Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437: 556-559

Laboratory of Neuromodulation and Behavior, Department of Psychiatry, University of Pennsylvania, 705 Stellar Chance/6100 422 Curie Blvd, Philadelphia, Pennsylvania 19104-6100, USA.
Nature (Impact Factor: 41.46). 10/2005; 437(7058):556-9. DOI: 10.1038/nature04071
Source: PubMed


The lateral hypothalamus is a brain region historically implicated in reward and motivation, but the identity of the neurotransmitters involved are unknown. The orexins (or hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamus neurons. Although knockout and transgenic overexpression studies have implicated orexin neurons in arousal and sleep, these cells also project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area. This indicates a possible role for these neurons in reward function and motivation, consistent with previous studies implicating these neurons in feeding. Here we show that activation of lateral hypothalamus orexin neurons is strongly linked to preferences for cues associated with drug and food reward. In addition, we show that chemical activation of lateral hypothalamus orexin neurons reinstates an extinguished drug-seeking behaviour. This reinstatement effect was completely blocked by prior administration of an orexin A antagonist. Moreover, administration of the orexin A peptide directly into the ventral tegmental area also reinstated drug-seeking. These data reveal a new role for lateral hypothalamus orexin neurons in reward-seeking, drug relapse and addiction.

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    • "Our data reveal an apparent lack of any differential targeting of the NI by hypothalamic orexinergic neuron groups, regardless of the scheme used to compartmentalise them into different zones. Our data and that of others (Fadel et al., 2002; Gonzalez et al., 2012) that demonstrates a lack of dichotomy in the output projections of orexin neurons to particular brain nuclei, together with experimental evidence of distinct neural inputs (Yoshida et al., 2006), differential sensitivity to stress and rewardrelated cues as well as to different drugs (Fadel et al., 2002; Harris et al., 2005), along with differences in the circadian fluctuations in activity (Estabrooke et al., 2001), strongly supports the proposed dichotomy in orexin neuron function, but arising from input rather than output projections. Moreover, in mice, two different types of orexin neurons were distinguished electrophysiologically: type H, characterised by hyperpolarised post-inhibitory rebound and type D, with depolarised post-inhibitory rebound (Williams et al., 2008). "
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    ABSTRACT: Orexin/hypocretin peptides play a central role in the integrated control of feeding/reward and behavioural activation, principally via interactions with other neural systems. A brainstem area involved in behavioural activation is the nucleus incertus (NI), located in the posterior ventromedial central grey. Several studies have implicated NI in control of arousal/stress and reward/feeding responses. Orexin receptor mRNA expression identifies NI as a putative target of orexin modulation. Therefore, in this study we performed neural tract-tracing and immunofluorescence staining to characterise the orexinergic innervation of NI. Our results indicate a convergent innervation of the NI area by different orexin neurons populations, along with an abundance of orexin-A-containing axons making putative synaptic contacts with relaxin-3-positive NI neurons. The influence of orexin-A on NI neuron activity was investigated using patch-clamp recordings. Orexin-A depolarised the majority (64%) of recorded neurons and this effect was maintained in the presence of tetrodotoxin and glutamate and GABA receptor antagonists, indicating a likely postsynaptic action. Voltage-clamp experiments revealed that in 'type I' NI neurons comprising relaxin-3-positive cells, orexin-A acted via L-type calcium channels, whereas in 'type II' relaxin-3-negative neurons, activation of a sodium/calcium exchanger was involved. A majority of the orexin-A sensitive neurons tested for the presence of orexin receptor mRNA, were OX2 mRNA-positive. Immunohistochemical staining for putative orexin receptors on NI neurons, confirmed stronger expression of OX2 than OX1 receptors. Our data demonstrate a strong influence of orexin-A on NI neurons, consistent with an important role for this hypothalamic/tegmental circuit in the regulation of arousal/vigilance and motivated behaviours. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 08/2015; DOI:10.1016/j.neuropharm.2015.08.014 · 5.11 Impact Factor
    • "Orexin neuropeptides are primarily expressed in the LH and stimulate food intake (Sakurai et al., 1998), in particular palatable food (Clegg et al., 2002; Thorpe et al., 2005). Orexins are also involved in neuronal and behavioural responses to drugs of abuse (Georgescu et al., 2003; Boutrel et al., 2005; Harris et al., 2005; Borgland et al., 2006; Narita et al., 2006), which may be mediated by DA neurons in the ventral tegmental area (VTA) (Kenny, 2011). On one hand, orexins have been shown to activate VTA DA neurons (Korotkova et al., 2003; Borgland et al., 2006). "
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    ABSTRACT: Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups, where orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying DA action on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using whole cell patch clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration dependent, bidirectional manner. Low (1 μM) and high concentrations (100 μM) of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G protein signaling inhibitor GDPβS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors, whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Neuroscience 06/2015; 42(3). DOI:10.1111/ejn.12967 · 3.18 Impact Factor
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    • "As mentioned above, LHA has been suggested as a target for leptin action to modulate the reward circuit. In addition, it has been suggested that the group of neuron in the LHA project to the mesolimbic regions to control DA action and reward (DiLeone et al., 2003; Harris et al., 2005; Kelley et al., 2005a; Opland et al., 2010). Among these, two populations of neurons have been identified: melanin concentrating hormone (MCH) and orexin expressing neurons. "
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    ABSTRACT: The central actions of leptin and insulin are essential for the regulation of energy and glucose homeostasis. In addition to the crucial effects on the hypothalamus, emerging evidence suggests that the leptin and insulin signaling can act on other brain regions to mediate the reward value of nutrients. Recent studies have indicated the midbrain dopaminergic neurons as a potential site for leptin' and insulin's actions on mediating the feeding behaviors and therefore affecting the energy balance. Although molecular details about the integrative roles of leptin and insulin in this subset of neurons remain to be investigated, substantial body of evidence by far imply that the signaling pathways regulated by leptin and insulin may play an essential role in the regulation of energy balance through the control of food-associated reward. This review therefore describes the convergence of energy regulation and reward system, particularly focusing on leptin and insulin signaling in the midbrain dopaminergic neurons.
    Frontiers in Psychology 08/2014; 5:846. DOI:10.3389/fpsyg.2014.00846 · 2.80 Impact Factor
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