September 2009

Document Type


Degree Name



Dept. of Behavioral Neuroscience


Oregon Health & Science University


Background: Neurons containing the neuropeptide orexin project from the lateral hypothalamus to reward-related areas such as the ventral tegmental area and nucleus accumbens (Harris & Aston-Jones, 2006). Recent studies have highlighted a role for orexin in drug-related behaviors, but investigation of the role of orexin in ethanolconditioned behaviors is lacking. The present experiments investigate orexin involvement 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 on locomotor activity were investigated where animals received 0, 10, 20 or 30 mg/kg IP and activity counts were measured (Experiment 1). SB-334867 was administered during acquisition of ethanol conditioned place preference on trials where DBA/2J mice received 2 g/kg ethanol to determine if orexin signaling is required for the development of ethanol CPP (Experiment 2). Blood ethanol concentrations were also measured from mice receiving SB-334867 or vehicle and 2 g/kg ethanol at 2.5, 10, and 60 min after injection to determine whether SB-334867 altered ethanol pharmacokinetics (Experiment 3). SB-334867 was also given before ethanol-free preference testing in 2 separate experiments to examine the effects of OX1R antagonism on expression of ethanol CPP (Experiments 4 and 5). Results: SB-334867 did not alter basal locomotor activity (Experiment 1). SB-334867 administered during conditioning did not affect the development of ethanol CPP, but at 30 mg/kg, locomotor stimulation to 2 g/kg ethanol was significantly reduced (Experiment 2). SB-334867 pretreatment before ethanol injection increased BEC at 10 min and 60 min post-injection suggesting that SB-334867 alters ethanol pharmacokinetics (Experiment 3). OX1R antagonism blocked the expression of a weak ethanol CPP disrupted by novel handling and pretreatment injection (Experiment 4), but did not affect expression of a strong CPP when animals were habituated to vehicle pretreatment injections (Experiment 5). Conclusions: The present studies indicate that blockade of OX1R by systemic administration of SB-334867 does not affect acquisition or expression of ethanol CPP in DBA/2J mice. Other neurotransmitter systems such as dopamine or glutamate may be sufficient to support acquisition and expression of CPP despite alterations in orexin signaling.




School of Medicine



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