Orexin/hypocretin role in reward: implications for opioid and other addictions

Abstract

Addiction is a devastating disorder that affects 15.3 million people worldwide. While prevalent, few effective treatments exist. Orexin receptors have been proposed as a potential target for anti-craving medications. Orexins, also known as hypocretins, are neuropeptides produced in neurons of the lateral and dorsomedial hypothalamus and perifornical area, which project widely throughout the brain. The absence of orexins in rodents and humans leads to narcolepsy. However, orexins also have an established role in reward seeking. This review will discuss some of the original studies describing the roles of the orexins in reward seeking as well as specific works that were presented at the 2013 International Narcotics Research Conference. Orexin signalling can promote drug-induced plasticity of glutamatergic synapses onto dopamine neurons of the ventral tegmental area (VTA), a brain region implicated in motivated behaviour. Additional evidence suggests that orexin signalling can also promote drug seeking by initiating an endocannabinoid-mediated synaptic depression of GABAergic inputs to the VTA, and thereby disinhibiting dopaminergic neurons. Orexin neurons co-express the inhibitory opioid peptide dynorphin. It has been proposed that orexin in the VTA may not mediate reward per se, but rather occludes the 'anti-reward' effects of dynorphin. Finally, orexin signalling in the prefrontal cortex and the central amygdala is implicated in reinstatement of reward seeking. This review will highlight recent work describing the role of orexin signalling in cellular processes underlying addiction-related behaviours and propose novel hypotheses for the mechanisms by which orexin signalling may impart drug seeking.

Linked articles: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Keywords: VTA; addiction; dopamine; dynorphin; hypocretin; morphine; orexin.

Figure 1

Simplified diagram of pathways involved in orexin signalling. Neurohumoural information about natural rewards is integrated by orexin neurons of the LH. Drugs of abuse may act both locally in the LH and at orexin terminals in VTA. Exposure to rewards or reward cues increases Fos expression and phospho-CREB in orexin neurons (inset, upper left). In the VTA (inset, upper right) orexin can affect glutamate release onto dopaminergic DA neurons as well as stimulating them directly via postsynaptic OX₁ receptors. Within DA neurons, OX₁ activation can recruit synthetic enzymes (PLC) for endocannabinoids such as 2-AG, which can inhibit GABA release from interneurons in a retrograde fashion. Co-released dynorphin may also modulate the excitatory effects of its co-transmitter orexin. MOP, KOP; μ-opioid, κ−opioid receptors: TASK, K_2P potassium channels.