Research ReportLateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction
Introduction
The neuropeptides orexin A and orexin B (synonymous with hypocretin 1 and hypocretin 2) are produced from a prepro-orexin molecule made solely in hypothalamic neurons. Since the discoveries by de Lecea et al. (1998) and Sakurai et al. (1998), considerable work has characterized this neurotransmitter system. Sakurai et al. (1998) characterized two receptors for the orexin system, termed OxR1 and OxR2 (also denoted HcrtR1 and HcrtR2). OxR1 binds orexin A with 30 nM affinity but has much lower affinity for orexin B, whereas OxR2 binds both orexin peptides with similar high affinity. Further, OxR1 is coupled exclusively to a Gq subclass of G proteins, and OxR2 is coupled to both Gq and Gi/o proteins (Zhu et al., 2003). The orexin neurons give rise to a highly divergent system of fiber projections that spans the entire neuraxis, including innervation in the cerebral cortex, hippocampus, thalamus, midbrain, and spinal cord (Peyron et al., 1998, Sutcliffe and de Lecea, 2002). Likewise, the two orexin receptors are widely distributed in the CNS but are regionally selective and largely non-overlapping (Kilduff and de Lecea, 2001, Lu et al., 2000, Marcus et al., 2001, Trivedi et al., 1998).
Great interest was focused on this system shortly after its discovery, when two groups virtually simultaneously reported that dysfunction in the orexin system is strongly associated with narcoleptic symptoms in animals (Chemelli et al., 1999, Lin et al., 1999). Subsequent work in humans verified that narcoleptic patients (particularly those with cataplexy) have little orexin in their CSF and lack most or all orexin neurons (Nishino et al., 2000, Nishino, 2007). With these compelling findings, the prevailing view of orexin function focused on arousal and maintenance of the waking state. Supporting this view were findings that major targets of orexin projections are classic brain arousal nuclei such as the locus coeruleus (Peyron et al., 1998, Sutcliffe and de Lecea, 2002) and that orexin application typically strongly activates these cells (Brown et al., 2001, Eriksson et al., 2001, Horvath et al., 1999, Ivanov and Aston-Jones, 2000, Korotkova et al., 2003).
However, a potential role for orexins in reward processing was evident from one of the first publications of their discovery. Sakurai et al. (1998) reported that administration of orexin A or orexin B into the lateral ventricle produced feeding in rats, which prompted them to name the new peptides “orexins,” meaning appetite. The first report of a possible role for orexins in effects of addictive drugs appeared in 2003 and showed that orexin neurons play a role in opiate withdrawal (Georgescu et al., 2003). Subsequent studies examined a possible role for this novel neuropeptide system in reward processing and drug abuse. As reviewed below, orexin appears to play a prominent role in conditioned responses to stimuli associated with food and drug rewards. This reward-associated function of the orexin system may be separate from its role in maintenance of the waking state and mediated by a separate population of (laterally located) orexin neurons.
Section snippets
Orexin neurons are activated by reward-associated stimuli
Orexin neurons in lateral hypothalamus (LH) play an active role in reward processing and drug abuse. Mice with a genetic deletion of orexin completely lack conditioned place preference (CPP) for morphine (Narita et al., 2006). Further, there is a strong association between Fos activation in orexin neurons and the expression of CPP for drug or natural rewards (Harris et al., 2005). Rats conditioned with morphine, cocaine, or food in a CPP paradigm exhibited substantially increased Fos staining
Functional differences for LH versus DMH/PeF orexin neurons
As reviewed above, orexin neurons appear to be involved both in arousal and in reward-seeking, and evidence indicates that orexin neurons are functionally dichotomous (Harris and Aston-Jones, 2006). Thus, reward-seeking functions are associated primarily with orexin cells in LH, whereas arousal- and stress-related processes are more associated with orexin neurons in the DMH and PeF. For example, Estabrooke et al. (2001) reported that PeF and DMH, but not LH, orexin neurons are Fos-activated
Orexin neurotransmission in VTA drives reinstatement
The orexin system projects widely throughout the CNS, so there are many possible targets where orexin might be acting during drug-seeking and reinstatement. One site that seemed likely was the VTA, where dopamine (DA) neurons that play a critical role in reward and reinforcement mechanisms are located. Microinjections of orexin directly into VTA robustly reinstated morphine preference in animals that had previously been extinguished (Harris et al., 2005), and intra-VTA orexin injections
Discussion and hypothesis
The recent data reviewed above indicate that orexin is involved in conditioned behavioral responding to drug-associated stimuli. Cocaine self-administration studies found that OxR1 antagonism significantly attenuated cocaine-seeking elicited by stimuli previously associated with cocaine. SB reduced cue- and context-induced reinstatement of extinguished cocaine-seeking, as well as relapse responding after 2 weeks of abstinence. On the other hand, SB had no effect on reinstatement of
Acknowledgments
This work was supported by PHS grants R37 DA06214, R01 DA017289, P50 DA015369, F31 DA019733, and T32 AA007474.
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