Involvement of the orexin/hypocretin system in ethanol conditioned place preference

Rationale: Recent studies suggest that orexin/hypocretin is involved in drug reward and drug-seeking behaviors, including ethanol self-administration. However, orexin's role in ethanol-induced seeking behaviors remains unclear. Objective: These studies examined the role of orexin in the acquisition and expression of ethanol conditioned place preference (CPP) using the orexin 1 receptor (OX1R) antagonist SB-334867. Methods: Effects of SB-334867 (0-30 mg/kg) on locomotor activity were determined in DBA/2J mice (Experiment 1). SB-334867 (0-30 mg/kg) was administered during acquisition of ethanol (2 g/kg) CPP to determine whether orexin signaling is required (Experiment 2). Blood ethanol concentrations (BECs) were measured after ethanol (2 g/kg) injection to determine whether SB-334867 (30 mg/kg) pretreatment altered ethanol pharmacokinetics (Experiment 3). Finally, SB-334867 (0-40 mg/kg) was given before ethanol-free preference testing (Experiments 4 and 5). Results: SB-334867 did not alter basal locomotor activity (Experiment 1). SB-334867 (30 mg/kg) reduced ethanol-induced locomotor stimulation, but did not affect the acquisition of ethanol CPP (Experiment 2) or BEC, suggesting no alteration in ethanol pharmacokinetics (Experiment 3). Although OX1R antagonism blocked expression of a weak ethanol CPP (Experiment 4), it did not affect expression of a moderate to strong CPP (Experiment 5). Conclusions: Blockade of OX1R by systemic administration of SB-334867 reduced ethanol-stimulated activity, but did not affect acquisition or expression of ethanol-induced CPP, suggesting that orexin does not influence ethanol's primary or conditioned rewarding effects. Other neurotransmitter systems may be sufficient to support acquisition and expression of CPP despite alterations in orexin signaling.