The RyR antagonist dantrolene reduces cocaine (Kurokawa et al., 2011) and methamphetamine (Kurokawa et al., 2010) induced conditioned place preference, ethanol withdrawal symptoms (Kurokawa et al., 2013) and motivation to self-administer ethanol after chronic exposure in a dose-dependent manner in rats (Supplementary Figure S9), but these studies are limited by the nonspecificity of dantrolene, an antagonist of both ryanodine and inositol triphosphate receptors, the latter functioning upstream of RyR activation. In myocytes, RyRs provide the Ca2+ ions that activate BK channels (Lifshitz et al., 2011), which have strong effects on ethanol response in vivo and in vitro (Davies et al., 2003; Martin et al., 2008). Ethanol modulates BK channel function in a calcium-dependent manner (Liu et al., 2008) and we hypothesize that RyRs may be involved in this calcium-dependent modulation of BK channel function.
