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Doctoral Thesis
DOI
10.11606/T.59.2010.tde-09082010-143444
Document
Author
Full name
Lucas Albrechet de Souza
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2010
Supervisor
Committee
Brandao, Marcus Lira (President)
Souza, Ricardo Luiz Nunes de
Cruz, Antonio Pedro de Mello
Genaro, Gelson
Molina, Victor Alejandro
Title in Portuguese
Fatores hormonais, cognitivos e neuroanatômicos associados ao comportamento exploratório de ratos submetidos ao teste e reteste no labirinto em cruz elevado
Keywords in Portuguese
benzodiazepínicos
córtex cingulado anterior
corticosterona
labirinto em cruz elevado
proteína Fos
sessão reteste
Abstract in Portuguese
O protocolo de teste/reteste no labirinto em cruz elevado (LCE) mostra que a experiência prévia no labirinto produz alterações duradouras nas respostas comportamentais de roedores. Nesse contexto, ratos submetidos ao LCE pela primeira vez apresentam um aumento característico na exploração dos braços abertos e uma redução dos comportamentos de avaliação de risco após a administração de drogas ansiolíticas. Na reexposição ao labirinto, porém, essas drogas tornam-se ineficazes em alterar as medidas tradicionais do LCE. Esse fenômeno foi inicialmente observado com o benzodiazepínico clordiazepóxido e referido como one-trial tolerance (tolerância de um ensaio OTT). A proposta do presente estudo é compreender a OTT por meio do exame dos fatores hormonais, cognitivos e neuroanatômicos envolvidos nesse fenômeno. A administração sistêmica do benzodiazepínico midazolam ou de metirapona, um bloqueador da síntese de glicocorticóides, reduziu a frequência dos comportamentos de avaliação de risco e dos níveis plasmáticos de corticosterona quando injetados antes das sessões teste ou reteste. Além disso, a reexposição de ratos ao LCE foi caracterizada por uma avaliação de risco mais proeminente, de acordo com a análise fatorial, e pela ativação de estruturas límbicas envolvidas com aspectos cognitivos do medo, como a região ventral do córtex pré-frontal medial (CPFm) e a amígdala, mostrada por meio da distribuição da proteína Fos. Midazolam administrado antes da primeira exposição ao LCE produziu uma redução significativa do número de neurônios Fos-positivos no córtex cingulado anterior, área 1 (Cg1) e nos núcleos anterior e pré-mamilar dorsal do hipotálamo. Por outro lado, midazolam causou uma redução no número de neurônios Fos-positivos no CPFm, amígdala, núcleo dorsomedial do hipotálamo e núcleos da rafe em ratos reexpostos ao LCE. Cg1 foi a única estrutura-alvo do benzodiazepínico em ambas as sessões. Resultados comportamentais similares aos produzidos pelo tratamento sistêmico foram obtidos com infusões de midazolam intra-Cg1. Esses resultados apontam para um papel crucial dos comportamentos de avaliação de risco no desenvolvimento da OTT e indicam o Cg1 como um importante sítio de ação ansiolítica dos benzodiazepínicos em roedores.
Title in English
Hormonal, cognitive and neuroanatomical factors associated with the exploratory behavior of rats submitted to the test and retest session in the elevated plus maze
Keywords in English
anterior cingulate cortex
benzodiazepines
corticosterone
elevated plus maze
Fos protein
retest session
Abstract in English
The elevated plus maze (EPM) test/retest protocol has shown that prior experience to the maze produces enduring changes in behavioral responses of rodents. In this context, rats submitted for the first time to the EPM display a characteristic increase in open arm exploration and reduced risk assessment behaviors after the administration of anxiolytic drugs. Upon re-exposure to the maze, however, these drugs become unable to change the traditional measures of the EPM. This phenomenon was initially observed with the benzodiazepine chlordiazepoxide and referred to as one-trial tolerance (OTT). The purpose of the present study is to understand the OTT through the exam of the hormonal, cognitive and neuroanatomical factors involved in this phenomenon. The systemic administration of the benzodiazepine midazolam or metyrapone, a glucocorticoids synthesis blocker, reduced the frequency of risk assessment behaviors and the corticosterone levels when injected before the test or retest sessions. Moreover, the re-exposure of rats to the EPM was characterized by more prominent risk assessment behaviors, according to the factor analysis, and by activation of limbic structures involved with cognitive aspects of fear, such as the ventral regions of the medial prefrontal cortex (mPFC) and amygdala, as shown through the distribution of the Fos protein. Midazolam injected before the first exposure to the EPM produced a significant decrease in the number of Fos-positive neurons in the anterior cingulate cortex, area 1 (Cg1), anterior and dorsal premammillary nuclei of hypothalamus. On the other hand, midazolam caused a decrease in the number of Fos-positive neurons in the mPFC, amygdala, dorsomedial nucleus of hypothalamus and raphe nuclei in rats re-exposed to the EPM. Cg1 was the only structure targeted by the benzodiazepine in both sessions. Behavioral results similar to those produced by systemic treatment were obtained with intra-Cg1 infusions of midazolam. These results point to a crucial role of the risk assessment behaviors in the development of the OTT and indicate the Cg1 as an important locus for the anxiolytic-like action of benzodiazepines in rodents.
 
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Publishing Date
2011-06-14
 
WARNING: The material described below relates to works resulting from this thesis or dissertation. The contents of these works are the author's responsibility.
  • ALBRECHET-SOUZA, L., et al. The anterior cingulate cortex is a target structure for the anxiolytic-like effects of benzodiazepines assessed by repeated exposure to the elevated plus maze and Fos immunoreactivity [doi:10.1016/j.neuroscience.2009.08.038]. Neuroscience [online], 2009, vol. 164, n. 2, p. 387-397.
  • ALBRECHET-SOUZA, Lucas, et al. Increases in plasma corticosterone and stretched-attend postures in rats naive and previously exposed to the elevated plus-maze are sensitive to the anxiolytic-like effects of midazolam [doi:10.1016/j.yhbeh.2007.05.002]. Hormones and Behavior [online], 2007, vol. 52, n. 2, p. 267-273.
  • ALBRECHET-SOUZA, Lucas, and BRANDãO, Marcus. Hormonal and cognitive factors associated with the exploratory behavior of rats submitted to repeated sessions of the elevated plus-maze [doi:10.3922/j.psns.2010.1.005]. Psychology and Neuroscience [online], 2010, vol. 3, n. 1, p. 43-52.
  • ALBRECHET-SOUZA, Lucas, BORELLI, Karina G., and BRANDãO, Marcus L.. Activity of the medial prefrontal cortex and amygdala underlies one-trial tolerance of rats in the elevated plus-maze [doi:10.1016/j.jneumeth.2007.11.025]. Journal of Neuroscience Methods [online], 2008, vol. 169, n. 1, p. 109-118.
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