On the other hand, several lines of evidence suggest that the physiological effects of acute ethanol oppose or are antagonized by the EC system. For instance, EC release from medium-spiny neurons in the dorsomedial striatum is associated with a long-lasting disinhibition of these cells, and this effect is blocked by pre-treatment with ethanol (50 mM) via a pre-synaptic mechanism that is independent of EC synthesis and CB1 activation (Clarke and Adermark, 2010). Additionally, activation of CB1 by WIN is sufficient to block the pre-synaptic facilitation of GABAergic signaling on pyramidal neurons (PNs) in the central amygdala that is produced by acutely applied ethanol (Roberto et al., 2010). This effect of ethanol is likely due to presynaptic signal transduction mechanisms that converge with and oppose those of CB1 activation. Studies of cerebellar purkinje neurons have found that ethanol facilitates GABA release from pre-synaptic terminals via a PKA-dependent mechanism that liberates Ca2+ from internal stores and does not require EC synthesis (Kelm et al., 2007). However, activation of CB1 blocks the enhancement IPSC frequency by ethanol in these neurons leading the authors
