RESUMO
RATIONALE: Recently, we demonstrated that the activation of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) signaling facilitates depressive-like behaviors. Additionally, literature findings support the ability of the N/OFQ-NOP system to modulate the hypothalamic-pituitary-adrenal (HPA) axis. OBJECTIVES: Considering that dysfunctional HPA axis is strictly related to stress-induced psychopathologies, we aimed to study the role of the HPA axis in the pro-depressant effects of NOP agonists. METHODS: Mice were treated prior to stress with the NOP agonist Ro 65-6570, and immobility time in the forced swimming task and corticosterone levels were measured. Additionally, the role of endogenous glucocorticoids and CRF was investigated using the glucocorticoid receptor antagonist mifepristone and the CRF1 antagonist antalarmin in the mediation of the effects of Ro 65-6570. RESULTS: The NOP agonist in a dose-dependent manner further increased the immobility of mice in the second swimming session compared to vehicle. By contrast, under the same conditions, the administration of the NOP antagonist SB-612111 before stress reduced immobility, while the antidepressant nortriptyline was inactive. Concerning in-serum corticosterone in mice treated with vehicle, nortriptyline, or SB-612111, a significant decrease was observed after re-exposition to stress, but no differences were detected in Ro 65-6570-treated mice. Administration of mifepristone or antalarmin blocked the Ro 65-6570-induced increase in the immobility time in the second swimming session. CONCLUSIONS: Present findings suggest that NOP agonists increase vulnerability to depression by hyperactivating the HPA axis and then increasing stress circulating hormones and CRF1 receptor signaling.
Assuntos
Cicloeptanos , Imidazóis , Peptídeos Opioides , Piperidinas , Receptores Opioides , Compostos de Espiro , Camundongos , Animais , Receptores Opioides/fisiologia , Peptídeos Opioides/metabolismo , Glucocorticoides/farmacologia , Nortriptilina/farmacologia , Receptor de Nociceptina , Corticosterona/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Mifepristona/farmacologia , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
BACKGROUND: The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ-NOP receptor system in resilience to stress is unclear. AIMS: The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress. METHODS: The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01-1 mg/kg) and MCOPPB (0.1-10 mg/kg), and the NOP antagonist SB-612111 (1-10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated. RESULTS: The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture. CONCLUSIONS: These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.
Assuntos
Peptídeos Opioides/metabolismo , Receptores Opioides/metabolismo , Resiliência Psicológica/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacologia , Cicloeptanos/administração & dosagem , Cicloeptanos/farmacologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Knockout , Nortriptilina/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Receptores Opioides/efeitos dos fármacos , Receptores Opioides/genética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacologia , Estresse Psicológico/fisiopatologia , Receptor de Nociceptina , NociceptinaRESUMO
RATIONALE: Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of a Gi protein-coupled receptor named NOP. Both N/OFQ and NOP receptor are widely expressed in brain areas involved in the control of emotional processes. Clinical and preclinical studies support antidepressant effects due to the blockade of NOP receptor signaling. By contrast, NOP receptor activation did not evoke any change in behavioral despair tests. OBJECTIVES: The present study aimed to investigate the effects of the co-administration of NOP agonists and classic antidepressant drugs in the forced swimming test (FST) and learned helplessness model (LH) in mice. METHODS: Male Swiss mice were co-administered with NOP agonists (N/OFQ and Ro 65-6570) and antidepressants (nortriptyline, fluoxetine, and R-ketamine) or SB-612111 (NOP antagonist) and the behavioral effects were assessed in the FST and LH tests. RESULTS: Fluoxetine, nortriptyline, R-ketamine and the NOP antagonist SB-612111 displayed antidepressant-like effects in the FST. The administration of the NOP agonists N/OFQ and Ro 65-6570 did not induce any behavioral change. However, co-administration of NOP agonists blocked the antidepressant effects of SB-612111, fluoxetine, and nortriptyline, but not R-ketamine in the FST. Similarly, in the LH, the systemic injection of SB-612111, nortriptyline, and R-ketamine reversed helplessness. The co-administration of Ro 65-6570 blocked the antidepressant-like effects of SB-612111 and nortriptyline, but not R-ketamine. CONCLUSIONS: NOP receptor activation inhibits the acute antidepressant effects of nortriptyline and fluoxetine, but not R-ketamine. The present findings contribute to further understand the role played by the N/OFQ-NOP receptor system in regulating mood states.
Assuntos
Antidepressivos/farmacologia , Fluoxetina/farmacologia , Desamparo Aprendido , Ketamina/farmacologia , Nortriptilina/farmacologia , Peptídeos Opioides/agonistas , Anestésicos Dissociativos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Emoções/efeitos dos fármacos , Emoções/fisiologia , Fluoxetina/antagonistas & inibidores , Imidazóis/farmacologia , Masculino , Camundongos , Nortriptilina/antagonistas & inibidores , Peptídeos Opioides/metabolismo , Receptores Opioides/agonistas , Receptores Opioides/metabolismo , Compostos de Espiro/farmacologia , Natação/fisiologia , Natação/psicologia , NociceptinaRESUMO
RATIONALE: Several model organisms have been employed to study the impacts of stress on biological systems. Different models of unpredictable chronic stress (UCS) have been established in rodents; however, these protocols are expensive, long-lasting, and require a large physical structure. Our group has recently reported an UCS protocol in zebrafish with several advantages compared to rodent models. We observed that UCS induced behavioral, biochemical, and molecular changes similar to those observed in depressed patients, supporting the translational relevance of the protocol. OBJECTIVES: Considering that a pharmacological assessment is lacking in this zebrafish model, our aim was to evaluate the effects of anxiolytic (bromazepam) and antidepressant drugs (fluoxetine and nortriptyline) on behavioral (novel tank test), biochemical (whole-body cortisol), and molecular parameters (cox-2, tnf-α, il-6, and il-10 gene expression) in zebrafish subjected to UCS. RESULTS: We replicated previous data showing that UCS induces behavioral and neuroendocrine alterations in zebrafish, and we show for the first time that anxiolytic and antidepressant drugs are able to prevent such effects. Furthermore, we extended the molecular characterization of the model, revealing that UCS increases expression of the pro-inflammatory markers cox-2 and il-6, which was also prevented by the drugs tested. CONCLUSIONS: This study reinforces the use of zebrafish as a model organism to study the behavioral and physiological effects of stress. The UCS protocol may also serve as a screening tool for evaluating new drugs that can be used to treat psychiatric disorders with stress-related etiologies.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Bromazepam/farmacologia , Fluoxetina/farmacologia , Nortriptilina/farmacologia , Estresse Psicológico/metabolismo , Animais , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Feminino , Hidrocortisona/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Masculino , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Peixe-ZebraRESUMO
Melanin-concentrating hormone (MCH) administered within the rat dorsal raphe nucleus (DRN) has been shown to elicit prodepressive behaviors in the forced-swim test. The present study was designed to evaluate the time course (30 and 60 min) and dose dependence (25-100 ng) of this effect, and whether it would be antagonized by an intra-DRN microinjection of the MCH-1 receptor antagonist ATC0175 (ATC, 1 mmol/l) or intraperitoneal pretreatment with the noradrenergic antidepressant nortriptyline (20 mg/kg). The results showed that the behavioral effect of MCH was time and dose dependent as immobility was increased, and climbing decreased, only by the 50 ng MCH dose at T30. The effect was mediated by MCH-1 receptors as a significant blockade of this behavioral response was observed in ATC-pretreated animals. ATC did not by itself modify animal behavior. Nortriptyline also prevented the prodepressive-like effect of MCH. Concomitantly, the effect of MCH (50 ng) at T30 on anxiety-related behaviors was assessed using the elevated plus-maze. Interestingly, these behaviors were unchanged. In conclusion, MCH administration within the DRN elicits, through the MCH-1 receptor, a depression-related behavior that is not accompanied by changes in anxiety and that is prevented by a noradrenergic antidepressant.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Depressão/induzido quimicamente , Núcleo Dorsal da Rafe/efeitos dos fármacos , Hormônios Hipotalâmicos/farmacologia , Melaninas/farmacologia , Hormônios Hipofisários/farmacologia , Animais , Antidepressivos/farmacologia , Antidepressivos Tricíclicos/farmacologia , Ansiedade/induzido quimicamente , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Depressores do Sistema Nervoso Central/antagonistas & inibidores , Cicloexilaminas/farmacologia , Depressão/fisiopatologia , Núcleo Dorsal da Rafe/fisiopatologia , Relação Dose-Resposta a Droga , Hormônios Hipotalâmicos/antagonistas & inibidores , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Melaninas/antagonistas & inibidores , Microinjeções , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Testes Neuropsicológicos , Nortriptilina/farmacologia , Hormônios Hipofisários/antagonistas & inibidores , Quinazolinas/farmacologia , Ratos Wistar , Receptores de Somatostatina/metabolismo , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: Transient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) are involved in many biological processes, including nociception and hyperalgesia. Whereas the involvement of TRPV1 in psychiatric disorders such as anxiety and depression has been reported, little is known regarding the role of TRPA1 in these conditions. EXPERIMENTAL APPROACH: We investigated the role of TRPA1 in mice models of depression [forced swimming test (FST)] and anxiety [elevated plus maze (EPM) test]. KEY RESULTS: Administration of the TRPA1 antagonist (HC030031, 30 nmol in 2 µL, i.c.v.) reduced immobility time in the FST. Similar results were obtained after oral administration of HC030031 (30-300 mg·kg(-1) ). The reduction in immobility time in FST induced by HC030031 (100 mg·kg(-1) ) was completely prevented by pretreatment with TRPA1 agonist, cinnamaldehyde (50 mg·kg(-1) , p.o.), which per se was inactive. In the EPM test, pretreatment with cinnamaldehyde (50 mg·kg(-1) , p.o.), which per se did not affect behaviour response, prevented the anxiolytic-like effect (increased open arm exploration) evoked by TRPA1 blockade (HC030031, 100 mg·kg(-1) , p.o.). Treatment with either cinnamaldehyde or HC030031 did not affect spontaneous ambulation. Furthermore, TRPA1-deficient mice showed anxiolytic- and antidepressant-like phenotypes in the FST and EPM test respectively. CONCLUSION AND IMPLICATIONS: The present findings indicate that genetic deletion or pharmacological blockade of TRPA1 produces inhibitory activity in mouse models of anxiety and depression. These results imply that TRPA1 exerts tonic control, promoting anxiety and depression, and that TRPA1 antagonism has potential as an innovative strategy for the treatment of anxiety and mood disorders.
Assuntos
Ansiedade/fisiopatologia , Depressão/fisiopatologia , Canais de Potencial de Receptor Transitório/fisiologia , Acetanilidas/farmacologia , Acroleína/análogos & derivados , Acroleína/farmacologia , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Comportamento Animal , Diazepam/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos Knockout , Nortriptilina/farmacologia , Purinas/farmacologia , Transdução de Sinais , Natação , Canal de Cátion TRPA1 , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/genéticaRESUMO
Treatment of major depression, posttraumatic stress disorder and other psychopathologies with antidepressants can be associated with improvement of the cognitive deficits related to these disorders. Although the mechanisms of these effects are not completely elucidated, alterations in the extinction of aversive memories are believed to play a role in these psychopathologies. We have recently verified that female rats present low levels of extinction when submitted to the plus-maze discriminative avoidance task. In the present study, female rats were treated long term with clinically used antidepressants (fluoxetine, nortriptyline or mirtazapine) and subjected to the plus-maze discriminative avoidance task to evaluate learning, memory, extinction and anxiety-related behaviors as well as behavioral despair in the forced swimming test. All groups learned the task and exhibited retrieval. Chronic treatment with fluoxetine (but not with the other antidepressants tested) increased extinction of the discriminative task. In the forced swimming test, the animals treated with fluoxetine and mirtazapine showed decreased immobility duration. In conclusion, fluoxetine potentiated extinction, while both fluoxetine and mirtazapine were effective in ameliorating depressive-like behavior in the forced swimming test, suggesting a possible dissociation between the effects on mood and the extinction of aversive memories in female rats.
Assuntos
Antidepressivos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Memória/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Animais , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Aprendizagem da Esquiva/fisiologia , Extinção Psicológica/fisiologia , Feminino , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Mianserina/análogos & derivados , Mianserina/farmacologia , Mianserina/uso terapêutico , Mirtazapina , Nortriptilina/farmacologia , Nortriptilina/uso terapêutico , Desempenho Psicomotor/fisiologia , Ratos , Ratos WistarRESUMO
Although it is long known that the tricyclic antidepressants amitriptyline, nortriptyline and imipramine inhibit the noradrenaline transporter and alpha(1)-adrenoceptors with similar affinities, which may lead to self-cancelling actions, the selectivity of these drugs for alpha(1)-adrenoceptor subtypes is unknown. The present study investigates the selectivity of amitriptyline, nortriptyline and imipramine for human recombinant and rat native alpha(1)-adrenoceptor subtypes. The selectivity of amitriptyline, nortriptyline and imipramine was investigated in HEK-293 cells expressing each of the human alpha(1)-subtypes and in rat native receptors from the vas deferens (alpha(1A)), spleen (alpha(1B)) and aorta (alpha(1D)) through [(3)H]prazosin binding, and noradrenaline-induced intracellular Ca(2+) increases and contraction assays. Amitriptyline, nortriptyline and imipramine showed considerably higher affinities for alpha(1A)- (approximately 25- to 80-fold) and alpha(1D)-adrenoceptors (approximately 10- to 25-fold) than for alpha(1B)-adrenoceptors in both contraction and [(3)H]prazosin binding assays with rat native and human receptors, respectively. In addition, amitriptyline, nortriptyline and imipramine were substantially more potent in the inhibition of noradrenaline-induced intracellular Ca(2+) increases in HEK-293 cells expressing alpha(1A)- or a truncated version of alpha(1D)-adrenoceptors which traffics more efficiently towards the cell membrane than in cells expressing alpha(1B)-adrenoceptors. Amitriptyline, nortriptyline and imipramine are much weaker antagonists of rat and human alpha(1B)-adrenoceptors than of alpha(1A)- and alpha(1D)-adrenoceptors. The differential affinities for these receptors indicate that the alpha(1)-adrenoceptor subtype which activation is most increased by the augmented noradrenaline availability resultant from the blockade of neuronal reuptake is the alpha(1B)-adrenoceptor. This may be important for the behavioural effects of these drugs.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Amitriptilina/farmacologia , Antidepressivos Tricíclicos/farmacologia , Imipramina/farmacologia , Nortriptilina/farmacologia , Amitriptilina/farmacocinética , Animais , Antidepressivos Tricíclicos/farmacocinética , Cálcio/metabolismo , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Relação Dose-Resposta a Droga , Humanos , Imipramina/farmacocinética , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Nortriptilina/farmacocinética , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/metabolismoRESUMO
Several works report brain impairment of metabolism as a mechanism underlying depression. Citrate synthase and succinate dehydrogenase are enzymes localized within cells in the mitochondrial matrix and are important steps of Krebs cycle. In addition, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase and succinate dehydrogenase activities from rat brain after chronic administration of paroxetine, nortriptiline and venlafaxine. Adult male Wistar rats received daily injections of paroxetine (10mg/kg), nortriptiline (15mg/kg), venlafaxine (10mg/kg) or saline in 1.0mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activities of citrate synthase and succinate dehydrogenase were measured. We verified that chronic administration of paroxetine increased citrate synthase activity in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected. Chronic administration of nortriptiline and venlafaxine did not affect the enzyme activity in these brain areas. Succinate dehydrogenase activity was increased by chronic administration of paroxetine and nortriptiline in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected either. Chronic administration of venlafaxine increased succinate dehydrogenase activity in prefrontal cortex, but did not affect the enzyme activity in cerebellum, hippocampus, striatum and cerebral cortex. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in these enzymes by antidepressants may be an important mechanism of action of these drugs.
Assuntos
Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Citrato (si)-Sintase/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Succinato Desidrogenase/metabolismo , Animais , Antidepressivos/administração & dosagem , Encéfalo/anatomia & histologia , Ciclo do Ácido Cítrico/fisiologia , Cicloexanóis/administração & dosagem , Cicloexanóis/farmacologia , Masculino , Nortriptilina/administração & dosagem , Nortriptilina/farmacologia , Paroxetina/administração & dosagem , Paroxetina/farmacologia , Ratos , Ratos Wistar , Cloridrato de VenlafaxinaRESUMO
Major depression is a serious and recurrent disorder often manifested with symptoms at the psychological, behavioral, and physiological levels. In addition, several works also suggest brain metabolism impairment as a mechanism underlying depression. Creatine kinase (CK) plays a central role in the metabolism of high-energy consuming tissues such as brain, where it functions as an effective buffering system of cellular ATP levels. Considering that CK plays an important role in brain energy homeostasis and that some antidepressants may modulate energy metabolism, we decided to investigate CK activity from rat brain after chronic administration of paroxetine (selective serotonin reuptake inhibitor), nortriptiline (tricyclic antidepressant) and venlafaxine (selective serotonin-norepinephrine reuptake inhibitor). Adult male Wistar rats received daily injections of paroxetine (10 mg/kg), nortriptiline (15 mg/kg), venlafaxine (10 mg/kg) or saline in 1.0 mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activity of CK was measured. Our results demonstrated that chronic administration of paroxetine increased CK activity in the prefrontal cortex, hippocampus and striatum of adult rats. On the other hand, nortriptiline and venlafaxine chronic administration did not affect CK activity in these brain areas. In order to verify whether the effect of paroxetine on CK is direct or indirect, we also measured the in vitro effect of this drug on the activity of the enzyme. We verified that paroxetine did not affect CK activity in vitro. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in CK activity by antidepressants may be an important mechanism of action of these drugs.