ReviewRole of lateral hypothalamic orexin neurons in reward processing and addiction
Introduction
Orexin A and orexin B (also known as hypocretin 1 and hypocretin 2) are recently discovered peptides that are produced from a prepro-orexin molecule made solely in hypothalamic neurons. Since their nearly simultaneous discovery by de Lecea et al. and Sakurai et al. in 1998 (de Lecea et al., 1998, Sakurai et al., 1998), considerable work has been done to characterize this new peptide neurotransmitter system. Sakurai et al. (1998) also characterized two receptors for the orexin system, termed Ox1 and Ox2. The Ox1 receptor binds orexin A with 30 nM affinity but has much lower affinity for orexin B, whereas the Ox2 receptor binds both orexin peptides with similar high affinity. 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 (Lu et al., 2000, Marcus et al., 2001, Trivedi et al., 1998).
Great interest was focused on this system in the year after its discovery, when again 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, 2007, Nishino et al., 2000). 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, Gompf and Aston-Jones, 2008).
However, a potential role for orexins in reward processing was evident from one of the first publications of their discovery. Sakurai et al. 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 stimulants (Sakurai et al., 1998). The first report of a possible role for orexins in addiction appeared in 2003, with findings that orexin neurons play a role in opiate withdrawal (Georgescu et al., 2003). These and other findings prompted us to examine a possible role for this novel neuropeptide system in reward processing and drug abuse. As reviewed below, our studies along with those from others now indicate that orexins 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
Our report in 2005 was the first to demonstrate that orexin neurons in lateral hypothalamus (LH) play an active role in reward processing and drug abuse (Harris et al., 2005). We used a conditioned place preference (CPP) paradigm to measure Fos activation in orexin neurons associated with preference expressed for drug or natural rewards. We found that rats conditioned with morphine, cocaine or food in a CPP paradigm exhibited substantially increased Fos staining in LH orexin neurons on the
Orexin is involved in cue- but not cocaine-induced relapse: an hypothesis
One interesting outcome of our recent studies with self-administration of cocaine is that SB did not block reinstatement of cocaine-seeking induced by cocaine itself, nor did this compound significantly affect established cocaine self-administration. This contrasts sharply with the ability of SB to block cocaine-seeking induced by cues, and to attenuate responding on the first day of extinction. What might explain this difference in SB effects on stimulus-elicited vs cocaine-elicited
Acknowledgements
This work was supported by PHS grants R37 DA06214, R01 DA017289, P50 DA015369, F31 DA019733, and T32 AA007474.
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