Abstract
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.
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Acknowledgments
This research was supported by NIH-NIAAA grants AA007702 and AA007468, ARCS Foundation, and an N.L. Tartar Research Fellowship. We would like to thank Dr. Tara Fidler and Peter Groblewski for their help in conducting Experiment 3 and the Portland Alcohol Research Center Core for assistance with BEC analysis. Experiments 1 and 4 were described in a published abstract and were presented at the Research Society on Alcoholism Annual Meeting in 2009. Portions of these data were also included in a thesis submitted in partial fulfillment of requirements for the Masters of Science Degree at the Oregon Health and Science University.
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Voorhees, C.M., Cunningham, C.L. Involvement of the orexin/hypocretin system in ethanol conditioned place preference. Psychopharmacology 214, 805–818 (2011). https://doi.org/10.1007/s00213-010-2082-6
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DOI: https://doi.org/10.1007/s00213-010-2082-6