Pharmacological blockade of KORs has also been shown to reduce dysphoric-related behaviors associated with ethanol withdrawal. For example, nor-BNI attenuated withdrawal-induced anxiety-like behavior (indexed by time spent in the open arm of an elevated plus maze) in ethanol dependent rats, while having no effect on the same behavior in control (non-dependent) rats (Valdez and Harshberger, 2012). Similar results were reported in mice, with nor-BNI reducing marble-burying behavior during early withdrawal in ethanol dependent mice but not influencing this behavior in control mice (Rose et al., 2016). Another measure of negative affect associated with ethanol withdrawal (increased spontaneous 22-kHz ultrasonic vocalizations) was attenuated by nor-BNI administration in ethanol dependent rats, although these effects were not assessed in non-dependent rats (Berger et al., 2013). Another long-acting KOR antagonist, JDTic, was also shown to block anxiety-like behavior in the elevated plus-maze task during ethanol ‘hangover’ (i.e., acute withdrawal) in non-dependent rats (Schank et al., 2012a). Interestingly, the KOR agonist U50,488 produced anxiety-like behavior in the elevated plus-maze in both dependent and non-dependent rats, but ethanol dependent rats appeared more sensitive to the motor-impairing
