Role of orexin/hypocretin in conditioned sucrose-seeking in female rats

Abstract

The orexin/hypocretin system has recently been implicated in reward-seeking, especially for highly salient food and drug rewards. Given that eating disorders affect women more than men, we reasoned that the orexin system may be strongly engaged in female rats, and during periods of food restriction as we recently reported in male rats. Therefore, the present study examined the involvement of the orexin system in operant responding for sucrose, and in cue-induced reinstatement of extinguished sucrose-seeking, in ad libitum fed vs. food-restricted female subjects. Female Sprague Dawley rats were trained to self-administer sucrose pellets, and we determined the effects of pretreatment with the OxR1 receptor antagonist SB 334867 (SB; 10-30 mg/kg) on fixed ratio (FR) sucrose self-administration, and on cue-induced reinstatement of extinguished sucrose-seeking. SB decreased sucrose self-administration in food-restricted but not in ad libitum-fed females. SB did not alter active lever responding during cue-induced reinstatement of sucrose-seeking in either feeding group. These results confirm our previous results in male rats that signaling at the OxR1 receptor is involved in the sucrose reinforcement and self-administration in food-restricted subjects. However, the finding that SB is ineffective at attenuating cue-induced reinstatement in females, but was effective in food-restricted males, leads us to conclude that food seeking induced by conditioned stimuli engages the orexin system differentially in males and females.

Keywords: Conditioned stimuli; Females; Obesity; Orexin; Palatable food; Reward-based feeding.

Figure 1

Operant lever responding for sucrose in food-restricted and ad libitumfed female rats. Food-restricted female rats (n = 20) exhibited more active presses (p < 0.001) and obtained more sucrose pellets (p < 0.001) than ad libitum females (n = 24) during FR1 self-administration. There was no difference in the number of inactive presses between groups.

Figure 2

Attenuation of fixed ratio responding for sucrose in food-restricted female rats by the OxR1 antagonist SB-334867 (SB). Rats were pretreated with SB or vehicle 30 min prior to the self-administration session. SB 30 mg/kg reduced active lever presses in food-restricted rats (p < 0.05) compared to vehicle treated rats. SB had no significant effect on the number of sucrose pellets obtained or on inactive lever presses in food-restricted or ad libitum fed rats. * p < 0.01 versus vehicle injection.

Figure 3

Progressive ratio responding for sucrose was not affected in females by pretreatment with the OxR1 antagonist SB-334867 (SB). Rats were pretreated with SB or vehicle 30 min prior to the progressive ratio (PR) session. SB had no effect on PR breakpoint in food-restricted or ad libitum fed rats.

Figure 4

Cue-induced reinstatement of sucrose-seeking in female rats was not affected by pretreatment with the OxR1 antagonist SB-334867 (SB). In a within-subject design, female rats were pretreated with SB (30 mg/kg) or vehicle 30 min prior to late extinction sessions (no cues or sucrose) or cue-induced reinstatement (tone + light cues). SB increased active pressing during extinction (p < 0.05) regardless of food-restriction. Both ad libitum-fed and food-restricted females showed increased active lever responding following vehicle + cues (reinstatement session) compared to vehicle + no cues (late extinction session), and food-restricted rats showed greater reinstatement of active lever pressing compared to ad libitum fed rats (p < 0.05). Reinstatement of active lever pressing was not significantly affected in either group by pretreatment with 30 mg/kg SB (n = 18, ad libitum; n = 14 food-restricted). * p < 0.05 versus vehicle injection, # p < 0.05 versus ad libitum fed rats.