Investigação da participação do sistema endocanabinoide no prejuízo do comportamento social em ratos expostos a status epilepticus neonatal

• Ano de defesa: 2018
• Autor(a) principal: Ribeiro, Fernanda Teixeira
• Orientador(a): Cysneiros, Roberta Monterazzo
• Banca de defesa: Ribeiro, Miriam Oliveira , Silva, Sérgio Gomes da
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Presbiteriana Mackenzie
• Programa de Pós-Graduação: Distúrbios do Desenvolvimento
• Departamento: Centro de Ciências Biológicas e da Saúde (CCBS)
• País: Brasil
• Palavras-chave em Português: endocanabinoide; motivação social; memória social; sociabilidade; TEA
• Área do conhecimento CNPq: CNPQ::CIENCIAS BIOLOGICAS
• Link de acesso: http://dspace.mackenzie.br/handle/10899/22754

Rats exposed to neonatal seizures are a model for study brain circuits that underlies social impairment symptoms of Autism Spectrum Disorder (ASD). Animals submitted to status epilepticus neonatal (SE) - a single long-term seizure induced by pharmacological agent - show a lack of interest for social novelty and social discrimination deficit. We used this animal model for ASD to investigate a possible role of endocannabinoid system in ASD etiology, beased on evidences that comprove the role of endocannabinoids in multiple processes, as epileptic seizures supression and emotion regulation. Male Wistar rats were submitted to SE in ninenth day of life (P9) by pilocarpine injection (380 mg/kg, i.p.) - control animals received saline 0,9% (0,1 mL/ 10g). In P60 both groups were injected with JZL195 (0,01 mg/kg, i.p.) - inhibidor of FAAH and MAGL, enzimes that catalise endogenous cannabinoids agonists. After two hours, animals were submitted to behavioral tests that evaluated social memory, interest for social novelty and short-term memory (objects recognition test). Neurobiological correlation for the behavioral results was investigated by genic expression analysis of CNR1 gene (RT-PCR) and quantification of CB1 receptor (ELISA). Results of social memory test show a deficit of social investigation in control rats treated with JZL (F(1,18)=5,481; p=0,03), without affect social discrimination (F(1,18)=9,807; p=0,0058); there was no effect of JZL in experimental group (F(1,17)=2,509; n.s.). In social novelty test, JZL affected the investigation time in control group (F(1,19)=4,863; p=0,04) and the preference for investigating social novelty (t(20)=3,356; p<0,01); JZL had no effect on experimental group (F(1,19)=0,001; n.s.). In the test of objects recognition, JZL caused object discrimination deficit in control group (F(1,13)=4,955; p=0,04) and affected time investigation in experimental group (F(1,11)=5,999; p=0,03), without affect in discrimination (F(1,11)=0,860; n.s.). The analysis of total locomotion in open field showed that JZL caused hyperlocomotion specifically in control animals (F(1,24)=4,837; p=0,03); analysis of central locomotion showed that JZL affected both groups, reducing time spent in central area (F(1,24)=4,547; p=0,04). Genic expression analysis of CNR1 gene did not present any difference in mRNA expression in hippocampus, pre-frontal cortex, striatum and amygdala. CB1 quantification presented a difference in hippocampus of experimental animals (U=2000; p=0,03). Our results reinforce the idea that the animal model of rats exposed to neonatal SE is valid and relevant to the study of social motivation, compromised in ASD. Pharmacological interventions targeting CB1 receptors are a way to explore this circuitry, given the results of our behavioral tests (with specific impairment of controls on social memory and sociability tests) and the molecular differences identified in the hippocampus of experimental group. Our results suggest that the endocannabinoid system participates in the modulation of social behavior and that there is a neurobiological alteration of this circuit in ASD.