Inhibition of cholinergic muscarinic signaling by ethanol: Potential mechanism of developmental neurotoxicity and biological plausibility for the beneficial effects of choline supplementation

Abstract

Costa, L., Giordano, G., & Guizzetti, M. (2013). Inhibition of cholinergic muscarinic signaling by ethanol: Potential mechanism of developmental neurotoxicity and biological plausibility for the beneficial effects of choline supplementation. The International Journal Of Alcohol And Drug Research, 2(3), 17-25. doi:10.7895/ijadr.v2i3.72 (http://dx.doi.org/10.7895/ijadr.v2i3.72)Central nervous system dysfunctions are among the most significant effects of in utero exposure to ethanol. Ethanol has been shown to affect neurons and glial cells, causing cell loss and impaired cell migration and maturation. Multiple mechanisms have been suggested to underlie the effects of ethanol, including interference with growth factors, cytokines, cell adhesion molecules and neurotransmitters. Here, we propose that a relevant mechanism of ethanol’s developmental neurotoxicity may be its ability to inhibit the actions of acetylcholine in the developing nervous system mediated by activation of cholinergic muscarinic receptors. Acetylcholine has been shown to induce proliferation of astrocytes, to protect neurons against apoptotic cell death, and to foster astrocyte-neuronal interactions, thereby increasing neuritogenesis. By interfering with muscarinic receptor signal transduction pathways (mostly at the level of phospholipase D), ethanol inhibits all these effects of acetylcholine in the developing brain. Such action of ethanol may be responsible, at least in part, for some manifestations of developmental neurotoxicity, such as microencephaly, neuronal cell death and impaired neuronal differentiation. Among potential therapeutic interventions for fetal alcohol spectrum disorders, choline supplementation appears to be one of the most promising. The cholinergic hypothesis of ethanol’s developmental neurotoxicity provides biological plausibility for the beneficial effects of choline. Indeed, by “potentiating” the cholinergic system during development (through increased synthesis of acetylcholine and phosphatidylcholine, and increased phospholipase D activity), choline would antagonize at least some of the deleterious effects of ethanol.