Differential effects of the hypocretin 1 receptor antagonist SB 334867 on high‐fat food self‐administration and reinstatement of food seeking in rats

Background and purpose: Many studies have demonstrated a role of hypocretin 1 (orexin 1) receptors in home‐cage food consumption in rodents. However, the role of these receptors in operant food self‐administration or relapse to food seeking in animal models is unknown. Experimental approach: In Experiment 1, we trained food‐restricted rats (16–20 g per day) to lever press for high‐fat (35%) pellets (3–6 h per day, every other day). We then tested the effect of the hypocretin 1 receptor antagonist SB 334867 (10, 20 mg kg −1 , i.p) on pellet self‐administration. In Experiment 2, we trained rats to self‐administer the food pellets, and following extinction of the food‐reinforced responding, we tested the effect of hypocretin 1 (3 and 6 μg, i.c.v) on reinstatement of food‐seeking and the effect of SB 334867 on this reinstatement. In Experiment 3, we tested the effect of SB 334867 on reinstatement induced by non‐contingent pellet exposure (pellet‐priming) or the pharmacological stressor yohimbine (2 mg kg −1 , i.p). Key results: SB 334867 attenuated high‐fat pellet self‐administration. In contrast, SB 334867 had no effect on reinstatement of lever presses induced by hypocretin 1, pellet‐priming or yohimbine. Conclusions and implications: These data indicate that during dieting, hypocretin 1 receptors contribute to operant high‐fat pellet self‐administration, but not to relapse to food seeking induced by acute re‐exposure to the food itself or by the induction of a stress‐like state. British Journal of Pharmacology (2008) 154 , 406–416; doi: 10.1038/bjp.2008.3 ; published online 28 January 2008