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The Role of Orexin-1 Receptors Within the Hippocampal CA1 Area in the Extinction and Reinstatement of Methamphetamine-Seeking Behaviors

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Abstract

Psychostimulant addiction is a chronic brain disorder with high relapse rates, requiring new therapeutic strategies. The orexin system is highly implicated in processing reward and addiction through connections with critical areas such as the hippocampus. This study investigated the role of orexin-1 receptors (OX1R) within the CA1 subregion of the hippocampus in the extinction and reinstatement of the methamphetamine-induced conditioned place preference. After cannulae implantation, recovery, and establishing the methamphetamine place preference, 98 male Wistar rats received different doses of bilateral intra-CA1 selective OX1R antagonist, SB334867 (1, 3, 10, and 30 nmol/0.5 μl DMSO per side) during the 10-day extinction period (daily) or after extinction phase, just on the reinstatement day (single dose) in separate experimental and control groups. The findings indicated that bilateral microinjection of SB334867 into the CA1 area during the extinction period could significantly reduce the extinction latency and maintenance of rewarding aspects of methamphetamine dose-dependently (3, 10, and 30 nmol). In another set of experiments, a single dose of bilateral intra-CA1 SB334867 administration on the reinstatement phase prevented the methamphetamine-induced reinstatement of drug-seeking behaviors at the high doses (10, and 30 nmol). The present study provided more evidence for the implication of hippocampal OX1R in the maintenance of rewarding and reinforcing properties of methamphetamine and its role in the relapse of methamphetamine-seeking behavior. Further investigations on the role of the orexin system, including the orexin-2 receptors in treating addiction, are needed to introduce its antagonists as effective therapeutic options for psychostimulant addiction.

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Data Availability

Data will be made available upon request. The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

References

  1. Panenka WJ et al (2013) Methamphetamine use: a comprehensive review of molecular, preclinical and clinical findings. Drug Alcohol Depend 129(3):167–179

    Article  CAS  Google Scholar 

  2. American Psychiatric Association (2013) Neurocognitive disorders chapter in diagnostic and statistical manual of mental disorders, 5th edn, vol 21. Am Psychiatric Assoc, Arlington, VA, pp 591–643

  3. Batra V et al (2016) A general method for evaluating deep brain stimulation effects on intravenous methamphetamine self-administration. J Vis Exp 107:e53266

    Google Scholar 

  4. Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565–598

    Article  CAS  Google Scholar 

  5. Kelley AE (2004) Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44(1):161–179

    Article  CAS  Google Scholar 

  6. Kauer JA, Malenka RC (2007) Synaptic plasticity and addiction. Nat Rev Neurosci 8(11):844–858

    Article  CAS  Google Scholar 

  7. Kutlu MG, Gould TJ (2016) Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction. Learn Mem 23(10):515–533

    Article  CAS  Google Scholar 

  8. Avchalumov Y, Mandyam CD (2021) Plasticity in the hippocampus, neurogenesis and drugs of abuse. Brain Sci 11(3):404

    Article  CAS  Google Scholar 

  9. Sakurai T et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92(4):573–585

    Article  CAS  Google Scholar 

  10. de Lecea L et al (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95(1):322–327

    Article  Google Scholar 

  11. Baimel C et al (2015) Orexin/hypocretin role in reward: implications for opioid and other addictions. Br J Pharmacol 172(2):334–348

    Article  CAS  Google Scholar 

  12. Gotter AL et al (2012) International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. Pharmacol Rev 64(3):389–420

    Article  CAS  Google Scholar 

  13. Cason AM et al (2010) Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol Behav 100(5):419–428

    Article  CAS  Google Scholar 

  14. Farahimanesh S, Karimi S, Haghparast A (2018) Role of orexin-1 receptors in the dorsal hippocampus (CA1 region) in expression and extinction of the morphine-induced conditioned place preference in the rats. Peptides 101:25–31

    Article  CAS  Google Scholar 

  15. RayatSanati K et al (2021) Blockade of orexin receptors in the hippocampal dentate gyrus reduced the extinction latency of morphine-induced place preference in male rats. Neurosci Lett 756:135946

    Article  CAS  Google Scholar 

  16. Alizamini MM et al (2018) Intra-hippocampal administration of orexin receptor antagonists dose-dependently attenuates reinstatement of morphine seeking behavior in extinguished rats. Peptides 110:40–46

    Article  CAS  Google Scholar 

  17. Amirteymori H et al (2022) Hypocretin/orexin system in the nucleus accumbens as a promising player in the extinction and reinstatement of methamphetamine-induced CPP. Prog Neuropsychopharmacol Biol Psychiatry 120:110616

    Article  Google Scholar 

  18. Khosrowabadi E et al (2020) Differential roles of intra-accumbal orexin receptors in acquisition and expression of methamphetamine-induced conditioned place preference in the rats. Neurochem Res 45(9):2230–2241

    Article  CAS  Google Scholar 

  19. Karimi-Haghighi S, Dargahi L, Haghparast A (2020) Cannabidiol modulates the expression of neuroinflammatory factors in stress- and drug-induced reinstatement of methamphetamine in extinguished rats. Addict Biol 25(2):e12740

    Article  Google Scholar 

  20. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Elsevier, Amsterdam

    Google Scholar 

  21. James MH et al (2017) A decade of orexin/hypocretin and addiction: where are we now? Curr Top Behav Neurosci 33:247–281

    Article  Google Scholar 

  22. Brown MA, Guilleminault C (2011) A review of sodium oxybate and baclofen in the treatment of sleep disorders. Curr Pharm Des 17(15):1430–1435

    Article  CAS  Google Scholar 

  23. Tabaeizadeh M et al (2013) The differential effects of OX1R and OX2R selective antagonists on morphine conditioned place preference in naïve versus morphine-dependent mice. Behav Brain Res 237:41–48

    Article  CAS  Google Scholar 

  24. Bentzley BS, Aston-Jones G (2015) Orexin-1 receptor signaling increases motivation for cocaine-associated cues. Eur J Neurosci 41(9):1149–1156

    Article  Google Scholar 

  25. Azizbeigi R, Farzinpour Z, Haghparast A (2019) Role of orexin-1 receptor within the ventral tegmental area in mediating stress- and morphine priming-induced reinstatement of conditioned place preference in rats. Basic Clin Neurosci 10(4):373–382

    CAS  Google Scholar 

  26. Zarrabian S et al (2020) The potential role of the orexin reward system in future treatments for opioid drug abuse. Brain Res 1731:146028

    Article  CAS  Google Scholar 

  27. Guo SJ et al (2016) Orexin A-mediated AKT signaling in the dentate gyrus contributes to the acquisition, expression and reinstatement of morphine-induced conditioned place preference. Addict Biol 21(3):547–559

    Article  CAS  Google Scholar 

  28. Perrey DA, Zhang Y (2020) Therapeutics development for addiction: orexin-1 receptor antagonists. Brain Res 1731:145922

    Article  CAS  Google Scholar 

  29. Khoo SY, Brown RM (2014) Orexin/hypocretin based pharmacotherapies for the treatment of addiction: DORA or SORA? CNS Drugs 28(8):713–730

    Article  CAS  Google Scholar 

  30. Mahler SV et al (2012) Multiple roles for orexin/hypocretin in addiction. Prog Brain Res 198:79–121

    Article  CAS  Google Scholar 

  31. Boutrel B et al (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci U S A 102(52):19168–19173

    Article  CAS  Google Scholar 

  32. Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437(7058):556–559

    Article  CAS  Google Scholar 

  33. Sjulson L et al (2018) Cocaine place conditioning strengthens location-specific hippocampal coupling to the nucleus accumbens. Neuron 98(5):926-934.e5

    Article  CAS  Google Scholar 

  34. Thompson AM et al (2004) Modulation of long-term potentiation in the rat hippocampus following cocaine self-administration. Neuroscience 127(1):177–185

    Article  CAS  Google Scholar 

  35. North A et al (2013) Chronic methamphetamine exposure produces a delayed, long-lasting memory deficit. Synapse 67(5):245–257

    Article  CAS  Google Scholar 

  36. Yamazaki Y et al (2006) Nicotine exposure in vivo induces long-lasting enhancement of NMDA receptor-mediated currents in the hippocampus. Eur J Neurosci 23(7):1819–1828

    Article  Google Scholar 

  37. Lawrence AJ et al (2006) The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 148(6):752–759

    Article  CAS  Google Scholar 

  38. Lawrence AJ (2010) Regulation of alcohol-seeking by orexin (hypocretin) neurons. Brain Res 1314:124–129

    Article  CAS  Google Scholar 

  39. Walker LC, Lawrence AJ (2017) The role of orexins/hypocretins in alcohol use and abuse. Curr Top Behav Neurosci 33:221–246

    Article  Google Scholar 

  40. Kenny PJ (2011) Tobacco dependence, the insular cortex and the hypocretin connection. Pharmacol Biochem Behav 97(4):700–707

    Article  CAS  Google Scholar 

  41. Farahimanesh S, Zarrabian S, Haghparast A (2017) Role of orexin receptors in the ventral tegmental area on acquisition and expression of morphine-induced conditioned place preference in the rats. Neuropeptides 66:45–51

    Article  CAS  Google Scholar 

  42. Jamali S, Zarrabian S, Haghparast A (2021) Similar role of mPFC orexin-1 receptors in the acquisition and expression of morphine- and food-induced conditioned place preference in male rats. Neuropharmacology 198:108764

    Article  CAS  Google Scholar 

  43. Sahafzadeh M et al (2018) Role of the orexin receptors within the nucleus accumbens in the drug priming-induced reinstatement of morphine seeking in the food deprived rats. Brain Res Bull 137:217–224

    Article  CAS  Google Scholar 

  44. Edalat P et al (2018) Role of orexin-1 and orexin-2 receptors in the CA1 region of hippocampus in the forced swim stress- and food deprivation-induced reinstatement of morphine seeking behaviors in rats. Brain Res Bull 142:25–32

    Article  CAS  Google Scholar 

  45. Voorhees CM, Cunningham CL (2011) Involvement of the orexin/hypocretin system in ethanol conditioned place preference. Psychopharmacology 214(4):805–818

    Article  CAS  Google Scholar 

  46. Sharf R et al (2010) Orexin mediates morphine place preference, but not morphine-induced hyperactivity or sensitization. Brain Res 1317:24–32

    Article  CAS  Google Scholar 

  47. Sil’kis I (2013) Possible mechanisms for the effects of orexin on hippocampal functioning and spatial learning (analytical review). Neurosci Behav Physiol 43(9):1049–1057

    Article  Google Scholar 

  48. Lu GL, Lee CH, Chiou LC (2016) Orexin A induces bidirectional modulation of synaptic plasticity: inhibiting long-term potentiation and preventing depotentiation. Neuropharmacology 107:168–180

    Article  CAS  Google Scholar 

  49. Chen XY, Chen L, Du YF (2017) Orexin-A increases the firing activity of hippocampal CA1 neurons through orexin-1 receptors. J Neurosci Res 95(7):1415–1426

    Article  CAS  Google Scholar 

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Acknowledgements

This project was supported by the Vice-Chancellor for Research & Technology of Behbahan Faculty of Medical Sciences (Grant No. 400064). Also, the authors would like to thank the Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences for cooperation in this work.

Funding

Funding for this study was provided by the grant (No. 400064) from Vice-Chancellor for Research & Technology of Behbahan Faculty of Medical Sciences, Behbahan, Iran. The Vice-Chancellor for Research & Technology had no further role in the design of the study; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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Authors and Affiliations

  1. Department of Physiology, Behbahan Faculty of Medical Sciences, Behbahan, Iran

    Ali Veisi

  2. Department of Physiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran

    Hossein Khaleghzadeh‐Ahangar

  3. Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

    Hossein Khaleghzadeh‐Ahangar

  4. Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, P.O.Box 19615-1178, Tehran, Iran

    Mojdeh Fattahi & Abbas Haghparast

  5. School of Cognitive Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran

    Abbas Haghparast

  6. Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran

    Abbas Haghparast

Authors
  1. Ali Veisi
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  2. Hossein Khaleghzadeh‐Ahangar
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  3. Mojdeh Fattahi
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Contributions

Abbas Haghparast was responsible for the study concept and design. Data collection were performed by Ali Veisi and Hossein Khaleghzadeh‐Ahangar. Abbas Haghparast and Mojdeh Fattahi assisted with data analysis and interpretation of findings. The first draft of the manuscript was written by Mojdeh Fattahi, and all authors commented on previous versions of the manuscript. All authors critically reviewed the content and approved the final version for publication.

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Correspondence to Abbas Haghparast.

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Veisi, A., Khaleghzadeh‐Ahangar, H., Fattahi, M. et al. The Role of Orexin-1 Receptors Within the Hippocampal CA1 Area in the Extinction and Reinstatement of Methamphetamine-Seeking Behaviors. Neurochem Res 48, 671–680 (2023). https://doi.org/10.1007/s11064-022-03793-9

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  • DOI: https://doi.org/10.1007/s11064-022-03793-9

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