Vimpocetina, um inibidor da fosfodiesterase, ameniza hiperatividade e déficits de memória/aprendizado de camundongos expostos à nicotina e etanol no período perinatal

Abstract

Epidemiological studies indicate that there is a strong relationship between smoking and alcohol drinking, so that co-consumption is very frequent. This suggests that the co-use and co-abuse of tobacco and ethanol often occur during pregnancy as well. Developmental exposure to nicotine or ethanol evokes hyperactivity and memory/learning deficits and recent reports indicate that impairments in both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling cascades contribute to these phenotypes. Despite that, there is a lack of studies that investigate the effects of nicotine combined to ethanol during development. Here, we used a mice model to investigate the effects of exposure to nicotine and/or ethanol in the perinatal period on locomotor activity and memory/learning, AMPc, GMPc, total CREB and pCREB levels in the hippocampus and cerebral cortex. Additionally, we investigated the effects of the treatment with vinpocetine, (a phosphodiesterase inhibitor that increases intracellular cAMP and cGMP levels) on these behaviors and biochemical measures. Swiss male and female mice were exposed to nicotine free base (50g/ml) dissolved in saccharin 2% or to saccharin 2% to drink during gestation and until the 8th day of postnatal life (PN8). Ethanol (5g/kg, i.p.) or saline were injected in the pups in alternate days from the 2nd to the 8th day of postnatal life. Accordingly, four groups were analyzed: VEH, NIC, ETOH and NIC+ETOH. At the 30th postnatal day the animals either received vinpocetine (20mg/Kg i.p.) or vehicle before memory/learning was evaluated in the step-down passive avoidance test and object recognition test and locomotor activity was evaluated in the open field. After the behavioral tests, the animals were decapitated and the brain regions fast-frozen and stored until analysis. In the step-down passive avoidance test, there were memory/learning deficits in NIC, ETOH and NIC+ETOH mice and the treatment with vinpocetine mitigated the ETOH and NIC+ETOH-induced deficits. In the object recognition test, short-term memory deficits were identified in the NIC and ETOH groups. These effects were also mitigated by vinpocetine administration. Locomotor hyperactivity was identified only in the NIC+ETOH group. This effect was ameliorated with treatment with vinpocetine. While cyclic nucleotides levels were reduced by NIC, ETOH and NIC+ETOH exposures, this effect was more consistent in the NIC+ETOH group, in which vinpocetine effectively restored cyclic nucleotides levels. pCREB levels were increased in response to vinpocetine administration, with stronger effects in the NIC+ETOH group. These data lend support to the idea that cAMP and cGMP signaling cascades contribute to NIC+ETOH-induced hyperactivity and memory/learning deficits and provide evidence for the potential therapeutic use of vinpocetine in individuals co-exposed to these drugs during development.