Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone

Abstract

The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4–6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking “drive”.

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

“…The doses of ALM and ZOL used in the present study (100 mg/kg, p.o) were chosen because they have roughly equivalent sleep induction efficacy in rats and, for ALM, result in high occupancy of both Hcrt receptors (Morairty et al, 2012(Morairty et al, , 2014. Both ALM and ZOL significantly decreased the latency to first NREM sleep bout relative to VEH (18.6 ± 2.6 min for ALM, 16.1 ± 3.9 min for ZOL vs 36.7 ± 7.6 min for VEH; po0.05 for both comparisons with VEH) in rats left undisturbed after dosing.…”

Homeostatic Sleep Pressure is the Primary Factor for Activation of Cortical nNOS/NK1 Neurons

“…Surgical procedures involved implantation of sterile telemetry transmitters (F40-EET, Data Sciences International, St Paul, MN, USA) as previously described (Morairty et al, , 2008(Morairty et al, , 2012. Briefly, transmitters were placed intraperitoneally under isoflurane anesthesia.…”

“…Behavioral state determinations and data analyses were conducted as previously described (Morairty et al, , 2012. After at least 3-week postsurgical recovery, EEG and EMG were recorded via telemetry using DQ ART 4.1 software (Data Sciences International).…”

“…in 2 ml/kg for both drugs. Perfusion occurred at ZT14 for VEH and ZOL groups and at ZT14.5 for ALM groups due to its longer latency to sleep onset (Black et al, 2013;Morairty et al, 2012Morairty et al, , 2014. Rats in the high sleep pressure conditions were sleep deprived during the 6 h prior to dosing (Figure 1).…”

Orexin deficiency and narcolepsy

“…Rather, the OXR-1 antagonist attenuated the sleep-promoting effects of the OXR-2 antagonist when simultaneously administered, possibly by increasing dopamine release in the prefrontal cortex. On the other hand, another report suggested that a DORA is more effective for sleep promotion than antagonism of either receptor alone (42). Further research using selective antagonists is required to conclude the effectiveness, advantages and disadvantages of these compounds.…”