Journal
BIOLOGICAL PSYCHIATRY
Volume 67, Issue 8, Pages 753-760Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2009.12.035
Keywords
Food reward; hypocretin; instrumental learning; motivation; orexin; SB-334867
Categories
Funding
- National Institutes of Health [RO1DA017676, F32DA023739, RL1AA017537]
- State of Connecticut, Department of Mental Health and Addiction Services
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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.
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