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
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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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    • "Several recent studies have shown the key role that orexin signaling plays in addictive behaviors modulated through the VTA, including the ability to block amphetamine sensitization and nicotine reinstatement with selective orexin receptor antagonists (Winrow et al., 2010; Aston-Jones et al., 2009, 2010). The studies described here strengthen the role for orexin signaling through the VTA and point to a previously unknown connection between SNCA and orexin signaling in VTA function. "
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    ABSTRACT: The combination of stable isotope labeling of amino acids in mammals (SILAM) and laser capture microdissection (LCM) for selective proteomic analysis of the targeted tissues holds tremendous potential for refined characterization of proteome changes within complex tissues such as the brain. The authors have applied this approach to measure changes in relative protein abundance in ventral tegmental area (VTA) of the rat brain that correlate to pharmacological perturbations. Enriched 13C6 15N2-lysine was introduced in vivo via diet. These animals were sacrificed during the middle of the 12-hour light period to extract isotopically “heavy” proteins, which were then used as a reference for extracts from dosed, unlabeled rats. Animals were administered an orexin peptide (Ox-B), an orexin receptor antagonist (ORA), or a mixture of both (Ox-B + ORA). All samples were obtained at same phase of the sleep cycle. Labeled-pair identification and differential quantitation provided protein identification and expression ratio data. Five proteins were found to exhibit decreased relative abundance after administration of an ORA, including α-synuclein and rat myelin basic protein. Conversely, six proteins showed increased relative abundance upon antagonist treatment, including 2’,3’-cyclic nucleotide 3’-phosphodiesterase.
    Journal of neurogenetics 03/2014; 28(1-2). DOI:10.3109/01677063.2014.883389 · 1.27 Impact Factor
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    • "The analysis of orexinergic inputs to DA neurons of this region has shown that SN DA neurons of rats as well as humans receive direct innervation from hypothalamic orexinergic neurons. Although this input is quite sporadic, it is important to note that a similarly sparse innervation is capable of inducing robust behavioral effects in the rodent VTA [4], [29], [30], [40], [41]. Functional evidence also exists that orexins can act in the SN to influence important motor functions. "
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    ABSTRACT: The mesolimbic reward pathway arising from dopaminergic (DA) neurons of the ventral tegmental area (VTA) has been strongly implicated in reward processing and drug abuse. In rodents, behaviors associated with this projection are profoundly influenced by an orexinergic input from the lateral hypothalamus to the VTA. Because the existence and significance of an analogous orexigenic regulatory mechanism acting in the human VTA have been elusive, here we addressed the possibility that orexinergic neurons provide direct input to DA neurons of the human VTA. Dual-label immunohistochemistry was used and orexinergic projections to the VTA and to DA neurons of the neighboring substantia nigra (SN) were analyzed comparatively in adult male humans and rats. Orexin B-immunoreactive (IR) axons apposed to tyrosine hydroxylase (TH)-IR DA and to non-DA neurons were scarce in the VTA and SN of both species. In the VTA, 15.0±2.8% of TH-IR perikarya in humans and 3.2±0.3% in rats received orexin B-IR afferent contacts. On average, 0.24±0.05 and 0.05±0.005 orexinergic appositions per TH-IR perikaryon were detected in humans and rats, respectively. The majority (86-88%) of randomly encountered orexinergic contacts targeted the dendritic compartment of DA neurons. Finally, DA neurons of the SN also received orexinergic innervation in both species. Based on the observation of five times heavier orexinergic input to TH-IR neurons of the human, compared with the rat, VTA, we propose that orexinergic mechanism acting in the VTA may play just as important roles in reward processing and drug abuse in humans, as already established well in rodents.
    PLoS ONE 12/2013; 8(12):e83029. DOI:10.1371/journal.pone.0083029 · 3.23 Impact Factor
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