Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner

Abstract

Orexin (ORX, also known as hypocretin, HRCT) neurons are located exclusively in the posterior hypothalamus and are involved in a wide range of behaviors, including motivation for drugs of abuse such as alcohol. Hypothalamic subregions contain functionally distinct populations of ORX neurons that may play different roles in regulating drug- and alcohol-motivated behaviors. To investigate the role of ORX neurons in alcohol seeking, we measured Fos activation of ORX neurons in rats following three different measures of alcohol seeking and preference: 1) context-induced reinstatement, or ABA renewal, 2) cue-induced reinstatement of extinguished responding for alcohol, and 3) a home cage task in which preference for alcohol (vs. water) was measured in the absence of either reinforcer. We found significant activation of ORX neurons in multiple subregions across all three behavioral tests. Notably, ORX neuron activation in lateral hypothalamus (LH) correlated with the degree of seeking in context reinstatement and degree of preference in home cage preference testing. In addition, Fos activation in ORX neurons in dorsomedial (DMH) and perifornical (PF) areas was correlated with context- and home cage seeking/preference, respectively. Surprisingly, we found no relationship between the degree of cue-induced reinstatement and ORX neuron activation in any region despite robust activation overall during reinstatement. These results demonstrate a strong relationship between ORX neuron activation and alcohol seeking/preference, but one that is differentially expressed across ORX field subregions depending on reinstatement modality.

Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats

“…Our pharmacological results are supported by the observation that activation of specific populations of ORX neurons is correlated with preference for and seeking of a variety of rewards, including alcohol (Hamlin et al, 2008; Harris et al, 2005; Harris et al, 2007; Lasheras et al, 2015; Mahler et al, 2012; Moorman et al, 2016; Richardson and Aston-Jones, 2012). Further, a number of previous studies have shown that the ORX system is particularly involved in elevated motivation for drugs of abuse and natural rewards.…”

“…These results align with findings in ethanol-preferring rats (Jupp et al, 2011; Lawrence et al, 2006), and extend those results to show that the effect of OX1R antagonism on alcohol drinking is maximally efficacious for individuals with high motivation to drink alcohol, compared to those with low motivation. These findings are also consistent with Fos activation of ORX neurons, in which strength of such activation typically correlates with alcohol seeking (Hamlin et al, 2007; Moorman et al, 2016). Taken together, these results indicate that OX1R treatment may be particularly important in individuals prone to alcohol abuse or addiction.…”

“…In previous work we showed that OX1R antagonism decreased homecage ethanol drinking selectively in high-ethanol-preferring animals (Lopez et al, 2016; Moorman and Aston-Jones, 2009), and that activation of specific populations of ORX neurons is correlated with alcohol preference and seeking (Moorman et al, 2016). Here, we extend these findings to demonstrate that SB-334867 treatment decreased both operant self-administration and cue-induced reinstatement of ethanol seeking after extinction selectively in high-, but not low-responding animals.…”

“…Of particular importance, the OX1R has been widely associated with motivation for drugs of abuse, including alcohol (Brown et al, 2013a; Dayas et al, 2008; Jupp et al, 2011; Lawrence et al, 2006; Mahler et al, 2012; Martin-Fardon and Weiss, 2014; Moorman and Aston-Jones, 2009; Moorman et al, 2016). The OX1R-selective antagonist SB-334867 (SB) decreases seeking of multiple drugs of abuse (Bentzley and Aston-Jones, 2015; James et al, 2012; Mahler et al, 2012; Plaza-Zabala et al, 2012; Porter-Stransky et al, 2015).…”

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

“…The activity of OX-expressing neurons is increased prior to voluntary alcohol drinking, consistent with the results of injection studies suggesting that this neuropeptide initiates and promotes alcohol intake. Specifically, levels of c-Fos are increased in OX neurons under conditions that induce relapse of alcohol seeking, including the presentation of an alcohol-paired cue (Dayas, McGranahan, Martin-Fardon, & Weiss, 2008), temporary inactivation of the nucleus accumbens (Millan, Furlong, & McNally, 2010), and placement into an alcohol-paired context (Moorman, James, Kilroy, & Aston-Jones, 2016). In response to alcohol intake, there is a change in OX that varies with dose and across time.…”