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Orexin reserve: A mechanistic framework for the role of orexins (hypocretins) in addiction

  • Morgan H. James
    Correspondence
    Corresponding authors details: Morgan H. James, Ph.D., Office 164, 683 Hoes Lane West, Piscataway, NJ, 08854. P: (732) 235 6074 F: (732) 235 5814 E:
    Affiliations
    Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey, USA

    Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University and Rutgers Biomedical Health Sciences, Piscataway, New Jersey, USA
    Search for articles by this author
  • Gary Aston-Jones
    Correspondence
    Corresponding authors details: Gary Aston-Jones, Ph.D., Office 259, 683 Hoes Lane West, Piscataway, NJ, 08854. P: (732) 235 6074, F: (732) 235 5814. E:
    Affiliations
    Brain Health Institute, Rutgers University and Rutgers Biomedical and Health Sciences, Piscataway, New Jersey, USA

    Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University and Rutgers Biomedical Health Sciences, Piscataway, New Jersey, USA
    Search for articles by this author

      Abstract

      In 2014 we proposed that orexin signaling transforms motivationally relevant states into adaptive behavior directed toward exploiting an opportunity or managing a threat, a process we referred to as ‘motivational activation’. Advancements in animal models since then have permitted higher-resolution measurement of motivational states; in particular, the behavioral economics approach for studying drug demand characterizes conditions that lead to the enhanced motivation that underlies addiction. This ‘motivational plasticity’ is paralleled by persistently increased orexin expression in a topographically-specific manner – a finding confirmed across species, including in humans. Normalization of orexin levels also reduces drug motivation in addiction models. These new advancements lead us to update our proposed framework for orexin function. We now propose that the capacity of orexin neurons to exhibit dynamic shifts in peptide production contributes to their role in adaptive motivational regulation, and that this is achieved via an orexin neuron ‘reserve’. This reserve is normally bidirectionally recruited to permit motivational plasticity that promotes flexible, adaptive behavior. In pathological states such as addiction, however, we propose that the orexin system loses capacity to adaptively adjust peptide production, resulting in focused hypermotivation for drug driven by aberrantly and persistently high expression in the orexin reserve. This mechanistic framework has implications for understanding and treating several psychiatric disorders beyond addiction, particularly those characterized by motivational dysfunction.

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      References

        • Peyron C.
        • et al.
        A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains.
        Nat Med. 2000; 6: 991-997
        • de Lecea L.
        • et al.
        The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.
        Proc Natl Acad Sci U S A. 1998; 95
        • Sakurai T.
        • et al.
        Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.
        Cell. 1998; : 92
        • Chemelli R.M.
        • et al.
        Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.
        Cell. 1999; 98: 437-451
        • Lin L.
        • et al.
        The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.
        Cell. 1999; 98: 365-376
        • Harris G.C.
        • Wimmer M.
        • Aston-Jones G.
        A role for lateral hypothalamic orexin neurons in reward seeking.
        Nature. 2005; 437: 556-559
        • Mahler S.V.
        • et al.
        Motivational activation: a unifying hypothesis of orexin/hypocretin function.
        Nat Neurosci. 2014; 17: 1298-1303
        • Georgescu D.
        • et al.
        Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal.
        J Neurosci. 2003; 23: 3106-3111
        • Sharf R.
        • Sarhan M.
        • Dileone R.J.
        Orexin mediates the expression of precipitated morphine withdrawal and concurrent activation of the nucleus accumbens shell.
        Biol Psychiatry. 2008; 64: 175-183
        • James M.H.
        • et al.
        Increased Number and Activity of a Lateral Subpopulation of Hypothalamic Orexin/Hypocretin Neurons Underlies the Expression of an Addicted State in Rats.
        Biol Psychiatry. 2019; 85: 925-935
      1. Matzeu, A. and R. Martin-Fardon, Cocaine-Seeking Behavior Induced by Orexin A Administration in the Posterior Paraventricular Nucleus of the Thalamus Is Not Long-Lasting: Neuroadaptation of the Orexin System During Cocaine Abstinence. Frontiers in behavioral neuroscience, 2021. 15: p. 620868-620868.

        • Fragale J.E.
        • James M.H.
        • Aston-Jones G.
        Intermittent self-administration of fentanyl induces a multifaceted addiction state associated with persistent changes in the orexin system.
        Addict Biol. 2020; e12946
        • Thannickal T.C.
        • et al.
        Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy.
        Sci Transl Med. 2018; 10
        • Collier A.D.
        • et al.
        Embryonic Ethanol Exposure Affects the Early Development, Migration, and Location of Hypocretin/Orexin Neurons in Zebrafish.
        Alcohol Clin Exp Res. 2019; 43: 1702-1713
        • Collier A.D.
        • et al.
        Maternal ethanol consumption before paternal fertilization: Stimulation of hypocretin neurogenesis and ethanol intake in zebrafish offspring.
        Prog Neuropsychopharmacol Biol Psychiatry. 2020; 96109728
        • Collier A.D.
        • et al.
        Sexually dimorphic and asymmetric effects of embryonic ethanol exposure on hypocretin/orexin neurons as related to behavioral changes in zebrafish.
        Sci Rep. 2021; 1116078
        • Roberts D.C.
        • Loh E.A.
        • Vickers G.
        Self-administration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment.
        Psychopharmacology (Berl). 1989; 97: 535-538
        • Bentzley B.S.
        • Fender K.M.
        • Aston-Jones G.
        The behavioral economics of drug self-administration: a review and new analytical approach for within-session procedures.
        Psychopharmacology (Berl). 2013; 226: 113-125
        • Hursh S.R.
        • Silberberg A.
        Economic demand and essential value.
        Psychol Rev. 2008; 115: 186-198
        • Oleson E.B.
        • Roberts D.C.
        Behavioral economic assessment of price and cocaine consumption following self-administration histories that produce escalation of either final ratios or intake.
        Neuropsychopharmacology. 2009; 34: 796-804
        • Zimmer B.A.
        • Oleson E.B.
        • Roberts D.C.S.
        The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine.
        Neuropsychopharmacology. 2012; 37: 1901-1910
        • Siciliano C.A.
        • et al.
        Amphetamine Reverses Escalated Cocaine Intake via Restoration of Dopamine Transporter Conformation.
        The Journal of neuroscience : the official journal of the Society for Neuroscience. 2018; 38: 484-497
        • Calipari E.S.
        • et al.
        Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking.
        Neuropsychopharmacology. 2015; 40: 728-735
        • Bentzley B.S.
        • Jhou T.C.
        • Aston-Jones G.
        Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat.
        Proc Natl Acad Sci U S A. 2014; 111: 11822-11827
        • Cox B.M.
        • et al.
        Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand.
        Biol Psychiatry. 2017; 81: 949-958
        • Freeman L.R.
        • et al.
        Sex Differences in Demand for Highly Palatable Foods: Role of the Orexin System.
        Int J Neuropsychopharmacol. 2020;
        • Estabrooke I.V.
        • et al.
        Fos expression in orexin neurons varies with behavioral state.
        J Neurosci. 2001; 21: 1656-1662
        • Mileykovskiy B.Y.
        • Kiyashchenko L.I.
        • Siegel J.M.
        Behavioral correlates of activity in identified hypocretin/orexin neurons.
        Neuron. 2005; 46: 787-798
        • Furlong T.M.
        • et al.
        Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal.
        Eur J Neurosci. 2009; 30: 1603-1614
        • Harris G.C.
        • Aston-Jones G.
        Arousal and reward: a dichotomy in orexin function.
        Trends Neurosci. 2006; 29: 571-577
        • Yeoh J.W.
        • et al.
        Activation of lateral hypothalamic group III metabotropic glutamate receptors suppresses cocaine-seeking following abstinence and normalizes drug-associated increases in excitatory drive to orexin/hypocretin cells.
        Neuropharmacology. 2019; 154: 22-33
        • Kurose T.
        • et al.
        Effects of restricted feeding on the activity of hypothalamic Orexin (OX)-A containing neurons and OX2 receptor mRNA level in the paraventricular nucleus of rats.
        Regul Pept. 2002; 104: 145-151
        • Johnson P.L.
        • et al.
        Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network.
        Physiol Behav. 2012; 107: 733-742
        • Moorman D.E.
        • et al.
        Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner.
        Eur J Neurosci. 2016; 43: 710-720
        • McGregor R.
        • et al.
        Diurnal fluctuation in the number of hypocretin/orexin and histamine producing: Implication for understanding and treating neuronal loss.
        PLoS One. 2017; 12: e0178573
        • Prasad A.A.
        • McNally G.P.
        Effects of vivo morpholino knockdown of lateral hypothalamus orexin/hypocretin on renewal of alcohol seeking.
        PLoS One. 2014; 9: e110385
        • Lawrence A.J.
        • et al.
        The orexin system regulates alcohol-seeking in rats.
        Br J Pharmacol. 2006; 148: 752-759
        • Chang G.Q.
        • et al.
        Moderate Prenatal Ethanol Exposure Stimulates CXCL12/CXCR4 Chemokine System in Radial Glia Progenitor Cells in Hypothalamic Neuroepithelium and Peptide Neurons in Lateral Hypothalamus of the Embryo and Postnatal Offspring.
        Alcohol Clin Exp Res. 2020; 44: 866-879
        • Lemus M.B.
        • et al.
        A stereological analysis of NPY, POMC, Orexin, GFAP astrocyte, and Iba1 microglia cell number and volume in diet-induced obese male mice.
        Endocrinology. 2015; 156: 1701-1713
        • Wortley K.E.
        • et al.
        Orexin gene expression is increased during states of hypertriglyceridemia.
        American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2003; 284: R1454-R1465
        • Morganstern I.
        • et al.
        Increased orexin and melanin-concentrating hormone expression in the perifornical lateral hypothalamus of rats prone to overconsuming a fat-rich diet.
        Pharmacol Biochem Behav. 2010; 96: 413-422
        • Borgland S.L.
        • et al.
        Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers.
        J Neurosci. 2009; 29: 11215-11225
        • Fadel J.
        • Bubser M.
        • Deutch A.Y.
        Differential activation of orexin neurons by antipsychotic drugs associated with weight gain.
        J Neurosci. 2002; 22: 6742-6746
        • Pantazis C.B.
        • et al.
        The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand.
        Addict Biol. 2020; 25e12795
        • James M.H.
        • et al.
        Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin-1 receptor antagonist in rats.
        Eur J Neurosci. 2019; 50: 2602-2612
      2. O’Connor, S.L., et al., The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl. bioRxiv, 2020: p. 2020.04.25.061887.

        • Schmeichel B.E.
        • et al.
        Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats.
        Neuropsychopharmacology. 2015; 40: 1123-1129
        • Moorman D.E.
        • et al.
        Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats.
        Brain Res. 2017; (1654(Pt A): p. 34-42)
        • Mohammadkhani A.
        • et al.
        Orexin-1 receptor signaling in ventral pallidum regulates motivation for the opioid remifentanil.
        J Neurosci. 2019;
        • Wiskerke J.
        • James M.H.
        • Aston-Jones G.
        The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task.
        Brain Res. 2020; 1731146222
        • Vickers S.P.
        • et al.
        Effects of lisdexamfetamine in a rat model of binge-eating.
        J Psychopharmacol. 2015; 29: 1290-1307
        • Alcaraz-Iborra M.
        • et al.
        Binge-like consumption of caloric and non-caloric palatable substances in ad libitum-fed C57BL/6J mice: pharmacological and molecular evidence of orexin involvement.
        Behav Brain Res. 2014; 272: 93-99
        • Rorabaugh J.M.
        • Stratford J.M.
        • Zahniser N.R.
        A relationship between reduced nucleus accumbens shell and enhanced lateral hypothalamic orexin neuronal activation in long-term fructose bingeing behavior.
        PLoS One. 2014; 9e95019
        • Mehr J.B.
        • et al.
        Sleep dysregulation in binge eating disorder and "food addiction": the orexin (hypocretin) system as a potential neurobiological link.
        Neuropsychopharmacology. 2021;
        • Jupp B.
        • et al.
        The orexin(1) receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats.
        Brain Res. 2011; 1391: 54-59
        • Khoo S.Y.
        • Clemens K.J.
        • McNally G.P.
        Palatable food self-administration and reinstatement are not affected by dual orexin receptor antagonism.
        Prog Neuropsychopharmacol Biol Psychiatry. 2018; (87(Pt A): p. 147-157)
        • James M.H.
        • Aston-Jones G.
        Introduction to the Special Issue: "Making orexin-based therapies for addiction a reality: What are the steps from here?.
        Brain Res. 2020; 1731146665
      3. James, M.H., et al., Repurposing the dual orexin receptor antagonist suvorexant for the treatment of opioid use disorder: why sleep on this any longer? Neuropsychopharmacology, 2020.

        • Cole S.
        • Mayer H.S.
        • Petrovich G.D.
        Orexin/Hypocretin-1 Receptor Antagonism Selectively Reduces Cue-Induced Feeding in Sated Rats and Recruits Medial Prefrontal Cortex and Thalamus.
        Scientific Reports. 2015; 516143
      4. Gentile, T.A., et al., Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine. Neuropsychopharmacology, 2017.

        • Rasmussen K.
        • White D.A.
        • Acri J.B.
        NIDA's medication development priorities in response to the Opioid Crisis: ten most wanted.
        Neuropsychopharmacology. 2019; 44: 657-659
        • Campbell E.J.
        • Marchant N.J.
        • Lawrence A.J.
        A sleeping giant: Suvorexant for the treatment of alcohol use disorder?.
        Brain Res. 2020; 1731145902
        • Campbell E.J.
        • et al.
        Suvorexant to treat alcohol use disorder and comorbid insomnia: Plan for a phase II trial.
        Brain Res. 2020; 1728146597
        • Matzeu A.
        • Martin-Fardon R.
        Targeting the Orexin System for Prescription Opioid Use Disorder.
        Brain Sci. 2020; 10
        • Fragale J.E.
        • et al.
        The Insomnia-Addiction Positive Feedback Loop: Role of the Orexin System.
        Front Neurol Neurosci. 2021; 45: 117-127
        • Akimoto H.
        • Honda Y.
        • Takahashi Y.
        Pharmacotherapy in narcolepsy.
        Dis Nerv Syst. 1960; 21: 704-706
        • Nishino S.
        • Mignot E.
        Pharmacological aspects of human and canine narcolepsy.
        Prog Neurobiol. 1997; 52: 27-78
        • Singer B.F.
        • et al.
        Are Cocaine-Seeking "Habits" Necessary for the Development of Addiction-Like Behavior in Rats?.
        J Neurosci. 2018; 38: 60-73
        • Kane J.K.
        • et al.
        Nicotine up-regulates expression of orexin and its receptors in rat brain.
        Endocrinology. 2000; 141: 3623-3629
        • Wortley K.E.
        • et al.
        Peptides that regulate food intake: orexin gene expression is increased during states of hypertriglyceridemia.
        Am J Physiol Regul Integr Comp Physiol. 2003; 284: R1454-R1465
        • Chen X.
        • Li S.
        • Kirouac G.J.
        Blocking of corticotrophin releasing factor receptor-1 during footshock attenuates context fear but not the upregulation of prepro-orexin mRNA in rats.
        Pharmacol Biochem Behav. 2014; 120: 1-6
      5. Chen, X., et al., Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks. Brain Struct Funct, 2013.

        • Chou T.C.
        • et al.
        Orexin (hypocretin) neurons contain dynorphin.
        J Neurosci. 2001; 21: RC168
        • Li Y.
        • van den Pol A.N.
        Differential target-dependent actions of coexpressed inhibitory dynorphin and excitatory hypocretin/orexin neuropeptides.
        J Neurosci. 2006; 26: 13037-13047
        • Muschamp J.W.
        • et al.
        Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area.
        Proc Natl Acad Sci U S A. 2014; 111: E1648-E1655
        • Baimel C.
        • et al.
        Projection-Target-Defined Effects of Orexin and Dynorphin on VTA Dopamine Neurons.
        Cell Rep. 2017; 18: 1346-1355
        • Matzeu A.
        • Martin-Fardon R.
        Drug Seeking and Relapse: New Evidence of a Role for Orexin and Dynorphin Co-transmission in the Paraventricular Nucleus of the Thalamus.
        Frontiers in Neurology. 2018; 9
        • Spangler R.
        • Unterwald E.M.
        • Kreek M.J.
        ‘Binge’ cocaine administration induces a sustained increase of prodynorphin mRNA in rat caudate-putamen.
        Molecular Brain Research. 1993; 19: 323-327
        • Schmeichel B.E.
        • et al.
        Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats.
        Neuropsychopharmacology. 2018;
        • Pantazis C.B.
        • et al.
        Orexin-1 receptor signaling in ventral tegmental area mediates cue-driven demand for cocaine.
        Neuropsychopharmacology. 2021;
        • Wang B.
        • You Z.B.
        • Wise R.A.
        Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network.
        Biol Psychiatry. 2009; 65: 857-862
        • Mahler S.V.
        • Smith R.J.
        • Aston-Jones G.
        Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats.
        Psychopharmacology (Berl). 2013; 226: 687-698
        • James M.H.
        • et al.
        Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking.
        Int J Neuropsychopharmacol. 2011; 14: 684-690
        • Borgland S.L.
        • Storm E.
        • Bonci A.
        Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons.
        Eur J Neurosci. 2008; 28: 1545-1556
        • Borgland S.L.
        • et al.
        Orexin A in the VTA Is Critical for the Induction of Synaptic Plasticity and Behavioral Sensitization to Cocaine.
        Neuron. 2006; 49: 589-601
        • Mehr J.B.
        • Bilotti M.M.
        • James M.H.
        Orexin (hypocretin) and addiction.
        Trends Neurosci. 2021;
        • Lei K.
        • et al.
        Nucleus Accumbens Shell Orexin-1 Receptors Are Critical Mediators of Binge Intake in Excessive-Drinking Individuals.
        Front Neurosci. 2019; 13: 88
        • Lei K.
        • et al.
        Nucleus Accumbens Shell and mPFC but Not Insula Orexin-1 Receptors Promote Excessive Alcohol Drinking.
        Frontiers in Neuroscience. 2016; 10
        • James M.H.
        • et al.
        The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse.
        Neuropharmacology. 2020; 183108359
        • Escrivá-Martínez T.
        • et al.
        Binge Eating and Binge Drinking: A Two-Way Road? An Integrative Review.
        Curr Pharm Des. 2020; 26: 2402-2415
        • Grafe L.A.
        • et al.
        Orexins Mediate Sex Differences in the Stress Response and in Cognitive Flexibility.
        Biol Psychiatry. 2017; 81: 683-692
        • Kim T.K.
        • et al.
        Antidepressant effects of exercise are produced via suppression of hypocretin/orexin and melanin-concentrating hormone in the basolateral amygdala.
        Neurobiol Dis. 2015; 79: 59-69
        • Yaeger J.D.W.
        • et al.
        Orexin 1 Receptor Antagonism in the Basolateral Amygdala Shifts the Balance From Pro- to Antistress Signaling and Behavior.
        Biol Psychiatry. 2022;
        • Gyawali U.
        • James M.H.
        Orexin (Hypocretin) Signaling in the Basolateral Amygdala Contributes to Individual Differences in Stress Sensitivity.
        Biological Psychiatry. 2022; 91: 775-777
      6. Tanaka, S., Chapter Five - Transcriptional Regulation of the Hypocretin/Orexin Gene, in Vitamins & Hormones, G. Litwack, Editor. 2012, Academic Press. p. 75-90.

        • Silva J.P.
        • et al.
        Regulation of adaptive behaviour during fasting by hypothalamic Foxa2.
        Nature. 2009; 462: 646-650
        • Tanaka S.
        • et al.
        Transcriptional regulation of the hypocretin/orexin gene by NR6A1.
        Biochemical and Biophysical Research Communications. 2010; 403: 178-183
        • Honda M.
        • et al.
        IGFBP3 colocalizes with and regulates hypocretin (orexin).
        PLoS One. 2009; 4: e4254
        • Nestler E.J.
        • Lüscher C.
        The Molecular Basis of Drug Addiction: Linking Epigenetic to Synaptic and Circuit Mechanisms.
        Neuron. 2019; 102: 48-59
        • Bali P.
        • Kenny P.J.
        Transcriptional mechanisms of drug addiction.
        Dialogues Clin Neurosci. 2019; 21: 379-387
        • Kenny P.J.
        Epigenetics, microRNA, and addiction.
        Dialogues Clin Neurosci. 2014; 16: 335-344
        • Rao Y.
        • et al.
        Repeated in vivo exposure of cocaine induces long-lasting synaptic plasticity in hypocretin/orexin-producing neurons in the lateral hypothalamus in mice.
        J Physiol. 2013; 591: 1951-1966
        • Yeoh J.W.
        • et al.
        Cocaine potentiates excitatory drive in the perifornical/lateral hypothalamus.
        J Physiol. 2012; 590: 3677-3689
        • Porkka-Heiskanen T.
        • et al.
        Orexin A and B levels in the hypothalamus of female rats: the effects of the estrous cycle and age.
        Eur J Endocrinol. 2004; 150: 737-742