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Blocking μ-opioid receptors attenuates reinstatement of responding to an alcohol-predictive conditioned stimulus through actions in the ventral hippocampus

Neuropsychopharmacology volume 48, pages 1484–1491 (2023)Cite this article

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Abstract

The µ-opioid system is involved in the reinstatement of responding that is immediately evoked by alcohol-predictive cues. The extent of its involvement in reinstatement observed in a new model that evaluates the delayed effects of re-exposure to alcohol, however, is unclear. The current study investigated the role of µ-opioid receptors (MORs) in the delayed reinstatement of an extinguished, Pavlovian conditioned response that was evoked 24 h after alcohol re-exposure. Female and male Long-Evans rats received Pavlovian conditioning in which a conditioned stimulus (CS) was paired with the delivery of an appetitive unconditioned stimulus (US; Experiments 1, 2, 4: 15% v/v alcohol; Experiment 3: 10% w/v sucrose) that was delivered into a fluid port for oral intake. During subsequent extinction sessions, the CS was presented as before but without the US. Next, the US was delivered but without the CS. A reinstatement test was conducted 24 h later, during which the CS was presented in the absence of the US. Silencing MORs via systemic naltrexone (0.3 or 1.0 mg/kg) attenuated reinstatement of port entries elicited by an alcohol-CS, but not those elicited by a sucrose-CS. Finally, blocking MORs in the ventral hippocampus via bilateral microinfusion of D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 2.5 or 5.0 µg/hemisphere) prevented reinstatement of port alcohol-CS port entries. These data show that MORs are involved in the delayed reinstatement of a Pavlovian conditioned response in an alcohol-specific manner. Importantly, these data illustrate, for the first time, that MORs in the ventral hippocampus are necessary for responding to an alcohol-predictive cue.

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Fig. 1: Systemic naltrexone attenuated reinstatement of responding to an alcohol-CS.
Fig. 2: Systemic naltrexone attenuated reinstatement of responding to an alcohol-CS in both female and male rats.
Fig. 3: Systemic naltrexone did not affect reinstatement of responding to a sucrose-CS.
Fig. 4: Bilateral microinfusions of CTAP into the vHipp prevented reinstatement of responding to an alcohol-CS.

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Acknowledgements

The authors would like to thank Dr. Uri Shalev for providing invaluable feedback on the manuscript. As well, the authors would like to thank Nadia Chaudhri for her supervision on this research project and years of mentorship. The authors would also like to thank Stephen Cabilio for support with Med-PC programming and data extraction.

Funding

This research was supported by the Canadian Institution of Health Research [MOP-137030, NC]. NC was the recipient of a Chercheur-Boursier award from the Fonds de la recherche en santé Québec and is a member of the Center for Studies in Behavioral Neurobiology. MRL was supported by a graduate scholarship from the Faculty of Arts and Science at Concordia University and by a Fonds de recherche du Québec—Nature et Technologies doctoral fellowship. The funding sources were not involved in the study design, data collection, analysis, or interpretation, in the writing of the report, nor in the decision to submit the article for publication.

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  1. Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada

    Mandy Rita LeCocq

  2. Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC, Canada

    Priya Chander & Nadia Chaudhri

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MRL Contributed to the conception and design of the work; the acquisition, analysis, and interpretation of data for the work; drafting and revising the work; giving final approval of the version to be published; and agreeing to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. PC: contributed to the acquisition, analysis, and interpretation of data. NC: contributed to the conception or design of the work; and the acquisition, analysis, and interpretation of data for the work.

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LeCocq, M.R., Chander, P. & Chaudhri, N. Blocking μ-opioid receptors attenuates reinstatement of responding to an alcohol-predictive conditioned stimulus through actions in the ventral hippocampus. Neuropsychopharmacol. 48, 1484–1491 (2023). https://doi.org/10.1038/s41386-023-01640-1

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