The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders

Abstract

The hypocretin/orexin (ORX) system has been repeatedly demonstrated to regulate motivation for drugs of abuse, including alcohol. In particular, ORX seems to be critically involved in highly motivated behaviors, as is observed in high-seeking individuals in a population, in the seeking of highly palatable substances, and in models of dependence. It seems logical that this system could be considered as a potential target for treatment for addiction, particularly alcohol addiction, as ORX pharmacological manipulations significantly reduce drinking. However, the ORX system also plays a role in a wide range of other behaviors, emotions, and physiological functions and is disrupted in a number of non-dependence-associated disorders. It is therefore important to consider how the ORX system might be optimally targeted for potential treatment for alcohol use disorders either in combination with or separate from its role in other functions or diseases. This review will focus on the role of ORX in alcohol-associated behaviors and whether and how this system could be targeted to treat alcohol use disorders while avoiding impacts on other ORX-relevant functions. A brief overview of the ORX system will be followed by a discussion of some of the factors that makes it particularly intriguing as a target for alcohol addiction treatment, a consideration of some potential challenges associated with targeting this system and, finally, some future directions to optimize new treatments.

Moderate Prenatal Ethanol Exposure Stimulates CXCL12/CXCR4 Chemokine System in Radial Glia Progenitor Cells in Hypothalamic Neuroepithelium and Peptide Neurons in Lateral Hypothalamus of the Embryo and Postnatal Offspring

“…These include differences in their anatomical distribution, with Hcrt/OX neurons denser in the medial area and MCH neurons denser in the lateral area of the LH (de Lecea et al, ; Sakurai et al, ), and also in their responses to the inflammatory agent liposaccharide (Palomba et al, ) and their coexpression of the peptide cocaine‐ and amphetamine‐regulated transcript (Jancsik et al, ). These Hcrt/OX and MCH neurons also differ in their functional activity, signaling through distinct electrical pathways to promote addictive‐like behaviors (DiLeone et al, ; Diniz and Bittencourt, ; Moorman, ). With the CXCL12/CXCR4 axis shown to modulate electrical excitability of peptide‐expressing neurons (Guyon et al, ), it may have differential effects on the signaling of Hcrt/OX and MCH neurons, with stronger effects on Hcrt/OX system due to its greater colocalization.…”

Embryonic Ethanol Exposure Affects the Early Development, Migration, and Location of Hypocretin/Orexin Neurons in Zebrafish

“…With hcrt neurons known to interact with a number of different neurotransmitter systems (Elbaz et al., ), these EtOH‐induced changes in anatomical location are likely to alter the functional connectivity with these other systems. The fibers of hcrt neurons are found in zebrafish (Kaslin et al., ) and rats (Baimel and Borgland, ; Moorman, ) to project toward clusters of dopaminergic neurons, a circuit shown to mediate reward‐related behaviors (Baimel and Borgland, ). With the IH (Ren et al., ) and PT (Tay et al., ) in zebrafish known to contain dopaminergic neurons that regulate reward and are functionally homologous to the mammalian mesodiencephalic dopamine system (Kastenhuber et al., ), the increased presence and close proximity of hcrt neurons in these 2 areas in EtOH fish may facilitate their signaling with dopaminergic neurons, possibly more on the left side of the brain where positive stimuli are believed to promote reward behaviors (Davidson, ).…”

“…Hypocretin/orexin (hcrt), an orexigenic neuropeptide expressed in a population of hypothalamic neurons, is known to be involved in promoting substance abuse and related behaviors such as increased EtOH consumption, arousal, anxiety, motivation, and stress (Li et al., ), suggesting that this neuropeptide is a potential therapeutic target for preventing the development of alcohol use disorder (Moorman, ). Studies in rats demonstrate that maternal EtOH consumption at low doses stimulates drinking in offspring and increases the expression and density of hcrt neurons (Chang et al., , ), and hypothalamic injection of this neuropeptide in adults increases EtOH intake and related emotional behaviors (Barson et al., ).…”

Orexin/hypocretin and dysregulated eating: Promotion of foraging behavior

“…With its varied behavioral effects, the precise underlying role of OX remains elusive. Several laboratories have hypothesized that OX serves to promote motivation in highly salient environmental contexts, and have suggested that an OX-based pharmacotherapy could be ideal for treating behaviors like reinstatement of extinguished drug seeking (Espana 2012, James et al 2017, Moorman 2018, as it would affect excessive but not homeostatic behavior. Interestingly, research reviewed here on the role of OX in feeding, even dysregulated feeding that resembles addiction, indicates that the conditions under which OX promotes this behavior are different than those under which it promotes drug use.…”