RESUMO
Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24 h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed.
Assuntos
Calcineurina/metabolismo , Cotinina/farmacologia , Depressão/tratamento farmacológico , Depressão/psicologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/metabolismo , Óleos/farmacologia , Administração Intranasal , Animais , Comportamento Animal , Condicionamento Psicológico , Cotinina/administração & dosagem , Cotinina/uso terapêutico , Euphausiacea/química , Camundongos Endogâmicos C57BL , Modelos Biológicos , Óleos/administração & dosagem , Sertralina/farmacologiaRESUMO
Posttraumatic stress disorder (PTSD), chronic psychological stress, and major depressive disorder have been found to be associated with a significant decrease in glial fibrillary acidic protein (GFAP) immunoreactivity in the hippocampus of rodents. Cotinine is an alkaloid that prevents memory impairment, depressive-like behavior and synaptic loss when co-administered during restraint stress, a model of PTSD and stress-induced depression, in mice. Here, we investigated the effects of post-treatment with intranasal cotinine on depressive- and anxiety-like behaviors, visual recognition memory as well as the number and morphology of GFAP+ immunoreactive cells, in the hippocampus and frontal cortex of mice subjected to prolonged restraint stress. The results revealed that in addition to the mood and cognitive impairments, restraint stress induced a significant decrease in the number and arborization of GFAP+ cells in the brain of mice. Intranasal cotinine prevented these stress-derived symptoms and the morphological abnormalities GFAP+ cells in both of these brain regions which are critical to resilience to stress. The significance of these findings for the therapy of PTSD and depression is discussed.
Assuntos
Cotinina/uso terapêutico , Depressão/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Estresse Psicológico/tratamento farmacológico , Administração Intranasal , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Química Encefálica/efeitos dos fármacos , Cotinina/administração & dosagem , Depressão/etiologia , Depressão/psicologia , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Restrição Física , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Natação/psicologiaRESUMO
BACKGROUND: The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non-pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions. CONCLUSION: In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Cotinina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Cotinina/farmacologia , Humanos , Fármacos Neuroprotetores/farmacologiaRESUMO
PURPOSE: Most cancer patients treated with systemic adjuvant chemotherapy endure long-lasting side effects including decrease in concentration, forgetfulness and slower thinking, which are globally termed "chemobrain." Cotinine, the main derivative of nicotine, improved visual and spatial working memory and decreased depressive-like behavior in an animal model of chemotherapy-induced cognitive impairment. METHODS: In this study, we investigated the effect of cotinine on weight gain, locomotor activity, cognitive abilities and depressive-like behavior in rats treated with the chemotherapy mix, cyclophosphamide, methotrexate and 5-fluorouracil. Locomotor activity and depressive-like behavior were assessed using the rotarod and Porsolt's tests, respectively. Changes in cognitive abilities were determined using the novel place recognition test. RESULTS: Female rats treated with cotinine after chemotherapy, recovered weight faster, showed superior cognitive abilities and lower levels of depressive-like behavior than chemotherapy, vehicle-treated rats. CONCLUSIONS: This evidence suggests that treatment with cotinine may facilitate the recovery and diminish the cognitive consequences of chemotherapy.