Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction

Abstract

Orexins (synonymous with hypocretins) are recently discovered neuropeptides made exclusively in hypothalamus. Behavioral, anatomical, and neurophysiological studies show that a subset of these cells, specifically those in lateral hypothalamus (LH), are involved in reward processing and addictive behaviors. Fos expression in LH orexin neurons varied in proportion to conditioned place preference (CPP) for morphine, cocaine, or food. This relationship occurred both in drug-naïve rats and in animals during protracted morphine withdrawal, when drug preference was elevated but food preference was decreased. Inputs to the LH orexin cell field from lateral septum and bed nucleus of the stria terminalis were Fos-activated during cocaine CPP in proportion to the preference expressed in each animal. This implies that these inputs may be involved in driving the conditioned responses in LH orexin neurons. Related studies showed that LH orexin neurons that project to ventral tegmental area (VTA) had greater Fos induction in association with elevated morphine preference during protracted withdrawal than non-VTA-projecting orexin neurons, indicating that the VTA is an important site of action for orexin's role in reward processing. In addition, stimulation of LH orexin neurons, or microinjection of orexin into VTA, reinstated an extinguished morphine preference. In self-administration studies, the orexin 1 receptor antagonist SB-334867 (SB) blocked cocaine-seeking induced by discrete or contextual cues previously associated with cocaine, but not by a priming injection of cocaine. There was no effect of SB on cocaine self-administration itself, indicating that it did not interfere with the drug's reinforcing properties. Neurophysiological studies revealed that locally applied orexin often augmented responses of VTA dopamine (DA) neurons to activation of the medial prefrontal cortex (mPFC), consistent with the view that orexin facilitates activation of VTA DA neurons by stimulus–reward associations. This LH-to-VTA orexin pathway was found to be necessary for learning a morphine place preference. These findings are consistent with results showing that orexin facilitates glutamate-mediated responses, and is necessary for glutamate-dependent long-term potentiation in VTA DA neurons. We surmise from these studies that LH orexin neurons play an important role in reward processing and addiction and that LH orexin cells are an important input to VTA for behavioral effects associated with reward-paired stimuli.

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 G_q subclass of G proteins, and OxR2 is coupled to both G_q and G_i/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.