Rationale The hypocretin (hcrt) system has been implicated in addiction-relevant effects of several drugs, but its role in nicotine dependence has been little studied. Objectives These experiments examined the role of the hcrt system in nicotine reinforcement. Methods Rats were trained for nicotine self-administration (NSA) on fixed-ratio schedules. The effects of acute, presession treatments with the hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant were examined on NSA maintained on a fixed-ratio (FR) 5 schedule. Gene expression for the hcrt system (mRNA for hcrt, hcrtR1, and hcrtR2) was measured in animals following NSA on a FR 1 schedule for a 19-day period. Results The hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant both reduced NSA dose-dependently (significantly at doses of 30 and 300 mg/kg, respectively); SB334867 did not affect food-maintained responding whereas almorexant (at the 300 mg/kg) did. Tissue from animals collected 5 h after self-administration showed an increase in hcrtR1 mRNA in the arcuate nucleus compared to control subjects. In tissue collected immediately after a similar 19-day self-administration period, mRNA for hcrtR1 was decreased in the rostral lateral hypothalamus compared to controls. Conclusions These data confirm a previous report (Hollander et al., Proc Natl Acad Sci U S A 105:19480-19485, 2008) that the hypocretin receptor hcrtR1 is activated in nicotine reinforcement and in addition show that both the arcuate nucleus and lateral hypothalamus are sites at which hcrt receptor mechanisms may influence reinforcement. Different patterns of mRNA expression at different times after NSA suggest that changes in the hcrt system may be labile with time.
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Acknowledgments This research was supported by a grant from the Academic Health Center of the University of Minnesota (Corrigall PI), NIDA grant DA020136 (LeSage PI), and funding from the Department of Veterans Affairs (Kotz PI). We are grateful to Dr. David McKinzie of Eli Lilly and Company for the gift of SB334867 and to Drs. Francois Jenck and Catherine Brisbare-Roch of Actelion Pharmaceuticals Limited for the gift of almorexant. In addition, we acknowledge the expert technical assistance of Martha A. Grace, Jennifer A. Teske, Andrew Kotz, and Mark Margosian.
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