Nucleus Accumbens Shell and mPFC but Not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking

Abstract

Addiction to alcohol remains a major social and economic problem, in part because of the high motivation for alcohol that humans exhibit and the hazardous binge intake this promotes. Orexin-1-type receptors (OX1Rs) promote reward intake under conditions of strong drives for reward, including excessive alcohol intake. While systemic modulation of OX1Rs can alter alcohol drinking, the brain regions that mediate this OX1R enhancement of excessive drinking remain unknown. Given the importance of the nucleus accumbens (NAc) and anterior insular cortex (aINS) in driving many addictive behaviors, including OX1Rs within these regions, we examined the importance of OX1Rs in these regions on excessive alcohol drinking in C57BL/6 mice during limited-access alcohol drinking in the dark cycle. Inhibition of OX1Rs with the widely used SB-334867 within the medial NAc Shell (mNAsh) significantly reduced drinking of alcohol, with no effect on saccharin intake, and no effect on alcohol consumption when infused above the mNAsh. In contrast, intra-mNAsh infusion of the orexin-2 receptor TCS-OX2-29 had no impact on alcohol drinking. In addition, OX1R inhibition within the aINS had no effect on excessive drinking, which was surprising given the importance of aINS-NAc circuits in promoting alcohol consumption and the role for aINS OX1Rs in driving nicotine intake. However, OX1R inhibition within the mPFC did reduce alcohol drinking, indicating cortical OXR involvement in promoting intake. Also, in support of the critical role for mNAsh OX1Rs, SB within the mNAsh also significantly reduced operant alcohol self-administration in rats. Finally, orexin ex vivo enhanced firing in mNAsh neurons from alcohol-drinking mice, with no effect on evoked EPSCs or input resistance; a similar orexin increase in firing without a change in input resistance was observed in alcohol-naïve mice. Taken together, our results suggest that OX1Rs within the mNAsh and mPFC, but not the aINS, play a central role in driving excessive alcohol drinking.

Different Molecular/Behavioral Endophenotypes in C57BL/6J Mice Predict the Impact of OX1 Receptor Blockade on Binge-Like Ethanol Intake

“…Further, OX1r antagonism/blockade reduced voluntary EtOH self-administration in rats selectively bred for high EtOH preference (Anderson et al, 2014 ) and EtOH binge-drinking in C57BL/6J mice (Anderson et al, 2014 ; Carvajal et al, 2015 ; Olney et al, 2015 ). Taking into account first, the particular function of OX1r within the medial NAcc Shell, a key region involved in EtOH consumption in both mice and rats (Lei et al, 2016 ), and second, previous literature showing a role for OX activity in high EtOH drinkers, additional studies combining regional OX molecular characterization with appetitive, rather than consummatory behavior testing, will help to understand how endophenotype differences in NAcc mRNA OXr expression links to potential endophenotype differences in EtOH seeking.…”

Neuroanatomical Relationships between Orexin/Hypocretin-Containing Neurons/Nerve Fibers and Nicotine-Induced c-Fos-Activated Cells of the Reward-Addiction Neurocircuitry

“…However, the mechanism by which orexinergic innervation of NIC-activated regions of Acb affects NIC- related addictive behavior is not known. Previous studies have shown that orexinergic innervation of Acb could promote feeding, drinking [ 51 ] and drug intake [ 52 ]. Lei et al [ 52 ] have demonstrated that activation of orexin-1 receptors within Acb promotes alcohol intake in mice.…”

“…Previous studies have shown that orexinergic innervation of Acb could promote feeding, drinking [ 51 ] and drug intake [ 52 ]. Lei et al [ 52 ] have demonstrated that activation of orexin-1 receptors within Acb promotes alcohol intake in mice. Others have reported that orexin-A in Acb is involved in feeding and drinking, but not alcohol preference [ 51 ].…”

Orexin/Hypocretin System: Role in Food and Drug Overconsumption

“…The OX1R antagonists reduce drinking in the dark when injected into the nucleus accumbens shell, central nucleus of the amygdala, or ventral tegmental area (Lei et al, 2016; Olney, Navarro, & Thiele, 2017) and intermittent access alcohol drinking when injected into the medial prefrontal cortex, but not the anterior insular cortex and substantia nigra (Lei et al, 2016; Srinivasan et al, 2012) or the paraventricular thalamus (Barson et al, 2015). This is in contrast to the OX2R antagonist TCS OX2 29, which reduces two-bottle choice alcohol drinking when injected into the paraventricular thalamus where OX-B increases it to a greater extent than an equimolar dose of OX-A (Barson et al, 2015; Barson et al, 2017), but which has no effect on drinking in the dark when injected into the nucleus accumbens shell, central nucleus of the amygdala, or ventral tegmental area (Lei et al, 2016; Olney et al, 2017). This evidence supports the idea that alcohol drinking is stimulated by OX1R in multiple limbic brain regions, while OX2R is most active in the paraventricular thalamus where it specifically promotes high-level drinking.…”

“…As with home-cage drinking, however, these receptor antagonists appear to exert their effects through different brain regions. This is suggested by the finding that operant self-administration of alcohol is reduced by injection of an OX1R antagonist into the shell of the nucleus accumbens (Lei et al, 2016) but by an OX2R antagonist in the core of the accumbens (Brown, Khoo, & Lawrence, 2013). …”