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Modulatory role of the mPFC orexin-2 receptors in the acquisition and expression in two paradigms of the natural- and drug-induced conditioned place preference in the rats.

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Title: Modulatory role of the mPFC orexin-2 receptors in the acquisition and expression in two paradigms of the natural- and drug-induced conditioned place preference in the rats.
Authors: Jamali S; Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran., Mirmohammadi M; Neurobiology Research Center Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran., Azizbeigi R; Department of Basic Sciences, Sa.C., Islamic Azad University, Sanandaj, Iran., Alizamini MM; Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran., Taslimi Z; Behavioral Disorders and Substance Abuse Research Center, Institute of Neuroscience and Mental Health, Hamadan University of Medical Sciences, Hamadan, Iran., Haghparast A; Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran; Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran; National Brain Mapping Laboratory (NBML), Tehran, Iran. Electronic address: Haghparast@yahoo.com.
Source: Behavioural brain research [Behav Brain Res] 2026 Oct 18; Vol. 515, pp. 116430. Date of Electronic Publication: 2026 Aug 10.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Elsevier/North-Holland Biomedical Press Country of Publication: Netherlands NLM ID: 8004872 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7549 (Electronic) Linking ISSN: 01664328 NLM ISO Abbreviation: Behav Brain Res Subsets: MEDLINE
Imprint Name(s): Original Publication: Amsterdam, Elsevier/North-Holland Biomedical Press.
MeSH Terms: Orexin Receptors*/metabolism , Orexin Receptors*/physiology , Orexin Receptors*/drug effects , Prefrontal Cortex*/drug effects , Prefrontal Cortex*/metabolism , Prefrontal Cortex*/physiology , Drug-Seeking Behavior*/drug effects , Drug-Seeking Behavior*/physiology , Behavior, Animal*/drug effects , Behavior, Animal*/physiology, Orexin Receptor Antagonists/pharmacology ; Orexin Receptor Antagonists/administration & dosage ; Morphine/pharmacology ; Morphine/administration & dosage ; Isoquinolines/pharmacology ; Benzoxazoles/pharmacology ; Animals ; Male ; Rats, Wistar ; Reward ; Rats ; Naphthyridines ; Pyridines
Abstract: The neuropeptide orexin/hypocretin regulates adaptive behaviors needed for survival, including food intake, sleep-wake regulation, mating, and maternal behavior. However, the orexinergic system plays a critical role in addictive behavior and promotes seeking and rewarding substances of abuse and palatable food. Plenty of orexin receptors exist in the medial prefrontal cortex (mPFC). The PFC input to the NAc mediates goal-directed behaviors such as seeking behavior and planning actions to obtain rewarding substances. This study investigated the role of mPFC orexin-2 receptors (Orx2Rs) in natural-and drug-reward-seeking behaviors. One hundred sixteen adult male Wistar rats received TCS OX2 29 (3, 10, and 30 nmol/0.5 µl DMSO 12%) as an Orx2R antagonist in the mPFC during the acquisition and expression phases of two different CPP paradigms, morphine- and food-induced CPP protocols. Findings demonstrated that intra-mPFC administration of Orx2R antagonist reduced the acquisition and expression of morphine- and food-induced CPP in the rats. However, blockades of Orx2Rs in the mPFC have more inhibitory effects in food-induced CPP than in morphine-induced CPP. In conclusion, this study proposes a differential involvement of mPFC Orx2Rs in the acquisition and expression phases of CPP, suggesting distinguishable behavioral effects between food and morphine reward models. However, further mechanistic studies are required to clarify the underlying neural substrates.
(Copyright © 2026 Elsevier B.V. All rights reserved.)
Competing Interests: Declaration of Competing Interest The authors declare that they do not have any conflict of interest.
Contributed Indexing: Keywords: Conditioned place preference; Drug reward; Food; Medial prefrontal cortex; Morphine; Natural reward; Orexin-2 receptor; Rat
Substance Nomenclature: 0 (Orexin Receptors)
0 (Orexin Receptor Antagonists)
76I7G6D29C (Morphine)
0 (Isoquinolines)
0 (1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone)
0 (Hcrtr2 protein, rat)
0 (Benzoxazoles)
0 (Naphthyridines)
0 (Pyridines)
Entry Date(s): Date Created: 20260810 Date Completed: 20260904 Latest Revision: 20260904
Update Code: 20260905
DOI: 10.1016/j.bbr.2026.116430
PMID: 42575364
Database: MEDLINE
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  Data: Modulatory role of the mPFC orexin-2 receptors in the acquisition and expression in two paradigms of the natural- and drug-induced conditioned place preference in the rats.
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  Data: <searchLink fieldCode="AU" term="%22Jamali+S%22">Jamali S</searchLink>; Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran.<br /><searchLink fieldCode="AU" term="%22Mirmohammadi+M%22">Mirmohammadi M</searchLink>; Neurobiology Research Center Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran.<br /><searchLink fieldCode="AU" term="%22Azizbeigi+R%22">Azizbeigi R</searchLink>; Department of Basic Sciences, Sa.C., Islamic Azad University, Sanandaj, Iran.<br /><searchLink fieldCode="AU" term="%22Alizamini+MM%22">Alizamini MM</searchLink>; Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran.<br /><searchLink fieldCode="AU" term="%22Taslimi+Z%22">Taslimi Z</searchLink>; Behavioral Disorders and Substance Abuse Research Center, Institute of Neuroscience and Mental Health, Hamadan University of Medical Sciences, Hamadan, Iran.<br /><searchLink fieldCode="AU" term="%22Haghparast+A%22">Haghparast A</searchLink>; Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran; Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran; National Brain Mapping Laboratory (NBML), Tehran, Iran. Electronic address: Haghparast@yahoo.com.
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– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: The neuropeptide orexin/hypocretin regulates adaptive behaviors needed for survival, including food intake, sleep-wake regulation, mating, and maternal behavior. However, the orexinergic system plays a critical role in addictive behavior and promotes seeking and rewarding substances of abuse and palatable food. Plenty of orexin receptors exist in the medial prefrontal cortex (mPFC). The PFC input to the NAc mediates goal-directed behaviors such as seeking behavior and planning actions to obtain rewarding substances. This study investigated the role of mPFC orexin-2 receptors (Orx2Rs) in natural-and drug-reward-seeking behaviors. One hundred sixteen adult male Wistar rats received TCS OX2 29 (3, 10, and 30 nmol/0.5 µl DMSO 12%) as an Orx2R antagonist in the mPFC during the acquisition and expression phases of two different CPP paradigms, morphine- and food-induced CPP protocols. Findings demonstrated that intra-mPFC administration of Orx2R antagonist reduced the acquisition and expression of morphine- and food-induced CPP in the rats. However, blockades of Orx2Rs in the mPFC have more inhibitory effects in food-induced CPP than in morphine-induced CPP. In conclusion, this study proposes a differential involvement of mPFC Orx2Rs in the acquisition and expression phases of CPP, suggesting distinguishable behavioral effects between food and morphine reward models. However, further mechanistic studies are required to clarify the underlying neural substrates.<br /> (Copyright © 2026 Elsevier B.V. All rights reserved.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Declaration of Competing Interest The authors declare that they do not have any conflict of interest.
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  Data: <i>Keywords: </i>Conditioned place preference; Drug reward; Food; Medial prefrontal cortex; Morphine; Natural reward; Orexin-2 receptor; Rat
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  Data: 0 (Orexin Receptors)<br />0 (Orexin Receptor Antagonists)<br />76I7G6D29C (Morphine)<br />0 (Isoquinolines)<br />0 (1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone)<br />0 (Hcrtr2 protein, rat)<br />0 (Benzoxazoles)<br />0 (Naphthyridines)<br />0 (Pyridines)
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  Data: 10.1016/j.bbr.2026.116430
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        Value: 10.1016/j.bbr.2026.116430
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      – Code: eng
        Text: English
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        StartPage: 116430
    Subjects:
      – SubjectFull: Orexin Receptor Antagonists pharmacology
        Type: general
      – SubjectFull: Orexin Receptor Antagonists administration & dosage
        Type: general
      – SubjectFull: Morphine pharmacology
        Type: general
      – SubjectFull: Morphine administration & dosage
        Type: general
      – SubjectFull: Isoquinolines pharmacology
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      – SubjectFull: Animals
        Type: general
      – SubjectFull: Male
        Type: general
      – SubjectFull: Rats, Wistar
        Type: general
      – SubjectFull: Reward
        Type: general
      – SubjectFull: Rats
        Type: general
      – SubjectFull: Naphthyridines
        Type: general
      – SubjectFull: Pyridines
        Type: general
      – SubjectFull: Orexin Receptors metabolism
        Type: general
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        Type: general
      – SubjectFull: Orexin Receptors drug effects
        Type: general
      – SubjectFull: Prefrontal Cortex drug effects
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      – SubjectFull: Prefrontal Cortex metabolism
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      – SubjectFull: Prefrontal Cortex physiology
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      – SubjectFull: Drug-Seeking Behavior drug effects
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      – SubjectFull: Drug-Seeking Behavior physiology
        Type: general
      – SubjectFull: Behavior, Animal drug effects
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      – SubjectFull: Behavior, Animal physiology
        Type: general
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      – TitleFull: Modulatory role of the mPFC orexin-2 receptors in the acquisition and expression in two paradigms of the natural- and drug-induced conditioned place preference in the rats.
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              Text: 2026 Oct 18
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