Role of the Hypocretin (Orexin) Receptor 2 (Hcrt-r2) in the Regulation of Hypocretin Level and Cataplexy

Abstract

Hypocretin receptor-2 (Hcrt-r2) mutated dogs exhibit all the major symptoms of human narcolepsy and respond to drugs that increase or decrease cataplexy as do narcoleptic humans, yet, unlike narcoleptic humans, the narcoleptic dogs have normal hypocretin levels. We find that drugs that reduce or increase cataplexy in the narcoleptic dogs, greatly increase and decrease, respectively, hypocretin levels in normal dogs. The effect of these drugs on heart rate and blood pressure, which were considerable, were not correlated with their effects on cataplexy. Administration of these drugs to Hcrt-r2 mutated dogs produced indistinguishable changes in heart rate and blood pressure, indicating that neither central nor peripheral Hcrt-r2 is required for these cardiovascular effects. However, in contrast to the marked Hcrt level changes in the normal dogs, these drugs did not alter hypocretin levels in the Hcrt-r2 mutants. We conclude that Hcrt-r2 is a vital element in a feedback loop integrating Hcrt, acetylcholine and norepinephrine function. In the absence of functional Hcrt-r2, Hcrt levels are not affected by monoaminergic and cholinergic drugs, despite the strong modulation of cataplexy by these drugs. Conversely, strong transient reductions of Hcrt level by these drugs do not produce episodes of cataplexy in normal dogs. The Hcrt-r2 mutation causes drug induced cataplexy by virtue of its longterm effect on the functioning of other brain systems, rather than by increasing the magnitude of phasic changes in Hcrt level. A similar mechanism may be operative in spontaneous cataplexy in narcoleptic dogs as well as in narcoleptic humans.

Highly Specific Role of Hypocretin (Orexin) Neurons: Differential Activation as a Function of Diurnal Phase, Operant Reinforcement versus Operant Avoidance and Light Level

“…Recent work shows that the dysfunction of Hcrt neurons causes a reorganization of other brain systems that is at least to some extent maladaptive. Our recent findings(Wu et al, 2011) showed that the Hcrt mutant narcoleptic dog has an abnormal response to activation of cholinergic and adrenergic receptors. Sharf et al, (Sharf et al, 2010) found that the KOs had deficits not seen when Hcrt receptors were completely blocked acutely.…”

Mechanistic insights into influenza vaccine-associated narcolepsy

“…The crucial HCRT receptors for this feedback suggested by Wu and colleagues 38 may be on HCRT neurons, and a recent in vitro study 39 demonstrated that such autoreceptors exists and are excitatory. Alternatively, or in addition, crucial receptors may be on non-HCRT cells, which produce an excitatory feedback excitation of HCRT cells 40 .…”

“…Finally, Wu and colleagues 38 in 2011 concluded that, HCRTr2 is a vital element in a feedback loop integrating HCRT, acetylcholine, and norepinephrine function. In the absence of functional HCRTr2 [in canine narcolepsy], HCRT levels were not affected by monoaminergic and cholinergic drugs [prazosin, physostigmine, methamphetamine, labetalol, and phenylephrine], despite the strong modulation of cataplexy by these drugs.…”

Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction

“…Some of these conflicts may stem from the limited temporal resolution of the Fos technique, which reflects activity occurring over the entire 2 h period prior to sacrifice. Others may be due to species differences and the brain reorganization that occurs in Hcrt mutant animals 6 .…”