Participação da neurotransmissão GABAérgica do colículo inferior, via ativação de receptores 5-HT2A, e seus correlatos neuroanatômicos na mediação da resposta de inibição por pré-pulso do reflexo de sobressalto acústico e interação social em ratos Wistar machos
Data
2021-12-17
Autores
Oliveira, Rodolpho Pereira de 
Orientadores
Silva, Regina Cláudia Barbosa da
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A esquizofrenia é um transtorno psiquiátrico devastador que acomete
aproximadamente 1% da população geral. A relação entre a disfunção serotoninérgica
e a esquizofrenia começou com a descoberta dos efeitos da dietilamida do ácido
lisérgico (LSD) que tem alta afinidade pelos receptores 5-HT2A. A ativação destes
receptores gera delírios e alucinações considerados sintomas positivos da
esquizofrenia. Outra substância, o 2,5-dimetoxi-4-iodoanfetamina (DOI), também
exibe propriedades alucinógenas sendo agonista 5-HT2A como o LSD. Dois modelos
experimentais bastante utilizados na pesquisa da fisiopatologia da esquizofrenia são:
inibição por pré-pulso (IPP) do reflexo de sobressalto acústico e interação social. A
função da resposta de IPP é de filtrar informações irrelevantes, possibilitando ao
indivíduo direcionar a sua atenção a aspectos mais importantes do ambiente refletindo
dessa forma um processo pré-atentivo, estando associado aos aspectos cognitivos da
esquizofrenia. O segundo é utilizado na investigação de um sintoma negativo deste
transtorno, o isolamento social. Esse quadro é caracterizado por uma interação pobre,
breve e superficial do indivíduo com os demais. Pacientes com esquizofrenia exibem
déficit atencional e, portanto, prejuízos na resposta de IPP além de déficit na interação
social. A via neuronal primária, que medeia à resposta de IPP encontra-se no tronco
encefálico, sendo o colículo inferior (CI) e o núcleo reticular caudal da ponte (nRCP)
estruturas chaves nesta circuitaria. Um estudo prévio realizado em nosso laboratório
mostrou que a microinjeção de DOI no CI levou a déficits nas respostas de IPP e
interação social em ratos Wistar machos. Neste contexto, o presente trabalho teve por
objetivos investigar: i) a existência de possíveis vias neuronais entre o CI e as
estruturas nRCP e nTPP possivelmente envolvidas na mediação das respostas de IPP
através do estudo de neurotraçamento; ii) se a microinjeção de DOI no CI ativaria
neurônios nestas estruturas e na amígdala através do estudo de imunoistoquímica para a marcação de c-Fos; iii) a ação do DOI microinjetado no CI, sobre os neurônios
GABAérgicos desta estrutura e do nTPP através da técnica de dupla marcação por
imunofluorescência para c-Fos e GAD67; iv) se os déficits nas respostas de IPP e
interação social, observados após a administração de DOI no CI, poderiam ser
prevenidos pela microinjeção concomitante de bicuculina, antagonista GABAA, no
nTPP. Analisamos a interação social entre pares de ratos na arena. Foi utilizado um
total de 81 ratos Wistar machos neste estudo. Em conjunto, os resultados apontaram
para a não existência de uma via neural direta do CI para o nRCP, mas sim uma via
bidirecional entre o CI e o núcleo tegmental pedúnculo-pontino (nTPP). Esta via
parece ser inibida pela microinjeção de DOI no CI, por meio da ativação de receptores
5-HT2A localizados em interneurônios GABAérgicos nesta estrutura, levando a um
aumento da neurotransmissão inibitória GABAérgica e gerando os déficits nas
respostas de IPP e interação social verificados . A microinjeção concomitante de
bicuculina no nTPP e de DOI no CI preveniu os déficits nestas respostas observados
após a administração de DOI no CI. Concluindo, os nossos resultados mostram que os
receptores 5-HT2A do CI podem estar envolvidos, ao menos parcialmente, na
regulação de vias inibitórias mediando as respostas de IPP e interação social nas
estruturas CI, nTTP e amígdala.
Schizophrenia is a devastating psychiatric disorder that affects approximately 1% of the general population. The relationship between serotonin dysfunction and schizophrenia began with the discovery of the effects of lysergic acid diethylamide (LSD) which has high affinity for 5-HT2A receptors. Activation of these receptors generates delusions and hallucinations considered to be positive symptoms of schizophrenia. Another substance, 2,5-dimethoxy 4-iodoamphetamine (DOI), also exhibits hallucinogenic properties, being a 5-HT2A agonist like LSD. Two experimental models widely used in research on the pathophysiology of schizophrenia are: prepulse inhibition (PPI) of the acoustic startle reflex and social interaction. The function of the IPP response is to filter out irrelevant information, enabling the individual to direct their attention to more important aspects of the environment, thus reflecting a pre-attentive process, being associated with the cognitive aspects of schizophrenia. The second is used to investigate a negative symptom of this disorder, social isolation. This picture is characterized by a poor, brief and superficial interaction between the individual and others. Patients with schizophrenia exhibit attention deficit and, therefore, impairments in the PPI response in addition to deficits in social interaction. The primary neuronal pathway, which mediates the IPP response, is found in the brainstem, with the inferior colliculus (IC) and the pons reticular reticular nucleus (PnC) being key structures in this circuitry. A previous study carried out in our laboratory showed that microinjection of DOI into the IC led to deficits in PPI responses and social interaction in male Wistar rats. In this context, the present work aimed to investigate: i) the existence of a direct neural pathway, possibly inhibitory, between the IC and the PnC involved in the mediation of PPI responses through the study of neurotracing; ii) if the microinjection of DOI in IC would activate neurons in this structure and in PnC through the study of immunohistochemistry for c- 11 Fos labeling; iii) the action of the DOI microinjected in the IC, on the GABAergic neurons of this structure and on the PnC through the double immunofluorescence labeling technique for c-Fos and GAD67; iv) whether the deficits in PPI responses and social interaction, observed after the administration of DOI in the IC, could be prevented by the concomitant microinjection of bicuculline, GABAA antagonist, in the PnC. We analyzed the social interaction between pairs of rats in the arena. A total of 83 male Wistar rats were used in this study. Together, the results pointed to the nonexistence of a direct neural pathway from the IC to the PnC, but rather a bidirectional pathway between the IC and the pedunculopontine tegmental nucleus (PPTg). This pathway seems to be inhibited by the microinjection of DOI in the IC, through the activation of 5-HT2A receptors located in GABAergic interneurons in this structure, leading to an increase in GABAergic inhibitory neurotransmission and generating deficits in PPI responses and social interaction verified. The concomitant microinjection of bicuculline in PPTg and DOI in the IC prevented the deficits in these responses observed after the administration of DOI in the IC. In conclusion, our results show that IC 5-HT2A receptors may be involved, at least partially, in the regulation of inhibitory pathways mediating PPI responses and social interaction in IC, PPTg and amygdala structures
Schizophrenia is a devastating psychiatric disorder that affects approximately 1% of the general population. The relationship between serotonin dysfunction and schizophrenia began with the discovery of the effects of lysergic acid diethylamide (LSD) which has high affinity for 5-HT2A receptors. Activation of these receptors generates delusions and hallucinations considered to be positive symptoms of schizophrenia. Another substance, 2,5-dimethoxy 4-iodoamphetamine (DOI), also exhibits hallucinogenic properties, being a 5-HT2A agonist like LSD. Two experimental models widely used in research on the pathophysiology of schizophrenia are: prepulse inhibition (PPI) of the acoustic startle reflex and social interaction. The function of the IPP response is to filter out irrelevant information, enabling the individual to direct their attention to more important aspects of the environment, thus reflecting a pre-attentive process, being associated with the cognitive aspects of schizophrenia. The second is used to investigate a negative symptom of this disorder, social isolation. This picture is characterized by a poor, brief and superficial interaction between the individual and others. Patients with schizophrenia exhibit attention deficit and, therefore, impairments in the PPI response in addition to deficits in social interaction. The primary neuronal pathway, which mediates the IPP response, is found in the brainstem, with the inferior colliculus (IC) and the pons reticular reticular nucleus (PnC) being key structures in this circuitry. A previous study carried out in our laboratory showed that microinjection of DOI into the IC led to deficits in PPI responses and social interaction in male Wistar rats. In this context, the present work aimed to investigate: i) the existence of a direct neural pathway, possibly inhibitory, between the IC and the PnC involved in the mediation of PPI responses through the study of neurotracing; ii) if the microinjection of DOI in IC would activate neurons in this structure and in PnC through the study of immunohistochemistry for c- 11 Fos labeling; iii) the action of the DOI microinjected in the IC, on the GABAergic neurons of this structure and on the PnC through the double immunofluorescence labeling technique for c-Fos and GAD67; iv) whether the deficits in PPI responses and social interaction, observed after the administration of DOI in the IC, could be prevented by the concomitant microinjection of bicuculline, GABAA antagonist, in the PnC. We analyzed the social interaction between pairs of rats in the arena. A total of 83 male Wistar rats were used in this study. Together, the results pointed to the nonexistence of a direct neural pathway from the IC to the PnC, but rather a bidirectional pathway between the IC and the pedunculopontine tegmental nucleus (PPTg). This pathway seems to be inhibited by the microinjection of DOI in the IC, through the activation of 5-HT2A receptors located in GABAergic interneurons in this structure, leading to an increase in GABAergic inhibitory neurotransmission and generating deficits in PPI responses and social interaction verified. The concomitant microinjection of bicuculline in PPTg and DOI in the IC prevented the deficits in these responses observed after the administration of DOI in the IC. In conclusion, our results show that IC 5-HT2A receptors may be involved, at least partially, in the regulation of inhibitory pathways mediating PPI responses and social interaction in IC, PPTg and amygdala structures
Descrição
Citação
OLIVEIRA, Rodolpho Pereira de. Participação da neurotransmissão GABAérgica do colículo inferior, via ativação de receptores 5-HT2A, e seus correlatos neuroanatômicos na mediação da resposta de inibição por pré-pulso do reflexo de sobressalto acústico e interação social em ratos Wistar machos. 2021. 92 f. Tese (Doutorado Interdisciplinar em Ciências da Saúde ) - Instituto de Saúde e Sociedade, Universidade Federal de São Paulo, Santos, 2021.