Nicotine self-administration in the rat: effects of hypocretin antagonists and changes in hypocretin mRNA

Abstract

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.

Fig 1

Effects of pre-session treatment with the selective hcrtR1 antagonist SB334867 (upper panels) and the mixed hcrtR1/2 antagonist almorexant (lower panels) on NSA and food-maintained responding. ^#Different from baseline, p<0.05. *Different from vehicle, p<0.05

Fig 2

(a) The 4 panels show the NSA data over 19-day periods for the 2 groups of animals used in the gene expression studies. Left-hand panels for each group show the total number of lever presses. The right-hand panels show the number of nicotine infusions obtained. The top two panels show data from the group in which brain tissue was collected 5 hr after the last NSA session, while the bottom two panels show data from the group in which tissue was collected immediately (1–11 min) after the final session. (b) Schematic shows the brain regions that were collected by micro-dissection in group 1.

Fig 2

(a) The 4 panels show the NSA data over 19-day periods for the 2 groups of animals used in the gene expression studies. Left-hand panels for each group show the total number of lever presses. The right-hand panels show the number of nicotine infusions obtained. The top two panels show data from the group in which brain tissue was collected 5 hr after the last NSA session, while the bottom two panels show data from the group in which tissue was collected immediately (1–11 min) after the final session. (b) Schematic shows the brain regions that were collected by micro-dissection in group 1.

Fig 3

(a) This figure shows mRNA values for hcrtR1 in the arcuate nucleus (ARC) in NSA and control animals from group 1 (*, p<0.05). (b) mRNA values for hcrtR1 in the rostral lateral hypothalamus (rLH) in NSA and control animals from group 2 (*, p<0.05). Data in both are presented as the mean values; error bars are s.e.m.

Fig 3

(a) This figure shows mRNA values for hcrtR1 in the arcuate nucleus (ARC) in NSA and control animals from group 1 (*, p<0.05). (b) mRNA values for hcrtR1 in the rostral lateral hypothalamus (rLH) in NSA and control animals from group 2 (*, p<0.05). Data in both are presented as the mean values; error bars are s.e.m.