Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin.

The hypocretins/orexins modulate behavioral state as well as a variety of state-dependent behaviors. Levels of hypocretin-1 and prepro-hypocretin mRNA vary in a circadian fashion, suggesting that hypocretin neurotransmission may vary across the circadian cycle. To better assess the circadian dependency of the behavioral actions of hypocretin-1, the behavioral effects of intracerebroventricular hypocretin-1 administration (3.0 nmol/2 microl) were examined at differing portions of the circadian cycle, when animals display either low levels of waking (light-period) or high levels of waking (dark-period). In addition, mediation analyses were conducted to better assess the contribution of the wake-promoting actions to other behavioral actions of hypocretin-1. During the light-period, hypocretin-1 administration increased time spent awake, grooming, feeding, locomotor activity and chewing of inedible material, a stress-related behavior. Comparable effects of hypocretin-1 on time spent awake, locomotor activity and the chewing of inedible material were observed during the dark-period. In contrast, hypocretin-1-induced feeding and drinking appeared largely circadian-dependent: hypocretin-1 had minimal effects on these behaviors during the dark-period. Hypocretin-1-induced increases in grooming appeared moderately circadian-dependent. These observations suggest that the previously described ability of hypocretin to increase feeding and drinking during the light-period may reflect, at least in part, a general behavioral activation associated with waking. Results from the mediation analyses support these conclusions, indicating that hypocretin-1-induced increases in waking largely account for hypocretin-1-induced increases in feeding and drinking. Additionally, given that chewing and grooming are stress-related behaviors, these observations provide further support for a possible function of HCRT in stress.