Orexin Receptor-1 (OX1R)
Orexin or hypocretin; a peptide that resembles the molecular structure of the gastric peptide secretin, was discovered in 1996 by two independent groups of researchers. One group named it orexin after the Greek word orexis which means “appetite,” while the other group named it hypocretin since it was synthesized in the hypothalamus and resembles secretin (Sakurai et al. 1998). Both the nomenclatures for orexins are currently in use. We would adhere to “orexin” for references to the peptides in this article.
These hypothalamic peptides are produced by orexin neurons in the dorsomedial (DMH), lateral (LH), and perifornical hypothalamic areas (PFA) (Sakurai et al. 1998). Since these areas of the hypothalamus are involved in arousal, sleep-wake cycle, thermoregulation, feeding and appetite, the function of orexins is implicated in the regulation of these behaviors. Furthermore, studies have shown that orexins are also involved in emotion, reward and drug seeking. Since these neuropeptides control a wide range of functions important for survival, they are implicated in a variety of neuropsychiatric conditions like obesity, drug addiction and sleep disorders (Sakurai et al. 1998).
Central and Peripheral Distribution of OX1R
Role of OX1R in Feeding Behavior
Orexins play a central role in appetite regulation since studies have shown the localization of orexin A peptide-releasing neurons in and around the lateral and posterior hypothalamus; classical brain regions implicated in food intake and energy homeostasis (Sakurai et al. 1998). Studies in the past have shown that centrally administered orexin A increases food consumption in rodents; however, the orexin receptor involved in this effect was unknown (Sakurai et al. 1998). Initial speculations about the involvement of the OX1R in this effect came from studies that demonstrated an increase in the OX1R mRNA in the hypothalamus following food deprivation (Lopez et al. 2000). Later, studies by Haynes A. and colleagues (2000) unraveled the role of OX1R in the actions of orexin A-facilitated feeding in non-fasting and fasting rats with the use of the selective OX1R antagonist, SB-334867. Interestingly, SB-334867 unlike other anti-obesity and sedative drugs just delayed rather than alter the onset of behavioral satiety (transition occurring naturally from feeding to resting) initiated by orexin A by increasing the time the animals spent resting rather than eating (Rodgers et al. 2001). The efficacy of SB-334867 was also demonstrated in a long-term period where chronic injections of SB-334867 (30 mg/kg, i.p. once/daily/7 days followed by twice/daily/7 days) reduced food intake over 2 weeks in genetically obese (ob/ob) mice (Haynes et al. 2002). Furthermore, in addition to the anorectic effect of SB-334867, it also had a thermogenic effect (reduced body fat) and an antidiabetic effect (reduced fasting glucose, and insulin levels) in the ob/ob mice, suggesting that OX1R may also be involved in obesity and diabetes (Haynes et al. 2002).
Orexin receptor-1s (OX1Rs) are expressed in various parts of the brain involved in imparting motivational salience to food. In a study by Sharf R. and colleagues (2010), the importance of activation of OX1R in food-reinforced motivation and operant responding in mice is well demonstrated. A recent study by Keefer S. and colleagues (2016) also showed that OX1Rs are involved in appetitive conditioning for food and also in the extinction of conditioned feeding behavior. Interestingly, altered motivation to eat in the absence of hunger leads to eating disorders, and studies have highlighted the intimate involvement of OX1Rs in the development of these disorders. In support of this, Cole S. and colleagues (2015) have shown that OX1Rs in the thalamus and medial prefrontal cortex motivate cue-driven feeding in sated rats suggesting the role of these receptors to respond to food cues even in the absence of hunger. Similarly, studies have also shown OX1Rs in the central nucleus of the amygdala play a role in feeding behavior based on preference for flavor and sweet-tasting foods, which may lead to obesity (Risco and Mediavilla 2014). Further evidence also demonstrates the role of OX1Rs in the ventral tegmental area in the consumption of high-palatable food (Terrill et al. 2016) and compulsive eating disorders like binge eating in female rats (Piccoli et al. 2012). These findings point out the contribution of OX1R in feeding behavior necessary for survival and also in maladaptive food habits that lead to eating disorders.
Role of OX1R in Mood- and Stress-Related Disorders
In addition to the involvement of OX1Rs in feeding behavior and associated disorders, these receptors have also been implicated in emotion, memory, mood and affective disorders. A study by Abbas M. and colleagues (2015) shows the contribution of OX1R in anxiety-like and depression-like behavior accompanied with reduced social interaction behavior in mice. Since OX1R is expressed in brain regions like the cortex, hippocampus, and amygdala which are involved in emotion and mood regulation, it is not surprising that these receptors are involved in regulating affective states. Furthermore the same research group also showed that mice lacking OX1Rs display an increased startle response and reduced prepulse inhibition response suggesting impairments in sensorimotor gating which may be related to schizophrenia-like symptoms in mice.
Additionally, seizures in epileptic patients contribute significantly in the loss of learning, memory and cognitive decline. It has been shown that neurogenesis in the hippocampus facilitates memory formation and cognition (Santarelli et al. 2003) which is severely impaired in patients suffering from epileptic seizures (Zhao et al. 2014). Interestingly, the latter research group has shown that treatment with orexin A repairs epileptic seizure-induced neuronal deficits in the hippocampus via a direct effect on OX1R in rats. The animals exhibited improved performance on the Morris water maze and showed remarkable increases in neurogenesis in the hippocampus which were reversed with the blockade of the OX1R, suggesting that the effects of orexin A on neurogenesis are mediated by OX1Rs. Also, evidence suggests that enhancement in neurogenesis in the hippocampal dentate gyrus region facilitates the efficacy of antidepressants in patients with mood disorders (Santarelli et al. 2003). Since OX1Rs are involved in hippocampal neurogenesis, it may be possible that these receptors may play a role in relieving altered affective states in such patients.
Furthermore, recent evidence points at the potential role of OX1Rs in stress-associated phenotypes that may lead to the induction of stress-related disorders. In line with this, Heidari-Oranjaghi N. and colleagues (2012) have shown the involvement of OX1Rs in the antinociceptive properties of stress, which was further shown to be caused by OX1R-mediated activation of endocannabinoid system in the periaqueductal gray in mice (Lee et al. 2016). In another stress-related function, a study by Soya S and colleagues (2013) demonstrated the role of OX1Rs on noradrenergic neurons in the locus coeruleus in fear memory consolidation and retrieval, suggesting the possibility that altered OX1R function may facilitate the induction of stress-related disorders like PTSD (post-traumatic stress disorder). Furthermore, Bonaventure P. and colleagues (2015) have shown that antagonism of OX1Rs in a rat model of psychological stress and panic vulnerability reduced the latency to sleep onset and panic-like behaviors without altering locomotor behavior, suggesting the hyperactivity of OX1R in such stress-related psychiatric paradigms.
Role of OX1R in Reward and Addiction
The distribution of OX1R in reward regions of the brain involving the mesocorticolimbic system, including the nucleus accumbens, ventral tegmental area, cortex and amygdala, points at a direct role of these receptors in reward-related behaviors including drug dependence.
Numerous studies have highlighted the involvement of OX1Rs in alcohol addiction and seeking behavior. Lawrence A. and colleagues (2006) have demonstrated the role OX1R in cue-induced reinstatement of alcohol-seeking behavior, while Richards J. and colleagues (2008) have shown the recruitment of OX1Rs in stress-induced alcohol-seeking behavior. These evidences shed light on the contribution of OX1Rs as a trigger to consume alcohol when exposed to previously paired alcohol stimuli or stress. On further investigation, a study by Brown R. and colleagues (2016) revealed that OX1Rs in the pre-limbic cortex and the ventral tegmental area mediate cue-induced alcohol-seeking behavior. Furthermore, Moorman D. and colleagues (2009) showed that antagonism of OX1Rs preferentially reduces alcohol intake in high alcohol-consuming rats, suggesting a role these receptors in binge-like alcohol intake. This observation was further confirmed in a study in mice where antagonism of OX1R reduced consumption only in mice exposed chronically to alcohol vapor but not moderate voluntary alcohol intake (Lopez et al. 2016).
Similar to alcohol, OX1R has been shown to mediate dependence to cocaine. A study by Smith R. and colleagues (2009) in rats showed that OX1Rs play a role in reinstatement of cue-induced cocaine-seeking behavior, however, the acquisition of cocaine-paired cues is OX1R independent. Furthermore, repeated (chronic) inhibition of OX1R enhances the efficacy of acute OX1R antagonism on reinstatement of cocaine-seeking behavior (Zhou et al. 2012). Interestingly, evidence in animals trained to self-administer cocaine suggests the robust role of OX1R in cocaine seeking where non-sedative doses of SB-334867 reduced responding for cocaine in high-effort operant paradigms (Brodnik et al. 2015). Furthermore, since cocaine mediates its effects through modulation of the dopaminergic system, fast scan voltammetric analysis of dopamine transmission in the nucleus accumbens core revealed a strong influence of OX1R in mediating cocaine-induced changes in dopamine signaling. This suggests that OX1Rs on dopaminergic neurons in the nucleus accumbens core or in the ventral tegmental area may mediate the effects of cocaine on dopaminergic system in the reward pathway (Prince et al. 2015). Remarkably, since OX1Rs are also involved in the acquisition of natural rewards, OX1R blockade selectively attenuates cocaine reinstatement without affecting natural rewards following extinction training in an operant conditioning paradigm, suggesting the pharmacotherapeutic benefit of OX1R antagonists for cocaine dependence (Martin-Fardon and Weiss 2014).
Orexins, orexin A and orexin B, are hypothalamic neuropeptides predominantly involved in arousal, appetite, and modulation of circadian rhythms. The receptors for orexinergic peptides, OX1R and OX2R, are well distributed in the brain. Since OX1R is expressed in key areas of the brain involving the hypothalamus and mesocorticolimbic reward system and other non-brain regions, it is strongly implicated in reward acquisition, emotion, and motivation in addition to appetite and wakefulness. The role of OX1Rs has been well studied in feeding behavior, and dysregulation in its function may lead to associated eating disorders. Furthermore, the involvement of OX1Rs in emotion and regulation of affective states implicates its function in mood disorders and other stress-related disorders like PTSD. Also, the role of OX1R in reward and motivation directly implicates them in addiction to drugs of abuse.
Antagonism of OX1Rs has shown promise in attenuating a wide range of disorders including feeding, mood, and addiction. The well-studied OX1R antagonist, SB-334867, shows promise as an excellent pharmacotherapeutic option to treat such disorders, opening the doors for other novel and more selective OX1R antagonists like GSK1059865 (Lopez et al. 2016), as potential treatment alternatives for these disorders.
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