PKA phosphorylates transcription Erlotinib factors such as CREB (cAMP response element

binding protein), and SRF (serum response factor), leading to the expression of genes that modulate the neuronal excitability and plasticity within brain regions such as the frontal cortex and the hippocampus (Goto and Grace, 2007, Gurden et al., 1999 and Gurden et al., 2000). The deletion of SRF in dopaminoceptive neurons of mice causes a marked locomotor hyperactivity (Parkitna et al., 2010). The PKA inhibition within the medial prefrontal cortex of rats produces inattention and hyperactivity (Paine et al., 2009). Interestingly, ethanol exposure during development can alter several key factors in the cAMP/PKA signaling pathway (Conway and Garbouzova, 1996,

Kumada et al., 2010 and Maas et al., 2005), with long-lasting effects. Neonatal ethanol exposure promotes a reduction in CREB phosphorylation in the adult mice hippocampus (Roberson et al., 2009) and in the visual cortex of ferrets (Krahe et al., 2009). The overexpression of SRF by a Sindbis viral vector long after the period of ethanol exposure restores the ocular dominance plasticity in the visual cortex of a ferret model of FASD (Paul et al., 2010). The use of pharmacological or molecular tools to strengthen this signaling pathway opens up a great therapeutic possibility. Particularly, vinpocetine, a derivative of the Vinca minor alkaloid vincamine, is a phosphodiesterase type 1 (PDE1) inhibitor that has been successfully

used for the treatment Decitabine molecular weight of neurobehavioral problems observed in animal models of FASD (Filgueiras et al., 2010, Krahe et al., 2009, Medina et al., 2006 and Medina, 2011b). The PDE1 inhibition prevents the breakdown of cAMP to 5′-AMP, maintaining activation of protein kinases and transcription factors CREB and SRF (Krahe et al., 2009, Medina and Krahe, 2008 and Paul et al., 2010). Considering that impairments in the cAMP/PKA signaling system may contribute to the hyperactivity observed in FASD, here we investigated whether the acute administration of the PDE1 inhibitor PD184352 (CI-1040) vinpocetine ameliorates the hyperactivity observed in mice exposed to ethanol during the third trimester equivalent of human gestation. Additionally, we investigated whether the cAMP levels in the hippocampus and frontal cortex of adolescent mice are affected by neonatal exposure to ethanol. This study was conducted under institutional approval (protocol#: CEUA/040/2010) of the Universidade do Estado do Rio de Janeiro. All experiments were carried out in compliance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health. Subjects were Swiss mice that were bred and maintained in our laboratory on a 12:12 h light/dark cycle (lights on: 2:00, lights off: 14:00) at a constant temperature (22 °C). Access to food and water was unrestricted. Original breeding stock was obtained from Instituto Vital Brazil (Rio de Janeiro, RJ, Brazil).