Expressão gênica de receptores e da catalase no circuito de recompensa de camundongos sensibilizados e não sensibilizados aos efeitos estimulantes do etanol

• Ano de defesa: 2009
• Autor(a) principal: Goeldner, Francine Oliveira [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Atividade motora/efeitos de drogas; Catalase/genética; Catalase/metabolismo; Receptores dopaminérgicos/genética; Receptores glutamatérgicos/genética; Receptores serotonérgicos/genética; Etanol
• Link de acesso: http://repositorio.unifesp.br/handle/11600/9624

Among the neuroadaptations that may contribute to the development of alcohol dependence is behavioral sensitization - defined as an increase in the locomotor or stimulant effect after repeated administration of the same dose of ethanol (ETOH) or other drugs. This phenomenon occurs due to the repeated activation of the brain reward circuit, involving projections of the dopaminergic mesocorticolimbic pathway. However, this process does not occur in the same way in all organisms treated with ETOH. In this study we evaluated if the repeated administration of ethanol could trigger different profiles of gene expression that could be associated with different behavioral patterns of sensitization development. After 21 days of treatment, ETOH-treated mice were classified into sensitized or non-sensitized, according to their locomotor activity during treatment. We compared the mRNA and protein expression of dopamine transporter and of D1 and D2 (long and short isoforms) receptors, of A and B subunits of 5-TH3 receptor, of NR2A and NR2B subunits of NMDA receptor, and of catalase enzyme in the ventral tegmental area (VTA), nucleus accumbens (NAc), amygdala (AMY), and medial prefrontal cortex (mPFC) of the sensitized, non-sensitized and control (treated with saline) mice. In VTA, we observed higher D1 and D2 receptors protein expression, higher D2 isoforms and 5-HT3A and 3B subunits gene expression, and higher catalase activity in the sensitized group than in the non-sensitized and control groups. In the mPFC, we observed lower mRNA and protein expression of NR2A and NR2B subunits in the non-sensitized group than in the sensitized and control groups. In separate experiments, similar procedures were carried out, with mice treated with association of ETOH with aminotriazole, catalase inhibitor. Aminotriazole led to a decrease in the intensity of ethanol behavioral sensitization in sensitized mice and to an increase in the locomotor activity in the nonsensitized group. In the mPFC, we detected lower gene and protein expression of NR2A and NR2B subunits in the non-sensitized group than in the sensitized and control groups. In another experiment, mice treated with the association ETOH and aminotriazole (catalase inhibitor) for 21 days showed lower intensity of behavioral sensitization than animals treated with ethanol alone. In another study, the administration of ondansetron (5-HT3 receptor antagonist) thirty minutes before that of ethanol reduced its stimulant effect in animals sensitized to the stimulant effect of ethanol. These data suggest that the effects of ethanol on dopaminergic neurotransmission in the VTA, but not in the mPFC, AMY or NAC, could be related to the susceptibility to the development of behavioral sensitization to ethanol.