Modulação dopaminérgica da memória operacional espacial no córtex pré-frontal medial em ratos: envolvimento de receptores dos tipos D1 e D4

• Ano de defesa: 2008
• Autor(a) principal: Valentim Junior, Saavedra José Rios
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal do Espírito Santo; BR; Doutorado em Ciências Fisiológicas; Centro de Ciências da Saúde; UFES; Programa de Pós-Graduação em Ciências Fisiológicas
• Palavras-chave em Português: Sistema Dopaminérgico; Sistema Glutamatérgico; Córtex Pré-Frontal Medial; Memória Operacional; Labirinto Radial; Fisiologia; 612
• Link de acesso: http://repositorio.ufes.br/handle/10/5162

The prefrontal cortex (PFC) is thought to be the anatomical site for working memory. Its medial region (mPFC) receives massive dopaminergic projections from ventral tegmental area through the mesocortical dopaminergic pathway. Dopaminergic activity is highly related to working memory function and the modulation of N-methyl-D18 aspartate (NMDA) receptors seem to be critical in these processes. Thefore, this study investigated the involvement of dopamine D1 receptors and its interaction with NMDA receptors in the medial prefrontal cortex (mPFC) on spatial working memory. Male Wistar rats with bilateral cannulae implanted in the mPFC (B: + 2,5 mm AP; +/- 1 mm L; - 2,7 mm V) were trained in the radial maze procedure and received intracortical administrations of the D1 selective agonist, SKF38393 [SKF: 0 (SAL); 0,56; 1,8; 5,6 µg], or D2/D4 antagonist, clozapine [0 (HCl 0,05N); 0,32; 1,0; 3,2 µg] , 10 min before the administration of MK-801 [MK: 0 (sal); 0,32; 1,0 or 3,2 µg]. After 5 min, animals were tested in 1-h delayed tasks in the radial maze. The effect of the administration of the D1 selective antagonist, SCH23390 [SCH: 0 (SAL) or 1,0 µg] before the SKF (0; 0,56 or 1,8µg), was also investigated. The D1 selective agonist, SKF produced, however, a significant (P < 0,01) increase in number of errors in small doses (0,56 e 1,8 µg) as compared to saline in the 1-h post-delay performance (mostly by reentry of arms visited in the pre-delay performance). This result suggests that the acute activation of D1 receptor located in mPFC impairs the long-term visuospatial working memory. The non-competitive antagonist of NMDA receptor, MK, disrupted the animals performance only at 1,0 µg dose (P < 0,05) (mostly by reentry of arms visited in the pre-delay performance). The lowest and highest dose did not differ from the control. This result suggests that the NMDA receptor blockade promotes an inverted U shaped modulation on working memory. SKF-38393, but not SCH-23390, administered into the mPFC increased the number of errors (mostly by reentry of arms visited in the pre-delay performance) in the 1-h post-delay performance at doses of 0.56 or 1.8 µg, but not at the highest dose. SCH-23390 1.0 µg blocked and MK-801 1.0 µg reversed the disruptive effect of SKF-38393 0.56 or 1.8 µg. The atypical antipsychotic, CZP, an antagonist of D2 and D4 receptors, did not alter working memory. Otherwise, their combination at 3,2 µg dose with 1,0 µg of MK increased the number of errors (mostly by reentry of arms visited in the pre-delay performance) as compared to the control treatment (P < 0,05) and also to others doses of CZP (0,32 and 1,0 µg) (P < 0,05). These results suggest that the blockade of D2 /D4 and NMDA receptors, simultaneously, are implicated in the impairment of this cognitive process. These results show that dopamine D1 receptors activation in the mPFC may disrupt the retention and/or recall of information in long-term delay. This impairment was blocked by dopamine D1 receptors antagonist and reversed by a non-competitive NMDA receptor antagonist, suggesting that dopamine D1 receptors and their interaction with NMDA receptors in the mPFC are crucial for adequate spatial working memory processing.