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A locus coeruleus to dorsal hippocampus pathway mediates cue-induced reinstatement of opioid self-administration in male and female rats

Neuropsychopharmacology volume 49, pages 915–923 (2024)Cite this article

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Abstract

Opioid use disorder is a chronic relapsing disorder encompassing misuse, dependence, and addiction to opioid drugs. Long term maintenance of associations between the reinforcing effects of the drug and the cues associated with its intake are a leading cause of relapse. Indeed, exposure to the salient drug-associated cues can lead to drug cravings and drug seeking behavior. The dorsal hippocampus (dHPC) and locus coeruleus (LC) have emerged as important structures for linking the subjective rewarding effects of opioids with environmental cues. However, their role in cue-induced reinstatement of opioid use remains to be further elucidated. In this study, we showed that chemogenetic inhibition of excitatory dHPC neurons during re-exposure to drug-associated cues significantly attenuates cue-induced reinstatement of morphine-seeking behavior. In addition, the same manipulation reduced reinstatement of sucrose-seeking behavior but failed to alter memory recall in the object location task. Finally, intact activity of tyrosine hydroxylase (TH) LC-dHPCTh afferents is necessary to drive cue induced reinstatement of morphine-seeking as inhibition of this pathway blunts cue-induced drug-seeking behavior. Altogether, these studies show an important role of the dHPC and LC-dHPCTh pathway in mediating cue-induced reinstatement of opioid seeking.

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Fig. 1: Inhibition of excitatory dHPC neurons attenuates cue-induced reinstatement of morphine-seeking.
Fig. 2: Inhibition of excitatory dHPC neurons does not alter memory recall during object location test.
Fig. 3: Inhibition of excitatory dHPC neurons attenuates cue-induced reinstatement of sucrose-seeking.
Fig. 4: Inhibition of LC-dHPCTh pathway diminishes cue-induced reinstatement of drug-seeking.

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Funding

This work was supported by US National Institutes of Health (NIH) grants DA054900 (JAM), DA045463 (JAM), DA041781 (JAM), DA042499 (JAM), DA055047 (JGM, NM), and NS117899 (JGM).

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Authors and Affiliations

  1. Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, USA

    Tamara Markovic, Jessica Higginbotham, Brian Ruyle, Nicolas Massaly, Hye Jean Yoon, Chao-Cheng Kuo, Jenny R. Kim, Jiwon Yi, Jeniffer J. Garcia, Eric Sze, Julian Abt, Rachel H. Teich, Joanna J. Dearman, Jordan G. McCall & Jose A. Morón

  2. Pain Center, Washington University in St Louis, St. Louis, MO, USA

    Tamara Markovic, Jessica Higginbotham, Brian Ruyle, Nicolas Massaly, Hye Jean Yoon, Chao-Cheng Kuo, Jenny R. Kim, Jiwon Yi, Jeniffer J. Garcia, Eric Sze, Julian Abt, Rachel H. Teich, Joanna J. Dearman, Jordan G. McCall & Jose A. Morón

  3. School of Medicine, Washington University in St Louis, St. Louis, MO, USA

    Tamara Markovic, Jessica Higginbotham, Brian Ruyle, Nicolas Massaly, Hye Jean Yoon, Chao-Cheng Kuo, Jenny R. Kim, Jiwon Yi, Jeniffer J. Garcia, Eric Sze, Julian Abt, Rachel H. Teich, Joanna J. Dearman, Jordan G. McCall & Jose A. Morón

  4. Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, USA

    Tamara Markovic, Jessica Higginbotham, Brian Ruyle, Nicolas Massaly, Hye Jean Yoon, Jiwon Yi, Jeniffer J. Garcia, Eric Sze, Julian Abt, Rachel H. Teich, Joanna J. Dearman & Jose A. Morón

  5. Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO, USA

    Chao-Cheng Kuo, Jenny R. Kim & Jordan G. McCall

  6. Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis, St. Louis, MO, USA

    Chao-Cheng Kuo, Jenny R. Kim & Jordan G. McCall

  7. Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA

    Jose A. Morón

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  1. Tamara Markovic
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Contributions

Conceptualization - TM, NM, JGM; and JAM; Methodology - TM, and JAM; Formal Analysis of all data - TM, and JAM; Operant behavior - TM, JH, NM, RHT, JJD, and HJY; Object location test – JY, JJG, ES; Immunohistochemistry - BR, TM, JA, and JJG; Surgeries - TM, JH, and NM; Electrophysiology – CK, JRK, and JGM; Writing (Original draft) - TM, and JAM; Writing (Review & Editing) - TM, JH, BR, and JAM; Funding Acquisition – JGM, NM, and JAM; Resources - JAM; Supervision - TM, JGM and JAM.

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Correspondence to Jose A. Morón.

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Markovic, T., Higginbotham, J., Ruyle, B. et al. A locus coeruleus to dorsal hippocampus pathway mediates cue-induced reinstatement of opioid self-administration in male and female rats. Neuropsychopharmacol. 49, 915–923 (2024). https://doi.org/10.1038/s41386-024-01828-z

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