Table 1.

Summary of animal studies showing behavioural effects of orexins in regions involved in the regulation of hedonic tone.

Reference	Effects of Orexin
Nucleus Accumbens
Assar et al., 2019 [79]	Administration of OX1R antagonists reduced acquisition of morphine sensitization OX2R antagonist produced a similar effect, but at a higher dose
Fartootzadeh, 2019 [80]	Administration of OX2R antagonists in NAcc inhibited nicotine-induced increase in neuronal excitation
Lai et al., 2018 [74]	Activation of OX1R by orexin A facilitated sucrose-stimulated DA transmission by increasing the basal activity of VTA DA neurons
Lei et al., 2016 [69]	Administration of OX1R antagonist in the medial NAcc shell and mPFC significantly reduced excessive alcohol intake
Castro et al., 2016 [70]	Orexin enhances sucrose “liking” and intake but scopolamine in the caudal shell shifts “liking” toward “disgust” and “fear”
Liu et al., 2020 [71]	Microinjection orexin-A significantly increased palatable food intake; the effect was inhibited by pretreatment with OX1R antagonist
Mayannavar et al., 2016 [81]	Microinjection of orexin A antagonist in the NAc reduced water and alcohol intake, but did not affect preference to alcohol
Patyal et al., 2012 [73]	Application of Orexin A increased dopamine release in the NAcc shell without altering reuptake at dopamine terminals, indicating that locally released orexin A can modulate dopamine release in NAcc shell
Sahafzadeh et al., 2018 [82]	Administration of OX1R and OX2R antagonists into the NAcc attenuated the effect of food deprivation on morphine reinstatement
Kwok, C et al., 2021 [83]	OX1R inhibition in NAcc shell altered alcohol intake in male, but not female mice. OX1R inhibition reduced compulsion-like alcohol intake in both sexes
Lei, K., et al., 2019 [84]	Activation of OX1Rs promoted alcohol intake during intermittent-access
Ventral Tegmental Area
Azizbeigi et al., 2019 [85]	OX1R antagonist suppressed morphine reinstatement induced by stress or drug priming
Azizbeigi et al., 2019 [86]	OX2R antagonist suppressed morphine reinstatement induced by stress or drug priming
Taslimi et al., 2012 [87]	Orexin A elicited conditioned place preference; the response was inhibited by administration of D1 and D2 receptor antagonists into the NAcc
Yazdi et al., 2015 [88]	Administration of OX2R antagonist into the VTA or NAcc dose-dependently inhibited the development of LH stimulation-induced conditioned place preference Co-administration of low doses of OX2R antagonist and CB1 receptor antagonist into the NAcc reduced conditioning scores
Azizi et al., 2018 [89]	OX2R antagonist inhibited the development of nicotine-induced conditioned place preference
Bernstein et al., 2018 [90]	OX1R knock-down delayed cocaine self-administration, indicating that OX1R are involved in motivation for cocaine
Brown et al., 2016 [91]	OX1R antagonist attenuated cue-induced reinstatement of ethanol-seeking
España et al., 2011 [75]	Orexin 1 increased the effect of cocaine on tonic and phasic DA signaling and increased the motivation to self-administer cocaine
Farahimanesh et al., 2017 [92]	OXR1 and OXR2 antagonists attenuated morphine conditioned place preference acquisition during the conditioning phase, and expression during the post-conditioning phase
James et al., 2011 [93]	OXR1 antagonist dose-dependently attenuated cue-induced reinstatement of cocaine-seeking
Moorman et al., 2010 [76]	Orexin (not specified if A or B) increased the activity of DA neurons and augmented excitatory responses to mPFC stimulation OX1R antagonist decreased tonic DA cell activity during active but not rest period
Muschamp et al., 2014 [94]	OX1R antagonism increased the threshold for intracranial self-stimulation; the response was blocked by a dynorphin receptor antagonist OXR1 antagonism reduced cocaine-induced impulsive behaviour Orexin A excited DA neurons in the VTA OX1R antagonist in the VTA reduced cocaine intake
Naghavi et al., 2019 [77]	Administration of D1 and D2 receptor antagonists attenuated the acquisition of place preference by orexin A
Olney et al., 2017 [95]	OX1R antagonist reduced binge-like ethanol intake but did not affect sucrose intake
Richardson et al., 2012 [96]	OX1R antagonist administration attenuated the morphine conditioned place preference score induced by administration of carbachol into the LGA, indicating that OX1R plays a role in sensitization to morphine
Saferi et al., 2019 [97]	OX1R and OXR2 antagonists reduced antinociceptive effect induced by carbachol administration into the lateral hypothalamus
Srinivasan et al., 2012 [98]	Administration of a dual OX1R and OXR2 antagonist into the VTA decreased operant self-administration of ethanol but not and sucrose Orexin A increased firing of VTA neurons
Taslimi et al., 2012 [87]	Orexin A administration induced conditioned place preference; the effect was inhibited by administration of D1 and D2 receptor antagonists
Terrill et al., 2016 [99]	Orexin-A increased intake of palatable food (high-fat food and sucrose), whereas OX1R antagonist suppressed sucrose intake
Wang et al., 2009 [100]	Orexin-A administration reinstated cocaine seeking and caused release of glutamate and dopamine in the VTA
Zarepour et al., 2014 [101]	OX1R antagonist inhibited the acquisition but not expression of LH stimulation-induced morphine conditioned place preference
Ventral Pallidum
Ho et al., 2013 [72]	Orexin amplified hedonic liking for sweetness
Mohammadkhani et al., [78]	OXR1 antagonist decreased motivation for remifentanil without affecting remifentanil consumption Thus, Orexin amplifies motivation to gain reward from drugs and sucrose.
Medial prefrontal cortex
Lei et al., 2016 [69]	OX1R antagonist reduced alcohol drinking
Cole et al., 2015 [102]	Systemic OX1R antagonist significantly reduced cue-driven consumption in sated rats and increased Fos expression in mPFC
Dimatelis et al., 2018 [103]	Maternal separation increased OXR1 and OXR2 levels in the PFC
Lambe et al., 2005 [29]	Similar to nicotine, orexin B infusion into the PFC improved accuracy under high attentional demand