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CB1 Receptor Signaling Modulates Amygdalar Plasticity during Context-Cocaine Memory Reconsolidation to Promote Subsequent Cocaine Seeking.
J Neurosci. 2021 01 27; 41(4):613-629.JN

Abstract

Contextual drug-associated memories precipitate craving and relapse in cocaine users. Such associative memories can be weakened through interference with memory reconsolidation, a process by which memories are maintained following memory retrieval-induced destabilization. We hypothesized that cocaine-memory reconsolidation requires cannabinoid type 1 receptor (CB1R) signaling based on the fundamental role of the endocannabinoid system in synaptic plasticity and emotional memory processing. Using an instrumental model of cocaine relapse, we evaluated whether systemic CB1R antagonism (AM251; 3 mg/kg, i.p.) during memory reconsolidation altered (1) subsequent drug context-induced cocaine-seeking behavior as well as (2) cellular adaptations and (3) excitatory synaptic physiology in the basolateral amygdala (BLA) in male Sprague Dawley rats. Systemic CB1R antagonism, during, but not after, cocaine-memory reconsolidation reduced drug context-induced cocaine-seeking behavior 3 d, but not three weeks, later. CB1R antagonism also inhibited memory retrieval-associated increases in BLA zinc finger 268 (zif268) and activity regulated cytoskeletal-associated protein (Arc) immediate-early gene (IEG) expression and changes in BLA AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subunit phosphorylation that likely contribute to increased receptor membrane trafficking and synaptic plasticity during memory reconsolidation. Furthermore, CB1R antagonism increased memory reconsolidation-associated spontaneous EPSC (sEPSC) frequency in BLA principal neurons during memory reconsolidation. Together, these findings suggest that CB1R signaling modulates cellular and synaptic mechanisms in the BLA that may facilitate cocaine-memory strength by enhancing reconsolidation or synaptic reentry reinforcement, or by inhibiting extinction-memory consolidation. These findings identify the CB1R as a potential therapeutic target for relapse prevention.SIGNIFICANCE STATEMENT Drug relapse can be triggered by the retrieval of context-drug memories on re-exposure to a drug-associated environment. Context-drug associative memories become destabilized on retrieval and must be reconsolidated into long-term memory stores to persist. Hence, targeted interference with memory reconsolidation can weaken maladaptive context-drug memories and reduce the propensity for drug relapse. Our findings indicate that cannabinoid type 1 receptor (CB1R) signaling is critical for context-cocaine memory reconsolidation and subsequent drug context-induced reinstatement of cocaine-seeking behavior. Furthermore, cocaine-memory reconsolidation is associated with CB1R-dependent immediate-early gene (IEG) expression and changes in excitatory synaptic proteins and physiology in the basolateral amygdala (BLA). Together, our findings provide initial support for CB1R as a potential therapeutic target for relapse prevention.

Authors+Show Affiliations

Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, Washington 99164.Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, Washington 99164.Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, Washington 99164. Department of Biological Engineering, University of Idaho, Moscow, Idaho 83844. WWAMI Medical Education, University of Idaho, Moscow, Idaho 83844.Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, Washington 99164.Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, Washington 99164.Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, North Carolina 27599.Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, Washington 99164. Washington State University Alcohol and Drug Abuse Research Program, Pullman, Washington 99164.Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, Washington 99164 rita.fuchs@wsu.edu. Washington State University Alcohol and Drug Abuse Research Program, Pullman, Washington 99164.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33257326

Citation

Higginbotham, Jessica A., et al. "CB1 Receptor Signaling Modulates Amygdalar Plasticity During Context-Cocaine Memory Reconsolidation to Promote Subsequent Cocaine Seeking." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 41, no. 4, 2021, pp. 613-629.
Higginbotham JA, Wang R, Richardson BD, et al. CB1 Receptor Signaling Modulates Amygdalar Plasticity during Context-Cocaine Memory Reconsolidation to Promote Subsequent Cocaine Seeking. J Neurosci. 2021;41(4):613-629.
Higginbotham, J. A., Wang, R., Richardson, B. D., Shiina, H., Tan, S. M., Presker, M. A., Rossi, D. J., & Fuchs, R. A. (2021). CB1 Receptor Signaling Modulates Amygdalar Plasticity during Context-Cocaine Memory Reconsolidation to Promote Subsequent Cocaine Seeking. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 41(4), 613-629. https://doi.org/10.1523/JNEUROSCI.1390-20.2020
Higginbotham JA, et al. CB1 Receptor Signaling Modulates Amygdalar Plasticity During Context-Cocaine Memory Reconsolidation to Promote Subsequent Cocaine Seeking. J Neurosci. 2021 01 27;41(4):613-629. PubMed PMID: 33257326.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CB1 Receptor Signaling Modulates Amygdalar Plasticity during Context-Cocaine Memory Reconsolidation to Promote Subsequent Cocaine Seeking. AU - Higginbotham,Jessica A, AU - Wang,Rong, AU - Richardson,Ben D, AU - Shiina,Hiroko, AU - Tan,Shi Min, AU - Presker,Mark A, AU - Rossi,David J, AU - Fuchs,Rita A, Y1 - 2020/11/30/ PY - 2020/06/02/received PY - 2020/11/16/revised PY - 2020/11/20/accepted PY - 2020/12/2/pubmed PY - 2021/3/27/medline PY - 2020/12/1/entrez KW - CB1 KW - amygdala KW - cocaine KW - endocannabinoid KW - memory reconsolidation KW - reinstatement SP - 613 EP - 629 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 41 IS - 4 N2 - Contextual drug-associated memories precipitate craving and relapse in cocaine users. Such associative memories can be weakened through interference with memory reconsolidation, a process by which memories are maintained following memory retrieval-induced destabilization. We hypothesized that cocaine-memory reconsolidation requires cannabinoid type 1 receptor (CB1R) signaling based on the fundamental role of the endocannabinoid system in synaptic plasticity and emotional memory processing. Using an instrumental model of cocaine relapse, we evaluated whether systemic CB1R antagonism (AM251; 3 mg/kg, i.p.) during memory reconsolidation altered (1) subsequent drug context-induced cocaine-seeking behavior as well as (2) cellular adaptations and (3) excitatory synaptic physiology in the basolateral amygdala (BLA) in male Sprague Dawley rats. Systemic CB1R antagonism, during, but not after, cocaine-memory reconsolidation reduced drug context-induced cocaine-seeking behavior 3 d, but not three weeks, later. CB1R antagonism also inhibited memory retrieval-associated increases in BLA zinc finger 268 (zif268) and activity regulated cytoskeletal-associated protein (Arc) immediate-early gene (IEG) expression and changes in BLA AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subunit phosphorylation that likely contribute to increased receptor membrane trafficking and synaptic plasticity during memory reconsolidation. Furthermore, CB1R antagonism increased memory reconsolidation-associated spontaneous EPSC (sEPSC) frequency in BLA principal neurons during memory reconsolidation. Together, these findings suggest that CB1R signaling modulates cellular and synaptic mechanisms in the BLA that may facilitate cocaine-memory strength by enhancing reconsolidation or synaptic reentry reinforcement, or by inhibiting extinction-memory consolidation. These findings identify the CB1R as a potential therapeutic target for relapse prevention.SIGNIFICANCE STATEMENT Drug relapse can be triggered by the retrieval of context-drug memories on re-exposure to a drug-associated environment. Context-drug associative memories become destabilized on retrieval and must be reconsolidated into long-term memory stores to persist. Hence, targeted interference with memory reconsolidation can weaken maladaptive context-drug memories and reduce the propensity for drug relapse. Our findings indicate that cannabinoid type 1 receptor (CB1R) signaling is critical for context-cocaine memory reconsolidation and subsequent drug context-induced reinstatement of cocaine-seeking behavior. Furthermore, cocaine-memory reconsolidation is associated with CB1R-dependent immediate-early gene (IEG) expression and changes in excitatory synaptic proteins and physiology in the basolateral amygdala (BLA). Together, our findings provide initial support for CB1R as a potential therapeutic target for relapse prevention. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/33257326/CB1_Receptor_Signaling_Modulates_Amygdalar_Plasticity_during_Context_Cocaine_Memory_Reconsolidation_to_Promote_Subsequent_Cocaine_Seeking_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=33257326 DB - PRIME DP - Unbound Medicine ER -