Role of lateral hypothalamic orexin neurons in reward processing and addiction

Department of Neurosciences, Medical University of South Carolina, Basic Science Building 403, 173 Ashley Avenue, MSC 510, Charleston, SC 29425-5100, USA.
Neuropharmacology (Impact Factor: 5.11). 01/2009; 56 Suppl 1((Suppl 1)):112-21. DOI: 10.1016/j.neuropharm.2008.06.060
Source: PubMed


Orexins (also known as hypocretins) are recently discovered neuropeptides made exclusively in hypothalamic neurons that have been shown to be important in narcolepsy/cataplexy and arousal. Here, we conducted behavioral, anatomical and neurophysiological studies that show that a subset of these cells, located specifically in lateral hypothalamus (LH), are involved in reward processing and addictive behaviors. We found that Fos expression in LH orexin neurons varied in proportion to preference for morphine, cocaine or food. This relationship obtained both in drug naïve rats and in animals during protracted morphine withdrawal, when drug preference was elevated but food preference was decreased. Recent studies showed that LH orexin neurons that project to ventral tegmental area (VTA) have 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, we found that stimulation of LH orexin neurons, or microinjection of orexin into VTA, reinstated an extinguished morphine preference. Most recently, using a self-administration paradigm we discovered that the Ox1 receptor antagonist SB-334867 (SB) blocks cocaine-seeking induced by discrete or contextual cues, but not by a priming injection of cocaine. 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. We also recently showed that orexin in VTA is necessary for learning a morphine place preference. These findings are consistent with results from others 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.

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Available from: David Moorman, Aug 06, 2014
    • "These Ox-containing neurons send projections to many brain regions (Peyron et al. 1998), including key regions that regulate arousal and motivational states such as the dorsal raphe nucleus (DRN), LC, arcuate nucleus, VTA, tuberomammillary nucleus (TMN), basal forebrain (BF) and laterodorsal and pedunculopontine tegmental nucleus (LDT/PPT) (Tsujino and Sakurai 2009). Through these and other neural connections, Ox play key roles in the regulation of important behaviours and physiological functions such as sleep-wake cycle, energy homeostasis, addiction, endocrine function, reward seeking, and emotional behaviour (de Lecea et al. 2006; Sakurai 2006, 2007, 2010, 2014; Tsujino and Sakurai 2009; Aston-Jones et al. 2009; López et al. 2010). Interestingly, many of these are disrupted in depression (Drevets 2001), suggesting that insights into Ox signaling may lead to a better understanding of the biological basis of depression. "
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    ABSTRACT: Psychiatric disorders such as unipolar depression have complex pathologies, which include disruptions in circadian and sleep-wake cycles. At the neurochemical level, psychiatric diseases can also be accompanied by changes in neuromodulator systems such as orexin/hypocretin and the monoamines. Indeed, for decades the monoamine hypothesis of depression has been instrumental in driving discoveries and developments of antidepressant drugs. Recent preclinical and clinical advancement strongly suggests that neuropeptides such as orexin can play an important part in the pathophysiology of depression. Due to the complexity and extensive connectedness of neurobiological systems, understanding the biological causes and mechanisms of psychiatric disorders present major research challenges. In this chapter, we review experimental and computational studies investigating the complex relationship between orexinergic, monoaminergic, circadian oscillators, and sleep-wake neural circuitry. Our main aim is to understand how these physiological systems interact and how alteration in any of these factors can contribute to the behaviours commonly observed in depressive patients. Further, we examine how modelling across different levels of neurobiological organization enables insight into these interactions. We propose that a multiscale systems approach is necessary to understand the complex neurobiological systems whose dysfunctions are the underlying causes of psychiatric disorders. Such an approach could illuminate future treatments.
    Orexin and Sleep: Molecular, Functional and Clinical Aspects, 1 edited by Takeshi Sakurai, S.R. Pandi-Perumal, Jaime M. Monti, 01/2015: chapter 16: pages 299-322; Springer International Publishing., ISBN: 978-3-319-23078-8
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    • "mPFC neurons induces a massive increase in DA neuron activity (Lodge, 2011). Several anatomical and electrophysiological studies demonstrate that mPFC regulates VTA dopaminergic activity by innervating those DA neurons that project back to the mPFC (Overton et al., 1996; Carr and Sesack, 2000; Aston-Jones et al., 2009; Lodge, 2011). In this context, it is interesting to note that intra-VTA infusion of the NMDA receptor antagonist AP5 immediately after IA training elicits a selective impairment of memory persistence without affecting memory formation (Rossato et al., 2009). "
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    ABSTRACT: Medial prefrontal cortex (mPFC) is essential for initial memory processing and expression but its involvement in persistent memory storage has seldom been studied. Using the hippocampus dependent inhibitory avoidance learning task and the hippocampus-independent conditioned taste aversion paradigm together with specific dopamine receptor agonists and antagonists we found that persistence but not formation of long-term aversive memories requires dopamine D1/D5 receptors activation in mPFC immediately after training and, depending on the task, between 6 and 12 h later. Our results indicate that besides its well-known participation in retrieval and early consolidation, mPFC also modulates the endurance of long-lasting aversive memories regardless of whether formation of the aversive mnemonic trace requires the participation of the hippocampus.
    Frontiers in Behavioral Neuroscience 11/2014; 8. DOI:10.3389/fnbeh.2014.00408 · 3.27 Impact Factor
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    • "For example, it has been shown that SB-334867 attenuates the self-administration of nicotine [9] [10], alcohol [11] [12] [13], and cocaine [7] [14]. Furthermore, this compound has been shown to reduce reinstatement produced by cues and contexts previously associated with the self-administration of alcohol [11] and cocaine [15] [16] [17]. Consistent with the involvement of OX1R on the incentive motivational effects of cues associated with drug administration, SB-334867 has also been shown to block conditioned place preference produced by ethanol [18] and morphine [19]. "
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    ABSTRACT: The orexinergic system has been implicated in a number of behaviors, including reward and incentive motivation. Orexin 1 receptor antagonism has been reported to reduce drug self-administration, conditioned place preference, and reinstatement in rodents, but the role of the orexin 2 receptor is unclear. Here we evaluated the impact of the novel and selective orexin 2 receptor antagonist, 2-SORA 18, on motivation for nicotine as measured by responding on a progressive ratio schedule, as well as cue-induced reinstatement of a response previously associated with nicotine reward, and nicotine-induced reinstatement. 2-SORA 18 demonstrated selective effects on these behaviors. Specifically, doses up to 60mg/kg 2-SORA 18 were without significant effect on nicotine self-administration or nicotine-induced reinstatement, but doses as low as 15mg/kg 2-SORA 18 completely blocked cue-induced reinstatement. These findings indicate that orexin 2 receptor antagonism might have utility for attenuating relapse, particularly for patients sensitive to environmental stimuli associated with drug taking.
    Behavioural brain research 04/2014; 269. DOI:10.1016/j.bbr.2014.04.012 · 3.03 Impact Factor
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