Thomas Thorne
ABSTRACT
Hypocretins (orexins) are a recently identified family of peptides composed of two peptides, hypocretin-1 and hypocretin-2. Recent observations suggest an involvement of these peptides in the regulation of behavioral state. For example, these peptides are found in a variety of brain regions associated with the regulation of forebrain neural and behavioral activity states. Furthermore, when infused into the lateral ventricles of awake animals, hypocretin-1 causes increased duration of awakening beyond that observed in vehicle-treated animals.
Previous studies have been limited to an examination of the effects of hypocretin-1 during sleep and wakefulness in awake animals. Currently, the effects of hypocretin-2 during sleep and wakefulness and the extent to which hypocretins can initiate wakefulness in the sleeping animal remain unclear. To better characterize the wake-promoting actions of hypocretins, the current studies examined the sleep-wake effects of different doses (0.007, 0.07, and 0.7 nmol) of hypocretin-1 and hypocretin-2 when administered to sleeping rats (e.g., remotely controlled animals). infusions).Infusions of hypocretin-1 and hypocretin-2 into the lateral ventricles caused a short-latency increase (0.7 nmol hypocretin-1; 93+/-30 s from the start of the 120 s infusion) in electroencephalographic values , electromyographic and waking behavior indices. These infusions also produced substantial reductions in slow-wave and rapid eye movement sleep.
Hypocretin-1 was more potent than hypocretin-2 in these actions. Interestingly, hypocretin-1 infused into the fourth ventricle caused less intense arousal that occurred with a longer latency than infusions into the lateral ventricles. These latter observations suggest that a forebrain site of action is involved in hypocretin-induced wakefulness. -1. Within the forebrain, a variety of basal forebrain structures, including the medial preoptic area, medial septal area, and substantia innominata, receive moderate hypocretin innervation.
Therefore, additional studies examined the sleep-wake effects of bilateral hypocretin-1 infusions in these basal forebrain structures. Strong increases in wakefulness were observed following infusions within, but not outside, the medial septal area, medial preoptic area, and substantia innominate. These results indicate a potentially prominent role for hypocretins in sleep-wake regulation through actions within certain basal forebrain structures and are consistent with studies indicating a prominent role for hypocretins in sleep/arousal disorders.