Orexin / hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking

Abstract

The orexin/hypocretin system is involved in several addiction-related behaviors. In the present experiments, we examined the involvement of orexin in heroin reinforcement and relapse by administering the orexin 1 receptor antagonist SB-334867 prior to heroin self-administration or prior to cue-induced or heroin-induced reinstatement of extinguished heroin seeking in male Sprague Dawley rats. SB-334867 (30 mg/kg, intraperitoneal) reduced heroin intake during self-administration under fixed ratio-1 and progressive ratio schedules. SB-334867 also attenuated reinstatement of heroin seeking elicited by cues, but not reinstatement elicited by a heroin prime. These results indicate that orexin antagonism reduces heroin self-administration, and they support a role for orexin in cue-triggered drug relapse.

© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Figures

Figure 1

Heroin self-administration under a fixed ratio-1 (FR-1; 20-sec timeout) schedule of reinforcement is reduced by the OX1R antagonist SB-334867 at 30 mg/kg. A) When administered prior to the tenth session of self-administration, SB-334867 reduced the mean number of heroin infusions earned (0.02 mg/inf), as compared to the sessions before and after (n=14; ***p<0.001). B) Heroin intake for individual animals shows a consistent effect of SB-334867 among all subjects. C) SB-334867 also reduced active lever presses on Session 10 of self-administration, as compared to Sessions 8, 9, and 12 (**p<0.01), but had no effect on inactive lever presses.

Figure 2

Heroin self-administration under a progressive ratio (PR) schedule of reinforcement is reduced by the OX1R antagonist SB-334867 at 30 mg/kg, but not 10 mg/kg. A) SB-334867 reduced the breakpoint (or last step completed) for heroin PR self-administration (0.02 mg/inf) as compared to vehicle (n=10; *p<0.05). To reduce total heroin exposure, some early PR steps were omitted, so that a modified step sequence was used (1, 4, 7, 8, 9, 10…, as shown on left y-axis). Corresponding ratios for each step are shown on the right y-axis. B) SB-334867 did not significantly affect the time of the last infusion (when the breakpoint occurred), indicating a slower rate of intake overall.

Figure 3

Reinstatement elicited by cues, but not a heroin prime, is attenuated by the OX1R antagonist SB-334867 at 30 mg/kg. A) SB-334867 attenuated cue-induced reinstatement of extinguished heroin seeking at 30 mg/kg (n=13; *p<0.05), but not 10 mg/kg, (n=13), as compared to vehicle. Extinction (ext) levels of responding prior to reinstatement are also shown. B) SB-334867 had no significant effect on heroin-induced reinstatement when administered at 10 mg/kg (n=8) or 30 mg/kg (n=9).

Figure 4

Time courses for the number of heroin infusions (A, B) or active lever presses (C, D) during A) fixed ratio-1 (FR-1) self-administration (n=14), B) progressive ratio (PR) self-administration (n=10), C) cue-induced reinstatement of extinguished heroin seeking (n=13), and D) heroin-induced reinstatement (n=9), following administration of SB-334867 (30 mg/kg) or vehicle. Significant overall effects are indicated by # (## p<0.01, ### p<0.001, n.s. = not significant), and significant post-hoc effects for individual time bins are indicated by * (*p<0.05, **p<0.01).