reduce the sensory component. Although the neural mechanisms underlying the effects of morphine on the sensory component of pain have been investigated extensively, those influencing the affective component remain to be elucidated. The bed nucleus of the stria terminalis (BNST) has been implicated in the regulation of various negative emotional states, including aversion, anxiety and fear. Thus, this study aimed to clarify the role of the ventral part of the BNST (vBNST) in the actions of morphine on the affective and sensory components of pain. First, the effects of intra-vBNST injections of morphine on intraplantar formalin-induced conditioned place aversion (CPA) and nociceptive behaviors were investigated. Intra-vBNST injections of morphine reduced CPA without affecting nociceptive behaviors, which suggests that intra-vBNST morphine alters the affective, but not sensory, component of pain. Next, to examine the effects of morphine on neuronal excitability in type II vBNST neurons, whole-cell patch-clamp recordings were performed in brain slices. Bath application of morphine hyperpolarized type II vBNST neurons. Thus, the suppressive effects of intra-vBNST morphine on pain-induced aversion may be due to its inhibitory effects on neuronal excitability in type II vBNST neurons. These results suggest that the vBNST is a key brain region involved in the suppressive effects of morphine on the affective component of pain.
Assuntos
Analgésicos Opioides/farmacologia , Condicionamento Clássico , Morfina/farmacologia , Nociceptividade , Dor/fisiopatologia , Núcleos Septais/efeitos dos fármacos , Potenciais de Ação , Animais , Masculino , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Núcleos Septais/citologiaRESUMO
Eicosapentaenoic acid (EPA)-derived resolvin E1 (RvE1) and E2 (RvE2) have antidepressant effects. Here, we investigated the antidepressant effects of resolvin E3 (RvE3) in a mouse model of lipopolysaccharide (LPS)-induced depression. We observed that LPS (0.8 mg/kg, i.p.) significantly increased immobility time on the tail suspension test, and this depression-like behavior was dose-dependently attenuated by intracerebroventricular infusion of RvE3 (10 or 100 ng). No effects of LPS or intracerebroventricular infusion of RvE3 on locomotor activity were observed. These results indicate that RvE3, as well as RvE1 and RvE2, have antidepressant effects.
Assuntos
Antidepressivos , Depressão/tratamento farmacológico , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos Insaturados/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Depressão/induzido quimicamente , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ácido Eicosapentaenoico , Infusões Intraventriculares , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos Endogâmicos BALB CRESUMO
Cocaine-associated environmental cues elicit craving and relapse to cocaine use by recalling the rewarding memory of cocaine. However, the neuronal mechanisms underlying the expression of cocaine-associated memory are not fully understood. Here, we investigated the possible contribution of γ-aminobutyrate (GABA)ergic neurons in the nucleus accumbens (NAc), a key brain region associated with the rewarding and reinforcing effects of cocaine, to the expression of cocaine-associated memory using the conditioned place preference (CPP) paradigm combined with designer receptors exclusively activated by designer drugs (DREADD) technology. The inhibitory DREADD hM4Di was selectively expressed in NAc GABAergic neurons of vesicular GABA transporter-Cre (vGAT-Cre) mice by infusing adeno-associated virus (AAV) vectors. Ex vivo electrophysiological recordings revealed that bath application of clozapine-N-oxide (CNO) significantly hyperpolarized membrane potentials and reduced the number of spikes induced by depolarizing current injections in hM4Di-positive NAc neurons. Additionally, systemic CNO injections into cocaine-conditioned mice 30 min before posttest session significantly reduced CPP scores compared to saline-injected mice. These results indicate that chemogenetic inhibition of NAc GABAergic neurons attenuated the expression of cocaine CPP, suggesting that NAc GABAergic neuronal activation is required for the environmental context-induced expression of cocaine-associated memory.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/psicologia , Cocaína/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Recompensa , Animais , Clozapina/análogos & derivados , Clozapina/farmacologia , Transtornos Relacionados ao Uso de Cocaína/patologia , Neurônios GABAérgicos/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Núcleo Accumbens/citologia , Núcleo Accumbens/fisiologia , Técnicas de Patch-Clamp , Reforço Psicológico , Potenciais Sinápticos/efeitos dos fármacosRESUMO
Background: Resolvin D1 and D2 are bioactive lipid mediators that are generated from docosahexaenoic acid. Although recent preclinical studies suggest that these compounds have antidepressant effects, their mechanisms of action remain unclear. Methods: We investigated mechanisms underlying the antidepressant effects of resolvin D1 and resolvin D2 in lipopolysaccharide (0.8 mg/kg, i.p.)-induced depression model mice using a tail suspension test. Results: I.c.v. infusion of resolvin D1 (10 ng) and resolvin D2 (10 ng) produced antidepressant effects; these effects were significantly blocked by a resolvin D1 receptor antagonist WRW4 (10 µg, i.c.v.) and a resolvin D2 receptor antagonist O-1918 (10 µg, i.c.v.), respectively. The mammalian target of rapamycin complex 1 inhibitor rapamycin (10 mg/kg, i.p.) and a mitogen-activated protein kinase kinase inhibitor U0126 (5 µg, i.c.v.) significantly blocked the antidepressant effects of resolvin D1 and resolvin D2. An AMPA receptor antagonist NBQX (10 mg/kg, i.p.) and a phosphoinositide 3-kinase inhibitor LY294002 (3 µg, i.c.v.) blocked the antidepressant effects of resolvin D1 significantly, but not of resolvin D2. Bilateral infusions of resolvin D1 (0.3 ng/side) or resolvin D2 (0.3 ng/side) into the medial prefrontal cortex or dentate gyrus of the hippocampus produced antidepressant effects. Conclusions: These findings demonstrate that resolvin D1 and resolvin D2 produce antidepressant effects via the mammalian target of rapamycin complex 1 signaling pathway, and that the medial prefrontal cortex and dentate gyrus are important brain regions for these antidepressant effects. These compounds and their receptors may be promising targets for the development of novel rapid-acting antidepressants, like ketamine and scopolamine.
Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/induzido quimicamente , Modelos Animais de Doenças , Elevação dos Membros Posteriores/métodos , Resposta de Imobilidade Tônica/efeitos dos fármacos , Injeções Intraventriculares , Lipopolissacarídeos/toxicidade , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/farmacologia , Estatísticas não ParamétricasRESUMO
Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.
Assuntos
Antidepressivos , Depressão , Ácido Eicosapentaenoico , Animais , Humanos , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ácido Eicosapentaenoico/farmacologia , Ácido Eicosapentaenoico/análogos & derivadosRESUMO
Vascular endothelial growth factor (VEGF) signaling is known to be involved in the antidepressant-like effects of conventional antidepressants, such as desipramine (DMI), a tricyclic antidepressant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor; however, the precise role of neuronal VEGF signaling in mediating these effects remains unclear. Using mice with excitatory neuron-specific deletion of VEGF and its receptor, fetal liver kinase 1 (Flk-1) in the forebrain, we examined the effects of forebrain excitatory neuron-specific deletion of VEGF or Flk-1 on the antidepressant-like effects of repeated DMI and chronic FLX administration in the forced swim test (FST). Repeated intraperitoneal (i.p.) injections of DMI (10, 10, and 20 mg/kg at 24, 4, and 1 h before the FST, respectively) significantly decreased immobility in control mice; however, this effect was completely blocked in mice with neuron-specific VEGF or Flk-1 deletion. Although chronic treatment with FLX (18 mg/kg/day, i.p.) did not impact immobility in control mice 1 day after the 22nd injection, immobility was significantly reduced 1 day after the preswim and the 23rd FLX injection. However, in mice with neuron-specific Flk-1 deletion, chronic FLX treatment significantly increased immobility in the preswim and failed to produce antidepressant-like effects. Collectively, these findings indicate that neuronal VEGF-Flk-1 signaling contributes to the antidepressant-like actions of conventional antidepressants.
Assuntos
Fluoxetina , Fator A de Crescimento do Endotélio Vascular , Camundongos , Animais , Fluoxetina/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Desipramina/metabolismo , Desipramina/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/farmacologia , Antidepressivos/farmacologia , Neurônios/metabolismoRESUMO
Nicotine has been shown to enhance object recognition memory in the novel object recognition (NOR) test by activating excitatory neurons in the medial prefrontal cortex (mPFC). However, the exact neuronal mechanisms underlying the nicotine-induced activation of mPFC neurons and the resultant memory enhancement remain poorly understood. To address this issue, we performed brain-slice electrophysiology and the NOR test in male C57BL/6J mice. Whole-cell patch-clamp recordings from layer V pyramidal neurons in the mPFC revealed that nicotine augments the summation of evoked excitatory postsynaptic potentials (eEPSPs) and that this effect was suppressed by N-[3,5-Bis(trifluoromethyl)phenyl]-N'-[2,4-dibromo-6-(2H-tetrazol-5-yl)phenyl]urea (NS5806), a voltage-dependent potassium (Kv) 4.3 channel activator. In line with these findings, intra-mPFC infusion of NS5806 suppressed systemically administered nicotine-induced memory enhancement in the NOR test. Additionally, miRNA-mediated knockdown of Kv4.3 channels in mPFC pyramidal neurons enhanced object recognition memory. Furthermore, inhibition of A-type Kv channels by intra-mPFC infusion of 4-aminopyridine was found to enhance object recognition memory, while this effect was abrogated by prior intra-mPFC NS5806 infusion. These results suggest that nicotine augments the summation of eEPSPs via the inhibition of Kv4.3 channels in mPFC layer V pyramidal neurons, resulting in the enhancement of object recognition memory.
Assuntos
Camundongos Endogâmicos C57BL , Nicotina , Córtex Pré-Frontal , Reconhecimento Psicológico , Animais , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Córtex Pré-Frontal/metabolismo , Nicotina/farmacologia , Camundongos , Reconhecimento Psicológico/efeitos dos fármacos , Canais de Potássio Shal/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Memória/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacosRESUMO
Ketamine, an N-methyl-D-aspartate receptor antagonist, elicits swift antidepressant effects even in subjects with treatment-resistant depression. Nonetheless, owing to the serious adverse effects associated with ketamine, including psychotomimetic effects, the development of safer rapid-acting antidepressants is imperative. The elucidation of the mechanisms underlying the antidepressant effects of ketamine will facilitate the advancement of these alternative treatments. Previous preclinical studies have indicated that the antidepressant properties of ketamine are mediated by the activity-dependent release of brain-derived neurotrophic factor (BDNF) and the subsequent activation of mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC). Our research has demonstrated that ketamine exerts antidepressant-like effects by inducing the release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) in the mPFC. Furthermore, our recent findings have revealed that resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), which are bioactive lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, exhibit antidepressant-like effects in rodent models. Notably, the antidepressant-like effects of RvD1, RvD2, and RvE1 require mTORC1 activation. Moreover, the intranasal administration of RvE1 elicits rapid antidepressant-like effects through the release of BDNF and VEGF in the mPFC and hippocampal dentate gyrus (DG), as well as mTORC1 activation in the mPFC, albeit not in the DG. These findings strongly suggest that resolvins, particularly RvD1, RvD2, and RvE1, hold promise as prospective candidates for novel, safer, and rapid-acting antidepressants.
Assuntos
Ketamina , Ketamina/farmacologia , Fator Neurotrófico Derivado do Encéfalo , Fator A de Crescimento do Endotélio Vascular , Antidepressivos/farmacologia , Ácidos Graxos , Alvo Mecanístico do Complexo 1 de RapamicinaRESUMO
The neurotrophic hypothesis of depression proposes that reduced levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) contribute to neuronal atrophy or loss in the prefrontal cortex (PFC) and hippocampus and impaired hippocampal adult neurogenesis, which are associated with depressive symptoms. Chronic, but acute, treatment with typical monoaminergic antidepressants can at least partially reverse these deficits, in part via induction of BDNF and/or VEGF expression, consistent with their delayed onset of action. Ketamine, an N-methyl-d-aspartate receptor antagonist, exerts rapid and sustained antidepressant effects. Rodent studies have revealed that ketamine rapidly increases BDNF and VEGF release and/or expression in the PFC and hippocampus, which in turn increases the number and function of spine synapses in the PFC and hippocampal neurogenesis. Ketamine also induces the persistent release of insulin-like growth factor 1 (IGF-1) in the PFC of male mice. These neurotrophic effects of ketamine are associated with its rapid and sustained antidepressant effects. In this review, we first provide an overview of the neurotrophic hypothesis of depression and then discuss the role of BDNF, VEGF, IGF-1, and other growth factors (IGF-2 and transforming growth factor-ß1) in the antidepressant effects of ketamine and its enantiomers. This article is part of the Special Issue on 'Ketamine and its Metabolites'.
Assuntos
Ketamina , Masculino , Camundongos , Animais , Ketamina/farmacologia , Ketamina/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator de Crescimento Insulin-Like I , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , DepressãoRESUMO
Intracerebroventricular infusion of resolvin E1 (RvE1), a bioactive metabolite derived from eicosapentaenoic acid, exerts antidepressant-like effects in a mouse model of lipopolysaccharide (LPS)-induced depression; these effects are blocked by systemic injection of rapamycin, a mechanistic target of rapamycin complex 1 (mTORC1) inhibitor. Additionally, local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) produces antidepressant-like effects. To evaluate the potential of RvE1 for clinical use, the present study examined whether treatment with RvE1 via intranasal (i.n.) route, a non-invasive route for effective drug delivery to the brain, produces antidepressant-like effects in LPS-challenged mice using tail suspension and forced swim tests. Intranasal administration of RvE1 significantly attenuated LPS-induced immobility, and these antidepressant-like effects were completely blocked by an AMPA receptor antagonist or L-type voltage-dependent Ca2+ channel blocker. The antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 were blocked by intra-mPFC infusion of a neutralizing antibody (nAb) for brain-derived neurotrophic factor (BDNF) or vascular endothelial growth factor (VEGF). Intra-mPFC infusion of rapamycin completely blocked the antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 as well as those of intra-mPFC infusion of BDNF and VEGF. Moreover, i.n. RvE1 produced antidepressant-like effects via mTORC1 activation in the mPFC of a mouse model of repeated prednisolone-induced depression. Intra-dorsal DG infusion of BDNF and VEGF nAbs, but not rapamycin, blocked the antidepressant-like effects of i.n. RvE1. These findings suggest that i.n. administration of RvE1 produces antidepressant-like effects through activity-dependent BDNF/VEGF release in the mPFC and dorsal DG, and mTORC1 activation in the mPFC, but not in the dorsal DG. Thus, RvE1 can be a promising candidate for a novel rapid-acting antidepressant.
Assuntos
Ácido Eicosapentaenoico , Fator A de Crescimento do Endotélio Vascular , Camundongos , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Administração Intranasal , Lipopolissacarídeos/toxicidade , Antidepressivos/farmacologia , Antidepressivos/metabolismo , Córtex Pré-Frontal/metabolismo , Depressão/tratamento farmacológicoRESUMO
Stress is one of the critical facilitators for seizure induction in patients with epilepsy. However, the neural mechanisms underlying this facilitation remain poorly understood. Here, we investigated whether noradrenaline (NA) transmission enhanced by stress exposure facilitates the induction of medial prefrontal cortex (mPFC)-originated seizures. In mPFC slices, whole-cell current-clamp recordings revealed that bath application of picrotoxin induced sporadic epileptiform activities (EAs), which consisted of depolarization with bursts of action potentials in layer 5 pyramidal cells. Addition of NA dramatically shortened the latency and increased the number of EAs. Simultaneous whole-cell and field potential recordings revealed that the EAs are synchronous in the mPFC local circuit. Terazosin, but not atipamezole or timolol, inhibited EA facilitation, indicating the involvement of α1 adrenoceptors. Intra-mPFC picrotoxin infusion induced seizures in mice in vivo. Addition of NA substantially shortened the seizure latency, while co-infusion of terazosin into the mPFC inhibited the effect of NA. Finally, acute restraint stress shortened the latency of intra-mPFC picrotoxin infusion-induced seizures, whereas prior infusion of terazosin reversed this stress-induced shortening of seizure latency. Our findings suggest that stress facilitates the induction of mPFC-originated seizures via NA stimulation of α1 adrenoceptors.