Binge‐Like Consumption of Ethanol and Other Salient Reinforcers is Blocked by Orexin‐1 Receptor Inhibition and Leads to a Reduction of Hypothalamic Orexin Immunoreactivity

Abstract

Background Orexin (OX) neurons originating in the lateral hypothalamus (LH) are ideally positioned to modulate reward processing as they form connections with several key brain regions known to be involved in the reward pathway. Consistent with these findings, a growing number of studies have implicated the OX system in modulating the rewarding properties of several drugs of abuse, including ethanol (EtOH). However, the role of the OX system in excessive binge-like EtOH intake remains relatively unexplored. Here, we assessed changes in OX immunoreactivity (IR) in the hypothalamus following repeated cycles of binge-like EtOH drinking and assessed the participation of the OX-1 receptor (OX1R) in binge-like EtOH consumption. Methods The drinking-in-the-dark (DID) paradigm was used to model binge-like EtOH drinking in male C57BL/6J mice. In the first experiment, mice experienced 1 or 3 cycles of binge-like EtOH or sucrose drinking with DID procedures to assess changes in OX IR in distinct subregions of the hypothalamus. Subsequent experiments examined binge-like EtOH and saccharin drinking following peripheral injections of 0.0, 5.0, or 10.0 mg/kg SB-334867 (SB), a selective OX1R antagonist. Finally, mice were given peripheral injections of SB and open-field locomotor activity was measured. Results Relative to water drinking controls, binge-like consumption of EtOH and sucrose resulted in a marked reduction in OX IR in the LH. Inhibition of the OX1R via SB blunted EtOH and saccharin drinking, but did not alter open-field locomotor activity. Conclusions Our observed reduction in OX IR in the LH indicates that the OX system in engaged during binge-like consumption of EtOH and sucrose. The observation that inhibition of the OX1R signaling blunted binge-like EtOH, and saccharin drinking suggests that reward-related OX circuits originating in the LH participate in the consumption of salient reinforcers regardless of calories.

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

“…The models include either the two-bottle choice procedure that provides 24-hour access to water plus 10-20% alcohol for 3 days per week (Carnicella, Ron, & Barak, 2014) or the “drinking in the dark” model that replaces the water bottle with a bottle of 20% alcohol for 2 to 4 hours (Thiele, Crabbe, & Boehm, 2014). With these intermittent access paradigms, peripheral administration of the OX1R antagonists SB-334867 and GSK1059865 are found to reduce alcohol intake and preference in both rats and mice (Lopez, Moorman, Aston-Jones, & Becker, 2016; Moorman & Aston-Jones, 2009; Olney, Navarro, & Thiele, 2015). Similarly, SB-334867 inhibits the lower-level drinking obtained from ad libitum home cage access (Anderson, Becker, Adams, Jesudason, & Rorick-Kehn, 2014).…”

“…While OX activity is inhibited by acute alcohol at a very high dose that promotes sleep (Sharma, Sahota, & Thakkar, 2014), similar to its inhibition after a physiological rise in glucose levels (Burdakov et al, 2005), gene expression and peptide levels of OX are significantly increased by alcohol administered at lower doses (Morganstern et al, 2010). Similarly, in response to voluntary intake, OX gene expression is stimulated during the first 30 minutes following the start of intake (Barson et al, 2015; Lawrence et al, 2006; Sterling, Karatayev, Chang, Algava, & Leibowitz, 2015) but is subsequently unaffected or reduced along with OX peptide levels over the next several hours (Morganstern et al, 2010; Olney et al, 2015, 2017). This time-dependent shift in the effects of alcohol on OX, a stimulation followed by a suppression, may help to explain why individuals engage in alcohol binge sessions of a discrete duration (Carnicella et al, 2014), with drinking continuing until blood alcohol levels are sufficiently high to alter behavior and then ceasing until blood levels have significantly declined.…”

The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice

“…In particular, ORX plays an important function in driving the seeking of drugs of abuse, including alcohol (Baimel et al, 2015; Brown and Lawrence, 2013; Lawrence, 2010; Mahler et al, 2012). The orexin peptide is increased in some animal models of alcohol drinking and decreased in others (Lawrence et al, 2006; Morganstern et al, 2010; Olney et al, 2015), and ORX neurons are activated following reinstatement of alcohol seeking (Dayas et al, 2008; Hamlin et al, 2007). Antagonism of the OX1R decreases alcohol drinking, notably in higher-drinking alcohol-preferring animals (Anderson et al, 2014; Moorman and Aston-Jones, 2009; Olney et al, 2015), decreases self-administration, progressive-ratio, and reinstatement of alcohol seeking (Jupp et al, 2011; Lawrence et al, 2006; Martin-Fardon and Weiss, 2014a; Richards et al, 2008).…”

Do Orexins contribute to impulsivity-driven binge consumption of rewarding stimulus and transition to drug/food dependence?

“…Second, consistent with a role for OX in impulsivity-like behaviors, the OXr1 antagonist SB-334867 peripherally administered regulated impulsive behavior under both baseline and cocaine-stimulated conditions in a dynorphin-sensitive manner in food-restricted rats, as measured by premature responses exhibited in the 5-choice serial reaction time task (5-CSRTT) (Muschamp et al, 2014). Third, recent studies have highlighted the role of OX system in binge-like consumption of rewarding stimulus (sucrose, saccharin and ethanol) in non-dependent animals (Alcaraz-Iborra et al, 2014;Anderson et al, 2014;Olney et al, 2015) as measured by the Drinking in the Dark (DID) paradigm, a wellestablished procedure to reproduce pre-dependent episodes of human binge consumption patterns in mice (Thiele and Navarro, 2014). Thus, the OXr1 antagonist SB-334867 reduced sucrose, saccharin (AlcarazIborra et al, 2014) and ethanol (Anderson et al, 2014;Olney et al, 2015) binge-like drinking when administered peripherally and ethanol binge-like drinking when centrally infused (Carvajal et al, 2015) in non-deprived mice.…”

“…Third, recent studies have highlighted the role of OX system in binge-like consumption of rewarding stimulus (sucrose, saccharin and ethanol) in non-dependent animals (Alcaraz-Iborra et al, 2014;Anderson et al, 2014;Olney et al, 2015) as measured by the Drinking in the Dark (DID) paradigm, a wellestablished procedure to reproduce pre-dependent episodes of human binge consumption patterns in mice (Thiele and Navarro, 2014). Thus, the OXr1 antagonist SB-334867 reduced sucrose, saccharin (AlcarazIborra et al, 2014) and ethanol (Anderson et al, 2014;Olney et al, 2015) binge-like drinking when administered peripherally and ethanol binge-like drinking when centrally infused (Carvajal et al, 2015) in non-deprived mice. Moreover, additional to pharmacological studies, in our lab we observed that following 4 repetitive episodes of bingelike consumption of both sucrose and saccharin, OX mRNA expression was dampened in the lateral hypothalamus (LH), suggesting a shortterm adaptive and compensatory reduction of OX synthesis in response to binge-like consumption (Alcaraz-Iborra et al, 2014).…”