These results support the hypothesis that both OrxR1 and OrxR2 play significant roles in drug self-administration and the reinstatement of drug-seeking behavior (Plaza-Zabala et al., 2012, 2013; Uslaner et al., 2014), further implicating the Orx system in maladaptive motivation, reflected by an increase in the motivation to drink and seek alcohol during dependence (Moorman and Aston-Jones, 2009; Moorman et al., 2017). This evidence concerns the gene HCRTR1 and substance dependence.