Molecular changes in the medial prefrontal cortex and nucleus accumbens are associated with blocking the behavioral sensitization to cocaine

Abstract

Previous studies have demonstrated that cocaine-induced behavioral sensitization is associated with persistent functional and structural alterations in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc); however, the molecular mechanisms underlying these changes have not been elucidated. In this study, the behavioral sensitization to cocaine was established in Sprague Dawley rats and was measured by locomotion and behavioral rating. The brain tissue homogenization was used for measuring the level of brain-derived neurotrophic factor (BDNF), the expression and activity of integrin-linked kinase (ILK), level of protein kinase B (Akt) phosphorylation at serine 473 and threonine 308, and the expression of p75NTR, TrkA, and TrkB protein. The Results showed that cocaine sensitization was associated with increased BDNF, ILK activity, phospho-Akt Ser473, p75NTR, and TrkB protein levels in the mPFC and NAc core. The combination of pergolide and ondansetron normalized not only behavioral sensitization, but also the increases in these molecular markers. Dual immunofluoresence staining showed that ILK expression is co-distributed with p75NTR and TrkA expression in both the mPFC and NAc core. Results suggested that the BDNF-TrkA/p75NTR-ILK-Akt signaling pathway may be active in cocaine sensitization and associated neural plasticity in the mPFC and NAc core.

Inhibition of DNA methyltransferases regulates cocaine self‐administration by rats: a genome‐wide DNA methylation study

“…Growth cone chemoattraction actually requires phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) production and Akt activation (Henle et al 2011) and cocaine-induced structural plasticity of the mesencephalic dopaminergic neurons are directly regulated by the dopamine D3 receptor and ERK/Akt pathways (Collo et al 2012). Moreover, it participates in psychostimulant-induced behavioral sensitization (Zhang et al 2015). Moreover, it participates in psychostimulant-induced behavioral sensitization (Zhang et al 2015).…”

“…In the NAc, hippocampus and PFCx, the Akt/GSK3 signaling pathway is critically implicated in the reconsolidation of cocaine contextual reward memory (Shi et al 2014). Moreover, it participates in psychostimulant-induced behavioral sensitization (Zhang et al 2015). In addition to the Akt pathway, axonal guidance is strongly controlled by the Rho family of GTPases.…”

Prefrontal cortical BDNF: A regulatory key in cocaine- and food-reinforced behaviors

“…, by replacing BDNF tone) has protective benefits during a quite narrow time window. This may be because endogenous BDNF protein and Bdnf mRNA appear to increase in the days and weeks following cocaine exposure, eventually exceeding typical levels (Hearing et al, 2008; McGinty et al 2010; Sadri-Vakili et al, 2010; Zhang et al, 2015) (summarized table 1). …”

“…Additionally, the development of cocaine-induced locomotor sensitization is delayed in Bdnf +/− mice (Horger et al, 1999). Locomotor sensitization can also be blocked by a combination of dopamine D 1 /D 2 receptor and 5-HT 3 receptor antagonists, which interferes with cocaine-induced increases in mPFC BDNF (Zhang et al, 2015). These studies suggest that mPFC BDNF-trkB could support the development and expression of cocaine-induced locomotor sensitization.…”

Efeitos comportamentais do enriquecimento ambiental de curta duração em camundongos: expressão de microRNAs e participação da via de sinalização BDNF - TrkB na sensibilização comportamental ao etanol.

“…Corroborando estes resultados, Nona, Guirguis e Nobrega (2013) obtiveram menores níveis de BDNF e de TrkB no córtex pré-frontal medial de camundongos tratados repetidamente com etanol, mas que não desenvolveram a sensibilização comportamental a esta droga. Ainda,Zhang et al, (2015) encontraram aumento de 66 BDNF e TrkB no córtex pré-frontal medial de ratos que desenvolveram sensibilização comportamental à cocaína, e tal aumento foi inibido com a administração conjunta de pergolida (agonista de receptores dopaminérgicos D1 e D2) e ondansetron (antagonista de receptores serotoninérgicos 5-HT3), que também impediu o desenvolvimento da sensibilização comportamental.Assim, temos que menores níveis de BDNF levariam à menor ativação da via MAPK/ERK, com subsequente diminuição da ativação de CREB e menor expressão de miR-132. Por sua vez, como em uma alça de feedback negativo, miR-132 leva à diminuição dos níveis proteicos de BDNF(Rahimian, He, 2016), o que tem implicações para possíveis futuros experimentos que visem a tentar reverter a sensibilização comportamental ao etanol por meio da aplicação de miR-132 exógeno no córtex préfrontal medial.…”