Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat.
Orexins are peptides produced by lateral hypothalamic neurons that exert a prominent role in the maintenance of wakefulness by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptor located in wake-active structures. Pharmacological blockade of both receptors by the dual OX1/2R antagonist (2R)-2-[(1S)-6,7-dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylethanamide (almorexant) has been shown to promote sleep in animals and humans during their active period. However, the selective distribution of OX1R and OX2R in distinct neuronal circuits may result in a differential impact of these receptors in sleep-wake modulation. The respective role of OX1R and OX2R on sleep in correlation with monoamine release was evaluated in rats treated with selective antagonists alone or in combination. When administered in either phase of the light/dark cycle, the OX2R antagonist 1-(2,4-dibromophenyl)-3-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea (JNJ-10397049) decreased the latency for persistent sleep and increased nonrapid eye movement and rapid eye movement sleep time. Almorexant produced less hypnotic activity, whereas the OX1R antagonist 1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea (SB-408124) had no effect. Microdialysis studies showed that either OX2R or OX1/2R antagonism decreased extracellular histamine concentration in the lateral hypothalamus, whereas both OX1R and OX1/2R antagonists increased dopamine release in the prefrontal cortex. Finally, coadministration of the OX1R with the OX2R antagonist greatly attenuated the sleep-promoting effects of the OX2R antagonist. These results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system. In addition, it is suggested that simultaneous inhibition of OX1R attenuates the sleep-promoting effects mediated by selective OX2R blockade, possibly correlated with dopaminergic neurotransmission.
Neuroscience, Johnson & Johnson PRD, 3210 Merryfield Row, San Diego, CA 92121, USA. cdugovic@its.jnj.com
Christine
C
Dugovic
Jonathan E
JE
Shelton
Leah E
LE
Aluisio
Ian C
IC
Fraser
Xiaohui
X
Jiang
Steven W
SW
Sutton
Pascal
P
Bonaventure
Sujin
S
Yun
Xiaorong
X
Li
Brian
B
Lord
Curt A
CA
Dvorak
Nicholas I
NI
Carruthers
Timothy W
TW
Lovenberg
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D064446:Orexin Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000502:physiology*; D012890:Sleep / Q000187:drug effects* / Q000502:physiology*
D000081:Acetamides; C578626:HCRTR2 protein, human; C578627:Hcrtr1 protein, rat; D007546:Isoquinolines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C519150:almorexant