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

Abstract

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.

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

“…In a conditioned place preference paradigm, where mice are conditioned to associate a distinct chamber with experimenter-administered alcohol, the OX2R antagonist JNJ-10397049 attenuates the acquisition, expression, and reinstatement of alcohol conditioned place preference (Shoblock et al, 2011). This is in contrast to the OX1R antagonist SB-334867 which, with the same dose of experimenter-administered alcohol, has no effect on the acquisition of alcohol conditioned place preference and blocks expression only of a weak place preference, but not a moderate or strong one (Voorhees & Cunningham, 2011). This suggests that reward following alcohol intake is primarily mediated by the OX2R.…”

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

“…[199] this may have more to do with mediating the rewarding properties of addictive drugs than the appetitive or drug-seeking phase. This is supported by findings that OX 2 receptor antagonism using JNJ-10397049 reduces CPP for alcohol [116], while OX 1 receptor antagonism does not [200]. A more recent study has also found no change in OX 2 receptor levels following withdrawal from cocaine selfadministration [201].…”

Factors Affecting Ethanol-Induced Conditioned Place Preference and Locomotor Sensitization in Mice

“…[8][9][10][11]29) Thus, the rewarding effects of low-dose/long-term EtOH administration protocols, which may have clinical relevance by modeling the early phase of the progression to alcoholism, are unknown. To this end, we investigated the reward strength of low-dose EtOH using several dose-term regimens with a constant total dose.…”

“…Previous CPP studies have reported that EtOH (2 g/kg for 2 weeks, total dose of 8 g/kg) induced a preference for the chamber associated with its rewarding effects. [8][9][10][11] To assess the rewarding effects of lower doses of EtOH, we administered EtOH (1 g/kg/week) for 4 weeks (medium dose) or EtOH (0.5 g/kg/week) for 8 weeks (low dose) for a total dose of 8 g/kg in both groups. Furthermore, we used Acam, which suppresses alcohol reward preclusively following i.p.…”