The role of orexins/hypocretins in alcohol use and abuse: an appetitive-reward relationship

Orexins (hypocretins) are neuropeptides synthesized in neurons located in the lateral (LH), perifornical, and dorsomedial (DMH) hypothalamus. These neurons innervate many regions in the brain and modulate multiple other neurotransmitter systems. As a result of these extensive projections and interactions orexins are involved in numerous functions, such as feeding behavior, neuroendocrine regulation, the sleep-wake cycle, and reward-seeking. This review will summarize the literature to date which has evaluated a role of orexins in the behavioral effects of alcohol, with a focus on understanding the importance of this peptide and its potential as a clinical therapeutic target for alcohol use disorders.

• Publication year

  2012

• Venue

  Frontiers in Behavioral Neuroscience

• Publication date

  2012-11-22

• Fields of study

  Medicine, Psychology

• Identifiers
  DOI 10.3389/fnbeh.2012.00078PMID 23189046PMCID 3504295
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2014cited by this paper
• Neurochemical heterogeneity of rats predicted by different measures to be high ethanol consumers.

  2013cited by this paper
• Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans.

  2013cited by this paper
• Glutamatergic input to the lateral hypothalamus stimulates ethanol intake: role of orexin and melanin-concentrating hormone.

  2013cited by this paper
• Differential orexin/hypocretin expression in addiction-prone and -resistant rats selectively bred for high (HiS) and low (LoS) saccharin intake.

  2012cited by this paper
• Arousal effects of orexin A on acute alcohol intoxication-induced coma in rats.

  2012cited by this paper
• Lateral Hypothalamic Orexin/Hypocretin Neurons That Project to Ventral Tegmental Area Are Differentially Activated with Morphine Preference

  2012influential reference
• Prenatal ethanol exposure stimulates neurogenesis in hypothalamic and limbic peptide systems: possible mechanism for offspring ethanol overconsumption.

  2012cited by this paper
• Hypocretin/orexin signaling in the hypothalamic paraventricular nucleus is essential for the expression of nicotine withdrawal.

  2012cited by this paper
• Orexin ⁄ hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking

  2012cited by this paper
• Convergent inputs from electrically and topographically distinct orexin cells to locus coeruleus and ventral tegmental area

  2012cited by this paper
• Orexin receptors as therapeutic drug targets.

  2012cited by this paper
• A Septal-Hypothalamic Pathway Drives Orexin Neurons, Which Is Necessary for Conditioned Cocaine Preference

  2012cited by this paper
• Orexin-1 Receptor Mediation of Cocaine Seeking in Male and Female Rats

  2012cited by this paper
• Orexin / hypocretin 1 receptor antagonist reduces heroin self‐administration and cue‐induced heroin seeking

  2012cited by this paper
• Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

  2011influential reference
• Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications

  2011cited by this paper
• Antagonism of orexin 1 receptors eliminates motor hyperactivity and improves homing response acquisition in juvenile rats exposed to alcohol during early postnatal period.

  2011cited by this paper
• Involvement of the orexin/hypocretin system in ethanol conditioned place preference

  2011cited by this paper
• Involvement of orexin in the regulation of stress, depression and reward in alcohol dependence.

  2011cited by this paper
• Discrete cue‐conditioned alcohol‐seeking after protracted abstinence: pattern of neural activation and involvement of orexin1 receptors

  2011influential reference
• Orexin A expression and promoter methylation in patients with alcohol dependence comparing acute and protracted withdrawal.

  2011cited by this paper
• Orexin receptors: pharmacology and therapeutic opportunities.

  2011cited by this paper
• Differential Effects of the Dual Orexin Receptor Antagonist Almorexant and the GABAA-α1 Receptor Modulator Zolpidem, Alone or Combined with Ethanol, on Motor Performance in the Rat

  2011cited by this paper
• Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking.

  2011cited by this paper
• The orexin₁ receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats.

  2011cited by this paper
• Functional Magnetic Resonance Imaging Reveals Different Neural Substrates for the Effects of Orexin-1 and Orexin-2 Receptor Antagonists

  2011cited by this paper
• Galanin knockout mice show disturbances in ethanol consumption and expression of hypothalamic peptides that stimulate ethanol intake.

  2010cited by this paper
• Accumbens Shell–Hypothalamus Interactions Mediate Extinction of Alcohol Seeking

  2010cited by this paper
• Hypocretins Regulate the Anxiogenic-Like Effects of Nicotine and Induce Reinstatement of Nicotine-Seeking Behavior

  2010cited by this paper
• Orexin/hypocretin is necessary for context-driven cocaine-seeking.

  2010cited by this paper
• Differential effects of acute and chronic ethanol exposure on orexin expression in the perifornical lateral hypothalamus.

  2010cited by this paper
• The Orexin-1 Receptor Antagonist SB-334867 Reduces Alcohol Relapse Drinking, but not Alcohol-Seeking, in Alcohol-Preferring (P) Rats

  2010cited by this paper
• Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity.

  2010cited by this paper
• Orexin receptor antagonism prevents transcriptional and behavioral plasticity resulting from stimulant exposure.

  2010cited by this paper
• Role of innate and drug-induced dysregulation of brain stress and arousal systems in addiction: Focus on corticotropin-releasing factor, nociceptin/orphanin FQ, and orexin/hypocretin.

  2010cited by this paper
• Orexin mediates morphine place preference, but not morphine-induced hyperactivity or sensitization.

  2010influential reference
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  2010cited by this paper
• Lateral Hypothalamus Is Required for Context-Induced Reinstatement of Extinguished Reward Seeking

  2009cited by this paper
• Orexin-1 receptor antagonism decreases ethanol consumption and preference selectively in high-ethanol--preferring Sprague--Dawley rats.

  2009cited by this paper
• Persistent Increase of Alcohol-Seeking Evoked by Neuropeptide S: an Effect Mediated by the Hypothalamic Hypocretin System

  2009cited by this paper
• Biomedical application of orexin/hypocretin receptor ligands in neuroscience.

  2009cited by this paper
• Blockade of Orexin-1 Receptors Attenuates Orexin-2 Receptor Antagonism-Induced Sleep Promotion in the Rat

  2009cited by this paper
• Biochemical and Electrophysiological Characterization of Almorexant, a Dual Orexin 1 Receptor (OX1)/Orexin 2 Receptor (OX2) Antagonist: Comparison with Selective OX1 and OX2 Antagonists

  2009cited by this paper
• Review

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• The philosophy of scientific experimentation: a review

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• Orexin A/Hypocretin-1 Selectively Promotes Motivation for Positive Reinforcers

  2009cited by this paper
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  2009cited by this paper
• Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network.

  2009cited by this paper
• Biochemical and behavioural characterization of EMPA, a novel high‐affinity, selective antagonist for the OX2 receptor

  2009cited by this paper
• Orexin/hypocretin signaling at the orexin 1 receptor regulates cue‐elicited cocaine‐seeking

  2009cited by this paper
• Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding.

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• Discovery of a Potent, CNS‐Penetrant Orexin Receptor Antagonist Based on an N,N‐Disubstituted‐1,4‐diazepane Scaffold that Promotes Sleep in Rats

  2009cited by this paper
• Hypocretin /orexin preferentially activates caudomedial ventral tegmental area dopamine neurons

  2008cited by this paper
• Stimuli linked to ethanol availability activate hypothalamic CART and orexin neurons in a reinstatement model of relapse.

  2008cited by this paper
• Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long–Evans rats

  2008influential reference
• Proline bis-amides as potent dual orexin receptor antagonists.

  2008cited by this paper
• The incentive sensitization theory of addiction: some current issues

  2008cited by this paper
• Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons

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• Distribution of orexin neurons in the adult rat brain

  2007cited by this paper
• HE NEURAL CORRELATES AND ROLE OF D1 DOPAMINE ECEPTORS IN RENEWAL OF EXTINGUISHED ALCOHOL-SEEKING

  2007cited by this paper
• Orexin axons in the rat ventral tegmental area synapse infrequently onto dopamine and γ‐aminobutyric acid neurons

  2007cited by this paper
• Orexigenic peptides and alcohol intake: differential effects of orexin, galanin, and ghrelin.

  2007cited by this paper
• Interactions of the basolateral amygdala with the dorsal hippocampus and dorsomedial prefrontal cortex regulate drug context‐induced reinstatement of cocaine‐seeking in rats

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• Selective inactivation of the ventral hippocampus attenuates cue-induced and cocaine-primed reinstatement of drug-seeking in rats.

  2007cited by this paper
• Quantification of Phosphorylated cAMP-Response Element-Binding Protein Expression throughout the Brain of Amphetamine-Sensitized Rats: Activation of Hypothalamic Orexin A-Containing Neurons

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• The neural correlates and role of D1 dopamine receptors in renewal of extinguished alcohol-seeking.

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• Arousal and reward: a dichotomy in orexin function.

  2006influential reference
• Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine.

  2006cited by this paper
• The orexin system regulates alcohol‐seeking in rats

  2006influential reference
• Direct Involvement of Orexinergic Systems in the Activation of the Mesolimbic Dopamine Pathway and Related Behaviors Induced by Morphine

  2006influential reference
• IL-13受体α2降低血吸虫病肉芽肿的炎症反应并延长宿主存活时间[英]/Mentink-Kane MM,Cheever AW，Thompson RW，et al//Proc Natl Acad Sci U S A

  2005cited by this paper
• Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior.

  2005cited by this paper
• The neural basis of addiction: a pathology of motivation and choice.

  2005cited by this paper
• A role for lateral hypothalamic orexin neurons in reward seeking

  2005influential reference
• The Role of the Dorsomedial Prefrontal Cortex, Basolateral Amygdala, and Dorsal Hippocampus in Contextual Reinstatement of Cocaine Seeking in Rats

  2005cited by this paper
• Neural substrates of cocaine-cue associations that trigger relapse.

  2005cited by this paper
• Characterisation of the binding of [3H]‐SB‐674042, a novel nonpeptide antagonist, to the human orexin‐1 receptor

  2004cited by this paper
• Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists.

  2004cited by this paper
• Reinstatement of cocaine-reinforced responding in the rat

  2004cited by this paper
• Excitation of Ventral Tegmental Area Dopaminergic and Nondopaminergic Neurons by Orexins/Hypocretins

  2003influential reference
• Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins.

  2003cited by this paper
• Direct and Indirect Excitation of Laterodorsal Tegmental Neurons by Hypocretin/Orexin Peptides: Implications for Wakefulness and Narcolepsy

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  2002cited by this paper
• Convergent Excitation of Dorsal Raphe Serotonin Neurons by Multiple Arousal Systems (Orexin/Hypocretin, Histamine and Noradrenaline)

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• SB‐334867, a selective orexin‐1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin‐A in rats

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• Centrally administered orexin/hypocretin activates HPA axis in rats

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• Hypocretin-1 Modulates Rapid Eye Movement Sleep through Activation of Locus Coeruleus Neurons

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• Acute effects of ethanol on GABAA and glycine receptor function.

  1999cited by this paper
• Hypothalamic Hypocretin (Orexin): Robust Innervation of the Spinal Cord

  1999cited by this paper
• Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems.

  1999cited by this paper
• Distribution of orexin neurons in the adult rat brain.

  1999cited by this paper
• Neuronal nicotinic acetylcholine receptors: a new target site of ethanol.

  1999cited by this paper

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  2016cites this paper
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  2015cites this paper
• Prenatal exposure to ethanol stimulates hypothalamic CCR2 chemokine receptor system: Possible relation to increased density of orexigenic peptide neurons and ethanol drinking in adolescent offspring.

  2015cites this paper
• Anterior thalamic paraventricular nucleus is involved in intermittent access ethanol drinking: role of orexin receptor 2

  2015cites this paper
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  2015cites this paper
• Relaxin-3/RXFP3 networks: an emerging target for the treatment of depression and other neuropsychiatric diseases?

  2014cites this paper
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  2014cites this paper
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  2014cites this paper
• Molecular determinants of orexin receptor-arrestinubiquitin complex formation

  2013cites this paper
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