Orexin signaling via the orexin 1 receptor mediates operant responding for food reinforcement.
BACKGROUND
Orexin (hypocretin) signaling is implicated in drug addiction and reward, but its role in feeding and food-motivated behavior remains unclear.


METHODS
We investigated orexin's contribution to food-reinforced instrumental responding using an orexin 1 receptor (Ox1r) antagonist, orexin -/- (OKO) and littermate wildtype (WT) mice, and RNAi-mediated knockdown of orexin. C57BL/6J (n = 76) and OKO (n = 39) mice were trained to nose poke for food under a variable ratio schedule of reinforcement. After responding stabilized, a progressive ratio schedule was initiated to evaluate motivation to obtain food reinforcement.


RESULTS
Blockade of Ox1r in C57BL/6J mice impaired performance under both the variable ratio and progressive ratio schedules of reinforcement, indicating impaired motivational processes. In contrast, OKO mice initially demonstrated a delay in acquisition but eventually achieved levels of responding similar to those observed in WT animals. Moreover, OKO mice did not differ from WT mice under a progressive ratio schedule, indicating delayed learning processes but no motivational impairments. Considering the differences between pharmacologic blockade of Ox1r and the OKO mice, animals with RNAi mediated knockdown of orexin were then generated and analyzed to eliminate possible developmental effects of missing orexin. Orexin gene knockdown in the lateral hypothalamus in C57BL/6J mice resulted in blunted performance under both the variable ratio and progressive ratio schedules, resembling data obtained following Ox1r antagonism.


CONCLUSIONS
The behavior seen in OKO mice likely reflects developmental compensation often seen in mutant animals. These data suggest that activation of the Ox1r is a necessary component of food-reinforced responding, motivation, or both in normal mice.
Sharf
Ruth
R
Department of Psychiatry, Ribicoff Research Facilities, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Sarhan
Maysa
M
Brayton
Catherine E
CE
Guarnieri
Douglas J
DJ
Taylor
Jane R
JR
DiLeone
Ralph J
RJ
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D003216:Conditioning, Operant / Q000502:physiology*; D003627:Data Interpretation, Statistical; D005502:Food; D007026:Hypothalamic Area, Lateral / Q000502:physiology; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009287:Naphthyridines; D009479:Neuropeptides / Q000502:physiology*; D064446:Orexin Receptors; D000068797:Orexins; D034622:RNA Interference; D018013:Receptors, Neuropeptide / Q000235:genetics* / Q000502:physiology*; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014780:Viruses / Q000235:genetics
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; C497459:Hcrtr1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D018013:Receptors, Neuropeptide; D014508:Urea