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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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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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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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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DOI: https://doi.org/10.1038/s41386-024-01828-z