Article

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: 4.82). 01/2009; 56 Suppl 1((Suppl 1)):112-21. DOI: 10.1016/j.neuropharm.2008.06.060
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ABSTRACT 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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    • "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 · 4.16 Impact Factor
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    • "Mice lacking orexins have a decreased tendency for addiction (DiLeone et al., 2003; Smith and Aston-Jones, 2012), but whether this occurs in people with narcolepsy is not yet clear (Dimitrova et al., 2011). This review will focus on the primary symptoms of narcolepsy, sleepiness and cataplexy, though numerous reviews discuss other roles for the orexin system (Aston-Jones et al., 2008; Mieda and Sakurai, 2009; Sakurai and Mieda, 2011; Sinton, 2011; Nixon et al., 2012). "
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/2012; 32(36):12305-11. DOI:10.1523/JNEUROSCI.2630-12.2012 · 6.75 Impact Factor
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    • "The extent to which hypocretins regulate the reinforcing actions of drugs has been studied across varying schedules of reinforcement . In initial studies, rats were implanted with a jugular catheter and then trained to self-administer cocaine on a fixed ratio 1 (FR1) schedule of reinforcement in which single lever presses resulted in cocaine delivery (Aston-Jones et al., 2009; España et al., 2010). With little restriction to cocaine access, rats are easily able to titrate blood levels of cocaine by spacing injections out over a session, and consequently, responding on an FR1 schedule provides information about an animal's preferred level of cocaine consumption (Norman and Tsibulsky, 2006). "
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    ABSTRACT: The hypocretins/orexins are comprised of two neuroexcitatory peptides that are synthesized exclusively within a circumscribed region of the lateral hypothalamus. These peptides project widely throughout the brain and interact with a variety of regions involved in the regulation of arousal-related processes including those associated with motivated behavior. The current review focuses on emerging evidence indicating that the hypocretins influence reward and reinforcement processing via actions on the mesolimbic dopamine system. We discuss contemporary perspectives of hypocretin regulation of mesolimbic dopamine signaling in both drug free and drug states, as well as hypocretin regulation of behavioral responses to drugs of abuse, particularly as it relates to cocaine.
    Frontiers in Behavioral Neuroscience 08/2012; 6:54. DOI:10.3389/fnbeh.2012.00054 · 4.16 Impact Factor
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