PDE-4 inhibitors, rolipram or Ro 20–1724, reduces ethanol intake and preference in mice. Rolipram also decreases ethanol consumption in Fawn-Hooded rats (Wen et al., 2012). Another study testing nine PDE inhibitors with different subtype selectivity shows that only the PDE-4 selective inhibitors reduce ethanol intake and preference (Blednov et al., 2014b). Roflumilast is another PDE-4 inhibitor that decreases ethanol consumption in mice (Liu et al., 2017). Rats genetically bred for high ethanol consumption also show reduced drinking in response to PDE-4 inhibition (Franklin et al., 2015). Apremilast, a PDE-4 inhibitor that is FDA-approved for the treatment of psoriasis and has less emetic activity than other PDE-4 inhibitors, reduces ethanol consumption and preference in male and female mice in different drinking tests (Blednov et al., 2018b). Apremilast also alters the acute behavioral effects of ethanol in mice, causing increased sedation, intoxication, and reduced acute functional tolerance, which may contribute to its ability to decrease drinking (Blednov et al., 2018a). PDE-4 may also regulate negative emotional states induced by ethanol abstinence; for example, rolipram produces anxiolytic- and antidepressant-like effects in acute, repeated, or protracted ethanol abstinence states in rodents (Gong et al., 2017). Jabaris et al. (2015) showed that low doses of
