Rationale-Recent studies suggest that orexin/hypocretin is involved in drug reward and drugseeking behaviors, including ethanol self-administration. However, orexin's role in ethanolinduced 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 ethanolstimulated 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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In order to alleviate the problem of drug addiction, it is essential to identify the neurobiological substrates that regulate the behavioral effects of these drugs. Inducible transcription factors, such as c‐FOS, are reliable markers for neuronal activity, which reveal brain regions affected by a particular drug. It has been shown that the non‐preganglionic Edinger‐Westphal nucleus (npEW), the main source of urocortin (Ucn) in the brain, is preferentially sensitive to ethanol. Animals with higher levels of Ucn in npEW show greater preference for ethanol and lesions of this nucleus block ethanol preference, indicating that npEW is involved in regulation of alcohol intake. The current study compared the response of npEW neurons to interperitoneal injections of ethanol (2.5 g/kg), cocaine (30 mg/kg), and methamphetamine (10 mg/kg) in male C57BL/6J mice. The immunohistochemical analysis shows that cocaine and ethanol, but not methamphetamine, induce c‐FOS in npEW. Double‐immunohistochemistry confirmed that c‐FOS induction occurred in Ucn‐containing neurons. The lack of npEW response to methamphetamine was not due to insufficient dose because other brain regions (the VTA and nucleus accumbens) were more responsive to this drug than cocaine or ethanol. These results point to npEW as a target of drug action, and potentially a critical region for drug addiction. Support: NIH grants AA013738 and AA016647