Ethanol can be considered a weak drug when compared to most other drugs of abuse. The molecule of ethanol has no asymmetric carbon. Being so, it does not interact with the biological substrates in a stereoselective way as most of the receptor ligand drugs do. Moreover, ethanol has a very simple chemical structure. Thus, the hydroxyl group provides a dipole that allows the formation of hydrogen bonds. It is the formation of hydrogen bonds that makes ethanol soluble in water. In contrast, ethanol presents an aliphatic moiety that provides a lipophilic group that can interact with non-polar cellular elements. However, contrary to what it is generally believed, ethanol has low lipid solubility. All these chemical properties of ethanol have led different authors to consider the first oxidative metabolite of ethanol as the biologically active compound. Nonetheless, ethanol produces quite complex effects on neuronal systems. Behavioral changes observed after ethanol administration are produced within very short periods of time (< 5 min). In this respect mobilization and/or modulation of some of these described ethanol neuronal substrates, requires reorganization of protein structures and/or in some cases early gene expression. It is unlikely that ethanol actions after acute administered are explained by processes such as induction of gene expression or new protein synthesis. As such, primary ethanol interactions among the neuronal substrate must be mediated by cellular mechanisms that can be controlled and triggered almost immediately. Interestingly, one of these posttranscriptional mechanisms that lead to protein modification is the phosphorylation, carried out by the activity of protein kinases. They represent one of the major classes of cell-regulatory molecules and are important mediators in signal-transduction pathways that affect cell physiology and behavior. In this respect, most of the previously described ethanol molecular targets require posttranscriptional phosphorylation to be fully active (DARPP-32, Fyn, etc). One key protein kinase that has been described as an important mediator involved in the neurobehavioral responses to ethanol is the cAMP dependent protein kinase (PKA). This kinase is the end point of a cAMP-dependent intracellular pathway. Moreover, this cAMP-dependent cascade is conformed by different intermediates that are Ca2+ sensitive (Hanoune and Defer, 2001, Nelson et al., 2003; Cali et al., 1994; Wang et al., 2003, Maas et al., 2005). All together, this pathway is conformed by different elements that control and modulate the activity of the PKA. The activated PKA transmits information rapidly across the cell and promotes changes in the cellular machinery and also is involved in the modulation of several ethanol neurobehavioral effects. Manipulations of the cAMP-dependent cascade modulate the acute stimulant effects of ethanol, ethanol-induced behavioral sensitization (Freund and Palmer, 1997; Tolliver et al., 1999; Hayes et al., 2012), ethanol sensitivity (Thiele et al., 2000; Wand et al., 2001), and ethanol intake (Pandey et al., 2005). Given this, in the present work we aimed to study the role of cellular Ca2+ distribution and flux on the modulation of a PKA/cAMP-dependent cascade as an ethanol central mechanism of action.