Hyperactivity and memory/learning deficits evoked by developmental exposure to nicotine and/or ethanol are mitigated by cAMP and cGMP signaling cascades activation

Abstract

Pregnant smoking women are frequently episodic drinkers. Here, we investigated whether ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to nicotine aggravates memory/learning deficits and hyperactivity, and associated cAMP and cGMP signaling disruption. To further investigate the role of these signaling cascades, we verified whether vinpocetine (a phosphodiesterase inhibitor) ameliorates the neurochemical and behavioral outcomes. Swiss mice had free access to nicotine (NIC, 50 μg/ml) or water to drink during gestation and until the 8th postnatal day (PN8). Ethanol (ETOH, 5 g/kg, i.p.) or saline were injected in the pups every other day from PN2 to PN8. At PN30, animals either received vinpocetine (20 mg/kg, i.p.) or vehicle before being tested in the step-down passive avoidance or open field. Memory/learning was impaired in NIC, ETOH and NIC + ETOH mice, and vinpocetine mitigated ETOH- and NIC + ETOH-induced deficits. Locomotor hyperactivity identified in ETOH and NIC + ETOH mice was ameliorated by vinpocetine. While cyclic nucleotides levels in cerebral cortex and hippocampus were reduced by NIC, ETOH and NIC + ETOH, this outcome was more consistent in the latter group. As observed for behavior, vinpocetine normalized NIC + ETOH nucleotides levels. pCREB levels were also increased in response to vinpocetine, with stronger effects in the NIC + ETOH group. Exposure to both drugs of abuse worsens behavioral and neurochemical disruption. These findings and the amelioration of deleterious effects by vinpocetine support the idea that cAMP and cGMP signaling contribute to nicotine- and ethanol-induced hyperactivity and memory/learning deficits.

Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress

“…Vinpocetine was suspended in 0.5% w/v carboxymethylcellulose (CMC) and was administered orally with the help of oral gavage in two doses (10 mg.kg À1 and 20 mg.kg À1 ; p.o.) (Abreu-Villaça et al, 2018;Guly as, Halldin, S ov ag o, et al, 2002;Ishola et al, 2018;Shibota et al, 1982).…”

“…In line with these observations, in our study vinpocetine administration resulted in amelioration of behavioral deficits produced by prenatal exposure to VPA. Vinpocetine is known to improve cAMP and cGMP levels and their common downstream component pCREB levels via the cAMP/CREB and PKG pathway in both cerebral cortex and hippocampus, areas of brain indicated to play a major role in locomotor activity (Abreu-Villaça et al, 2018). As impairments in social behavior and stereotypical behavior have previously been linked with reduced expression of synapsins (Provenzano et al, 2015), pCREB, BDNF (Xu et al, 2019) and DCX (Stephenson et al, 2011) in rodents.…”

“…Vinpocetine has been shown to correct primary deficits such as social behavior and repetitive behavior in a rodent model of entorhinal cortex lesion (Nyakas et al, 2009). Also, behavioral deficits, such as anxiety, hyperactivity/hyper‐locomotion and nociception were found to be mitigated in murine models of, schizophrenia, attention deficit hyperactivity disorder and inflammatory pain (Abreu‐Villaça et al, 2018; Ahmed et al, 2018; Ruiz‐miyazawa, Pinho‐ribeiro, et al, 2015). Further, PDE1 inhibition is known to ameliorate several neurochemical deficits, such as brain inflammation, brain oxidative stress and neuronal dysfunction, in rodent models of fetal alcohol syndrome, Huntington's disease and early ethanol exposure (Gupta & Sharma, 2014; Krahe et al, 2009; Swart et al, 2017).…”

Papaverine ameliorates prenatal alcohol‐induced experimental attention deficit hyperactivity disorder by regulating neuronal function, inflammation, and oxidative stress

“…In utero exposure to alcohol resulted in development of ADHD‐associated abnormalities in behaviour and biochemical markers of neuronal health possibly via the suppression of cAMP/pCREB pathway (Abreu‐Villaça et al., 2018; Nunes et al., 2011). It is widely accepted that the low central levels of pCREB and BDNF are associated with PAE in models of foetal alcohol syndrome (Caldwell et al., 2008; Mahabir et al., 2018).…”

Ethanol exposure during the brain growth spurt period increases ethanol‐induced aggressive behavior in adolescent male mice

“…In humans, the brain growth spurt period occurs during the third trimester of gestation when ethanol consumption frequently occurs (Ethen et al., 2009). Animal studies indicate that ethanol exposure during the brain growth spurt period evokes locomotor hyperactivity and learning and memory deficits, which are typical adverse behavioral outcomes of FASD (Abreu‐Villaça et al., 2018; Cristina‐Rodrigues et al., 2020; Filgueiras, Krahe, & Medina, 2010; Nunes et al., 2011). We recently reported that ethanol exposure during the brain growth spurt period impairs social behavior in adolescent males (Demarque et al., 2020).…”