Orexin-1 receptor antagonism does not reduce the rewarding potency of cocaine in Swiss–Webster mice

The orexin family of hypothalamic neuropeptides has been implicated in reinforcement mechanisms relevant to both food and drug reward. Previous behavioral studies with antagonists at the orexin A-selective receptor, OX1, have demonstrated its involvement in behavioral sensitization, conditioned place-preference, and self-administration of drugs of abuse. Adult male Swiss–Webster mice were implanted with stimulating electrodes to the lateral hypothalamus and trained to perform intracranial self-stimulation (ICSS). The effects of the OX1-selective antagonist SB 334867 on brain stimulation-reward (BSR) and cocaine potentiation of BSR were measured. SB 334867 (10–30 mg/kg, i.p.) alone had no effect on ICSS performance or BSR threshold. Cocaine (1.0–30 mg/kg i.p.) dose-dependently potentiated BSR, measured as lowering of BSR threshold. This effect was not blocked by 30 mg/kg SB 334867 at any cocaine dose tested. In agreement with previous reports, SB 334867 resulted in a reduction of body weight 24 h after acute administration. Based on these data, it is concluded that orexins acting at OX1 do not contribute to BSR; and are not involved in the reward-potentiating actions of cocaine on BSR. The data are discussed in the context of prior findings of SB 334867 effects on drug-seeking and drug-consuming behaviors.

► Orexin signaling is involved in the rewarding effects of drugs of abuse. ► Effects of the OX1 receptor antagonist SB 334867 were investigated in outbred mice. ► SB 334867 does not affect electrical brain stimulation reward (BSR) in mice. ► SB 334867 does not block the ability of cocaine to potentiate BSR in mice.