Hypocretin/orexin in arousal and stress

Abstract

Multiple lines of evidence indicate that hypocretin/orexin (HCRT) participates in the regulation of arousal and arousal-related process. For example, HCRT axons and receptors are found within a variety of arousal-related systems. Moreover, when administered centrally, HCRT exerts robust wake-promoting actions. Finally, a dysregulation of HCRT neurotransmission is associated with the sleep/arousal disorder, narcolepsy. Combined, these observations suggested that HCRT might be a key transmitter system in the regulation of waking. Nonetheless, subsequent evidence indicates that HCRT may not play a prominent role in the initiation of normal waking. Instead HCRT may participate in a variety of processes such as consolidation of waking and/or coupling metabolic state with behavioral state. Additionally, substantial evidence suggests a potential involvement of HCRT in high-arousal conditions, including stress. Thus, HCRT neurotransmission is closely linked to high-arousal conditions, including stress, and HCRT administration exerts a variety of stress-like physiological and behavioral effects that are superimposed on HCRT-induced increases in arousal. Combined, this evidence suggests the hypothesis that HCRT may participate in behavioral responding under high-arousal aversive conditions. Importantly, these actions of HCRT may not be limited to stress. Like stress, appetitive conditions are associated with elevated arousal levels and a stress-like activation of various physiological systems. These and other observations suggest that HCRT may, at least in part, exert affectively neutral actions that are important under high-arousal conditions associated with elevated motivation and/or need for action.

Figure 1

Wake-promoting effects of HCRT-1 infused into the lateral ventricle (Lv; Panel A), the fourth ventricle (IVv; Panel B) and the medial preoptic area (MPOA; Panel C). Symbols represent mean (± SEM) time (sec) spent awake per 30-min epoch. PRE1 and PRE2 represent pre-infusion epochs and POST1-POST3 represent post-infusion epochs. In all panels, vehicle-treated animals spent the majority of the testing period asleep. Panel A: HCRT-1 produces dose-dependent increases in waking, with significant increases observed at 0.07 and 0.7 nmol. Panel B: 0.07 nmol infusion of HCRT-1 produces a smaller magnitude in waking when infused into the fourth ventricle as compared to infusion into the lateral ventricle. Additionally, HCRT-induced waking following infusions into the fourth ventricle occurred with a longer latency than that observed following lateral ventricle infusions. Thus, latency to waking following fourth ventricular infusion of HCRT was 320 ± 40 sec from start of 120-sec infusion (Range = 216-416 sec) while the latency to waking following infusions into the lateral ventricle was 191 ± 48 sec from the start of the infusion (Range = 123-375 sec). Panel C: When infused bilaterally into the MPOA (250 nl/hemisphere), HCRT-1 produced a robust increase in waking similar to that seen with ICV infusions. Qualitatively similar effects were observed with HCRT-1 infusions into the medial septal area and substantia innominata. For all panels *P<0.01 significantly different from vehicle-treated animals. Modified from (España et al., 2001).

Figure 2

Effects of varying behavioral state/environmental conditions on the percentage of Fos-immunoreactive (ir) nuclei within hypocretin-synthesizing neurons (prepro-HCRT-ir) and hypocretin-1 receptor-expressing neurons (HCRTr1-ir). Shown are percentage Fos-positive HCRT neurons from diurnal sleeping (SLP), diurnal spontaneous waking (DSW), nocturnal spontaneous waking (NSW) and novelty-stress (STR) conditions. Neither diurnal sleeping nor diurnal spontaneous waking was associated with an increase in the percentage of Fos-ir within prepro-HCRT-ir neurons in LH. Nocturnal spontaneous waking was associated with a slight, yet significant, increase in the percentage of Fos-ir within prepro-HCRT-ir neurons. In contrast, novelty-stress produced a significantly higher percentage of Fos-ir within prepro-HCRT-ir relative to diurnal sleeping, diurnal spontaneous waking and nocturnal spontaneous waking. Within HCRTr1-ir neurons, only novelty-stress was associated with increased levels of Fos-ir. ⁺P < 0.05; ⁺⁺P < 0.01 significantly different from diurnal sleeping. **P < 0.01 significantly different from group indicated by brackets. Modified from (España et al., 2003).

Figure 3

Effects of pretreatment with the CRF antagonist, alpha-helical CRF_12-41, on HCRT-induced waking. Shown are the effects of vehicle pretreatment followed by a vehicle infusion (V + V), vehicle pretreatment followed by a 0.7 nmol HCRT infusion (V + 0.7), 1.5 nmol alpha-helical CRF pretreatment followed by a 0.7 nmol HCRT infusion (1.5 + 0.7) and 15.0 nmol alpha-helical CRF pretreatment followed by a 0.7 nmol HCRT infusion (15.0 + 0.7). All infusions were ICV (2 μl volume over 2-minutes). HCRT-1 preceded by vehicle pretreatment, significantly increased waking relative to vehicle-vehicle treatment (V+0.7 vs V+V). Pretreatment with alpha-helical CRF, resulted in a dose-dependent attenuation of HCRT-induced waking. *P<0.05; **P<0.01 significantly different from V + V; ⁺P < 0.01 significantly different from V + 0.7. (España and Berridge, unpublished observations).