Studies of ethanol interactions with GlyRs are a good example of the bottom-up approach. These studies initially focused on the molecular mechanisms of ethanol’s potentiation of GlyRs (Burgos et al., 2015; Mascia et al., 1996; Mihic, 1999; Perkins et al., 2010) and moved to studies of how ethanol’s effects on GlyRs contribute to changes in circuit function and behavior (Aguayo et al., 2014; Blednov et al., 2012, 2015). Ethanol’s effects on GlyR function have been identified in several brain regions (Badanich et al., 2013; Förstera et al., 2017; McCracken et al., 2017). There is also evidence for a glycinergic “tone” or steady-state receptor activation that can be potentiated by ethanol (Salling and Harrison, 2014; Zhang et al., 2008), but the site and basic mechanisms of glycine release remain unclear. The use of genetically engineered mice with alterations in receptor subunit expression or structure (knockouts and knockins) allow investigators to exploit the bottom-up approach and analyze the behavioral consequences of ethanol’s effects on specific targets. Mice lacking the GlyR alpha 2 subunit show reduced ethanol intake, but GlyR alpha 3 knockout
