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Made available in DSpace on 2022-05-01T06:31:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-01-01 Cohabitation with a partner undergoing chronic pain induces pain hypersensitivity. Among a lot of other neurochemical pathways, the serotonin (5-HT) role, specifically the 5-HT3 receptor (5-HT3R), in the amygdala has never been evaluated in this model. Here we studied the effects of the amygdala’s chemical inhibition, its neuronal activation pattern, and 5-HT, 5-HIAA, and 5-HT turnover within the amygdala. Furthermore, the systemic and intra-amygdala 5-HT3R activation and blockade in mice that cohabited with a conspecific subjected to chronic constriction injury were investigated. Male Swiss mice were housed in partners for 28 days. The dyads were divided into two groups on the 14th day: cagemate nerve constriction (CNC) and cagemate sham (CS). On the 24th day, cagemates underwent a stereotaxic surgery (when necessary) and, on the 28th day, they were evaluated on the writhing test. The amygdala inactivation promotes pain-hypersensitivity behaviors in groups and dyads; cohabitation with a partner with chronic pain did not change FosB-labeled cells in the amygdala’s nucleus and increases 5-HT turnover in cagemates. Systemic and intra-amygdala 5-HT3R activation attenuated and enhanced the number of writhes, respectively. In contrast, 5-HT3R blockade reduced hypersensitivity pain response. Results suggest the involvement of amygdala serotonergic signaling via 5-HT3R in empathy-like behavior. Psychobiology Group Department of Psychology/CECH Universidade Federal de São Carlos - UFSCar Joint Graduate Program in Physiological Sciences UFSCar/UNESP Lab. Pharmacology School of Pharmaceutical Sciences Univ. Estadual Paulista - UNESP Neuroscience and Behavior Institute - IneC Program in Psychology UFSCar Joint Graduate Program in Physiological Sciences UFSCar/UNESP Lab. Pharmacology School of Pharmaceutical Sciences Univ. Estadual Paulista - UNESP

Cohabitation with a partner undergoing chronic pain induces pain hypersensitivity. Among a lot of other neurochemical pathways, the serotonin (5-HT) role, specifically the 5-HT

A doença de Parkinson (DP) é caracterizada pela perda de neurônios dopaminérgicos da via nigroestriatal, cuja causa ainda é desconhecida. O tratamento mais efetivo para os sintomas motores da DP é por meio da administração de L-DOPA. A cronicidade desse tratamento leva ao desenvolvimento de discinesia induzida por L-DOPA (LID), caracterizado por movimentos involuntários anormais (AIMs). Observou-se no estriado lesionado de animais parkinsonianos com discinesia a presença de células gliais ativadas e o aumento da expressão de sintase do óxido nítrico induzida (iNOS), sugerindo o envolvimento de neuroinflamação na fisiopatologia da DP e da discinesia. A transcrição de iNOS é dependente de citocinas pró-inflamatórias, como o interferon-γ (IFN-γ). O IFN-γ pode ativar micróglia e de astrócitos. Foi observado o aumento da produção desta citocina no plasma e no cérebro de pacientes com DP, sugerindo sua participação na doença. Além disso, animais nocaute para IFN-γ apresentaram neuroproteção contra degeneração de neurônios dopaminérgicos no modelo de MPTP e paraquat, mas ainda não se conhecia sua influência sobre a LID. O objetivo deste estudo foi investigar se a deficiência de IFN-γ interfere sobre a degeneração de neurônios dopaminérgicos promovida pela neurotoxina 6-OHDA, no desenvolvimento da discinesia induzida pelo tratamento crônico com L-DOPA e na expressão de marcadores de neuroinflamação. No primeiro experimento analisamos a interferência do IFN-γ na lesão unilateral por 6-OHDA. Camundongos IFN-γ/KO e WT foram microinjetados com 6-OHDA no estriado e sacrificados 1, 3, 7 ou 21 dias após a cirurgia. A análise da imunorreatividade para enzima tirosina hidroxilase (TH) no estriado e na SNc indicou início da lesão dopaminérgica desde o primeiro dia após microinjeção, em ambas estruturas, com rápida progressão até o 21º dia, chegando a cerca de 85% no estriado e de 83% na SNc. Não houve diferença no desenvolvimento da lesão entre os grupos de animais. No segundo experimento, camundongos WT e IFN-γ/KO hemiparkinsonianos, foram tratados com L-DOPA por 21 dias. A análise dos AIMs indicou altos níveis de discinesia desde o primeiro dia de tratamento, que perdurou até o 21º dia, sendo semelhante entre os animais WT e IFN-γ/KO. A lesão da via nigroestriatal foi confirmada pelo teste do cilindro e imunohistoquímica para TH, indicando não haver diferença entre os grupos de animais. Foi observado maior número de neurônios TH+ no estriado lesionado dos animais IFN-γ/KO tratados com L-DOPA, em comparação aos animais WT. A análise da expressão de FosB no estriado não indicou diferenças entre os animais discinéticos. Os animais IFN-γ/KO tratados com L-DOPA apresentaram aumento da expressão de iNOS, Iba-1 (marcador de micróglia) e GFAP (marcador de astrócitos) no estriado lesionado, em comparação aos animais WT tratados com L-DOPA. A análise da morfologia indicou reatividade das células da glia no estriado lesionado. Foi encontrada correlação positiva entre a intensidade da discinesia e a expressão de micróglia no estriado de animais WT e IFN-γ/KO. O IFN-γ parece não interferir na lesão dopaminérgica por 6-OHDA ou na LID. Entretanto, sua ausência contribui para alterações das reações inflamatórias no estriado lesionado após tratamento com L-DOPA. Parkinson\'s disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons, which cause is still unknown. The most effective treatment for PD motor symptoms is through the administration of L-DOPA. The chronicity of this treatment leads to the development of L-DOPA-induced dyskinesia (LID) characterized by abnormal involuntary movements (AIMs). In the lesioned striatum of parkinsonian and dyskinetic animals, the presence of activated glial cells and increased expression of inducible nitric oxide synthase (iNOS) suggested the involvement of neuroinflammation in the pathophysiology of PD and dyskinesia. iNOS transcription is dependent on proinflammatory cytokines, including interferon-γ (IFN-γ). IFN-γ is a potent activator of both microglia and astrocytes, and it was observed increased levels of this cytokine on the plasma and brain of PD patients, suggesting its potential role in PD. The influence of IFN-γ on LID has not been studied yet. This study aimed to analyze the participation of IFN-γ on 6-OHDA-induced parkinsonism, on LID development and expression of neuroinflammatory mediators. In the first experiment, WT and IFN-γ/KO received unilateral injections of 6-OHDA into the striatum and were sacrificed after 1, 3, 7, or 21 days. The analysis of immunoreactivity for tyrosine hydroxylase (TH) in the striatum and SNc indicated the starting of dopaminergic lesion since the first day after microinjection in both structures with rapid progression until the 21st day, reaching about 85% in the striatum and 83% in SNc. There was no difference in the development of the lesion between the animal groups. In the second experiment, hemiparkinsonian WT and IFN- γ/KO mice were treated with L-DOPA for 21 days. The analysis of AIMs indicated high levels of dyskinesia from the first day of the treatment, which was stable until the 21st treatment day, being similar between WT and IFN-γ/KO groups. The nigrostriatal pathway lesion was confirmed by the cylinder test and immunohistochemistry for TH and indicated no difference between the groups. Higher expression of TH+ neurons was observed in the lesioned striatum of IFN-γ/KO animals treated with L-DOPA, compared to the WT group. The FosB expression analysis in the striatum did not indicate differences between dyskinetic animals. The L-DOPA treated IFN-γ/KO animals showed increased expression of iNOS, Iba- 1 (microglia marker), and GFAP (astrocyte marker) in the lesioned striatum, compared to LDOPA treated WT animals. Morphology analysis indicated glial cell reactivity in the lesioned striatum. A positive correlation was found between the intensity of dyskinesia and the expression of microglia in WT and IFN-γ/KO striatum. IFN-γ does not appear to interfere with dopaminergic degeneration induced by 6-OHDA or in LID development. However, its deficit contributes to alterations in neuroinflammatory reactions in the lesioned striatum after treatment with L-DOPA.