Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner

Abstract Orexin ( ORX ) (also known as hypocretin) neurons are located exclusively in the posterior hypothalamus, and are involved in a wide range of behaviours, including motivation for drugs of abuse such as alcohol. Hypothalamic subregions contain functionally distinct populations of ORX neurons that may play different roles in regulating drug‐motivated and alcohol‐motivated behaviours. To investigate the role of ORX neurons in ethanol (Et OH ) seeking, we measured Fos activation of ORX neurons in rats following three different measures of Et OH seeking and preference: (i) context‐induced reinstatement, or ABA renewal; (ii) cue‐induced reinstatement of extinguished responding for Et OH ; and (iii) a home cage task in which preference for Et OH (vs. water) was measured in the absence of either reinforcer. We found significant activation of ORX neurons in multiple subregions across all three behavioural tests. Notably, ORX neuron activation in the lateral hypothalamus correlated with the degree of seeking in context reinstatement and the degree of preference in home cage preference testing. In addition, Fos activation in ORX neurons in the dorsomedial hypothalamic and perifornical areas was correlated with context and home cage seeking/preference, respectively. Surprisingly, we found no relationship between the degree of cue‐induced reinstatement and ORX neuron activation in any region, despite robust activation overall during reinstatement. These results demonstrate a strong relationship between ORX neuron activation and Et OH seeking/preference, but one that is differentially expressed across ORX field subregions, depending on reinstatement modality.