Orexin/hypocretin in psychiatric disorders: present state of knowledge and future potential

The orexins (or hypocretins) are hypothalamic neuropeptides involved in the regulation of a variety of complex behaviors, ranging from feeding to sleep and arousal (Adamantidis and de Lecea, 2009). Recent evidence has shown that these peptides can modulate the mesocorticolimbic dopamine circuit, and thus they have also been implicated in the pathology of numerous psychiatric disorders, including schizophrenia, depression, and addiction. Orexin-containing neurons constitute a small population of lateral and perifornical hypothalamic neurons, but project widely throughout the brain, including a substantial projection to the ventral tegmental area (VTA), a region involved in motivation and reinforcement processes. Hence, orexin can modulate dopaminergic firing, enhance synaptic transmission, and increase dopamine release in target areas of VTA neurons, such as the nucleus accumbens and the prefrontal cortex.

The potential links between orexin and schizophrenia or depression have only recently been explored. Preclinical data suggest that certain neuroleptic drugs associated with weight gain can activate orexin neurons (Deutch and Busber, 2007), suggesting a secondary target for the drugs' actions. Furthermore, in patients suffering from schizophrenia, cerebrospinal fluid levels of orexin A are lower in those treated with neuroleptic drugs. Thus, the orexin system may be a potential target for the side effects of neuroleptic drugs and a promising candidate for pharmacological treatment in schizophrenia. Depression is associated with sleep disturbances and circadian abnormalities. Dampened diurnal variations in orexin have been observed in depressed subjects (Salomon et al, 2003). Although diminished orexin signaling does not recapitulate the full spectrum of symptoms observed in depression, orexin signaling appears to be involved in the antidepressant-like effect of calorie restriction (Lutter et al, 2008). This raises the interesting possibility that orexin receptor agonists, which are currently in development for narcolepsy treatment, may also have antidepressant-like activity.

Evidence supporting the central role of orexin in drug reward and addiction is abundant (reviewed in Bonci and Borgland, 2009). In preclinical studies, blockade of orexin signaling has been shown to sufficiently inhibit two main behaviors defining addiction: motivated drug seeking and relapse. Orexin neurons are activated by preference to a context associated with drug intake. Furthermore, orexin receptor 1 antagonists block stress- or cue-induced reinstatement of extinguished cocaine or ethanol seeking, as well as high-fat food, ethanol, and nicotine self-administration. However, the antagonists do not block self-administration of cocaine, water, or food, suggesting that the effects of orexin signaling on self-administration of natural or drug rewards may be specific to the qualities of the reinforcer (Bonci and Borgland, 2009). Some of the behavioral actions of orexins may be due to their neuroplastic effects at glutamatergic synapses in the VTA. Interestingly, the involvement of the VTA in the neuronal and behavioral changes caused by cocaine requires input from orexin neurons (Borgland et al, 2006). It will be interesting to determine whether orexin-mediated neuroplasticity in the VTA underlies the effects of other drugs of abuse, such as morphine. Orexin receptor antagonists, in particular those to the orexin 1 receptor, may be clinically useful in the treatment of craving or the prevention of relapse.

In summary, orexin activation of the mesolimbic dopamine system may underlie some of its actions in schizophrenia, depression, or addiction. New therapeutic strategies to either activate (in depression) or inactivate (in schizophrenia or addiction) the orexin system may prove to be effective approaches in the treatment of such disorders.