The orexin system regulates alcohol-seeking in rats

Abstract

1. Orexin-containing neurons have been implicated in feeding, sleep-wake cycles and more recently in drug-seeking behaviour. 2. Pretreatment of alcohol-preferring (iP) rats with an orexin1 receptor antagonist (SB-334867, 20 mg kg(-1), intraperitoneally) completely abolished an olfactory cue-induced reinstatement of alcohol-seeking behaviour, and also attenuated alcohol responding under an operant fixed ratio regimen without affecting water responding. 3. The mRNA encoding orexin within the hypothalamus was expressed at a similar density in iP and non-preferring (NP) rats; chronic consumption of ethanol in iP rats did not significantly regulate the density of this expression, but did increase the area of expression within the lateral, but not medial, hypothalamus. 4. These data indicate that while orexin may not be implicated in the development of an alcohol preference, re-exposure of cues previously associated with alcohol availability is sufficient and adequate to activate orexin-containing neurons and drive reinstatement of alcohol-seeking.

Figures

Figure 1

Extinction and cue-induced reinstatement of alcohol-seeking in iP rats (n=12). SB-334867 (20 mg kg−1, i.p.) specifically abolishes responding for alcohol (a), without affecting responding for water (b) upon reinstatement. Statistical analysis was performed using one-way ANOVA with Student–Newman–Keuls post hoc tests. Data are mean±s.e.m. *P<0.05 compared to extinction; #P<0.05 compared to vehicle.

Figure 2

Operant responding for 10% ethanol and water in iP rats (n=11) under an FR3 schedule. SB-334867 (20 mg kg−1, i.p.) reduces operant responding for ethanol (a) and consumption of ethanol (c) without impacting upon responding for water (b) or consumption of water (d). Data are mean±s.e.m. *P<0.05 compared to vehicle, one-way ANOVA with Student–Newman–Keuls post hoc tests.

Figure 3

Expression of the mRNA encoding pre–pro-orexin in iP and NP rat hypothalamus (a). a1 is a representative section from an NP rat, a2 from an alcohol-naïve iP rat and a3 from an iP rat following chronic alcohol consumption. Chronic consumption of ethanol had no impact upon the density of mRNA expression (b), but did increase the area of dense pre–pro-orexin mRNA expression within the lateral hypothalamus (c). Data are mean±s.e.m. (n=6–7 rats/group). *P<0.05, one-way ANOVA with Student–Newman–Keuls post hoc tests.