Abstract
Re-exposure to a cocaine-associated context triggers craving and relapse through the retrieval of salient context-drug memories. Upon retrieval, context-drug memories become labile and temporarily sensitive to modification before they are reconsolidated into long-term memory stores. The effects of systemic cannabinoid type 1 receptor (CB1R) antagonism indicate that CB1R signaling is necessary for cocaine-memory reconsolidation and associated glutamatergic plasticity in the basolateral amygdala (BLA); however, the contribution of BLA CB1R signaling to cocaine-memory reconsolidation is unknown. Here, we assessed whether intra-BLA CB1R manipulations immediately after cocaine-memory retrieval alter cocaine-memory strength indexed by subsequent drug context-induced cocaine-seeking behavior in an instrumental rodent model of drug relapse. Administration of the CB1R antagonist, AM251 (0.3 µg/hemisphere) into the BLA increased subsequent drug context-induced cocaine-seeking behavior in a memory retrieval-dependent and anatomically selective manner. Conversely, the CB1R agonist, WIN55,212-2 (0.5 or 5 µg/hemisphere) failed to alter this behavior. In follow-up experiments, cocaine-memory retrieval elicited robust hypothalamic-pituitary-adrenal axis activation, as indicated by a rise in serum corticosterone concentrations. Intra-BLA AM251 administration during memory reconsolidation selectively increased this cocaine-memory retrieval-induced corticosterone response. Intra-BLA corticosterone administration (3 or 10 ng/hemisphere) during memory reconsolidation did not augment subsequent cocaine-seeking behavior, suggesting that CB1R-dependent effects of corticosterone on memory strength, if any, are mediated outside of the BLA. Together, these findings suggest that CB1R signaling in the BLA gates cocaine-memory strength, possibly by diminishing the impact of cue-induced arousal on the integrity of the reconsolidating memory trace or on the efficacy of the memory reconsolidation process.
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Acknowledgements
The authors are grateful to Shi Min Tan, Ethan Hansen, and Justine Galliou for excellent technical assistance as well as to Dr. Anthony Berger for help with the corticosterone assays.
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JAH and RAF developed the study concept and experimental design; JAH, NMJ, RJM, RJC, JLR, and RAF collected the data; JAH, RAF, RJC, JLR, and RJM analyzed and interpreted the data; JAH and RAF wrote the manuscript with input from all authors. All authors have approved the version of the manuscript submitted for publication.
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Higginbotham, J.A., Jones, N.M., Wang, R. et al. Basolateral amygdala CB1 receptors gate HPA axis activation and context-cocaine memory strength during reconsolidation. Neuropsychopharmacol. 46, 1554–1564 (2021). https://doi.org/10.1038/s41386-020-00919-x
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DOI: https://doi.org/10.1038/s41386-020-00919-x
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