Restoration of circulating 2-arachidonoylglycerol levels attenuates cocaine self-administration through endocannabinoid-dopamine interactions in common marmosets
- 1Chungbuk National University
Abstract
To date, no pharmacotherapy has been approved for cocaine use disorder. Endocannabinoid signaling is closely related to dopamine-dependent reinforcement and may regulate cocaine-related behaviors. In this study, we used common marmosets (Callithrix jacchus) to investigate whether 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid lipid, reduces cocaine reinforcement in a non-restraint oral self-administration model. Marmosets performed oral cocaine self-administration under a fixed-ratio 1 schedule, and cocaine intake was confirmed using plasma benzoylecgonine detection. Dopamine transporter (DAT)-related positron emission tomography (PET) signal, DAT and G protein-coupled receptor 55 (GPR55)-associated fluorescent signals, GPR55/DAT immunofluorescence, and synaptosomal dopamine responses were assessed using 18F-N-(3-fluoropropyl)-2{beta}-carboxymethoxy-3{beta}-(4-iodophenyl) nortropane (18F-FP-CIT) PET imaging, ex vivo fluorescent ligand imaging, confocal microscopy, and dopamine quantification. Marmosets acquired oral cocaine self-administration with preferential active lever responding. Repeated cocaine self-administration reduced striatal DAT-related 18F-FP-CIT PET signal in vivo. In striatal slices, cocaine decreased fluorescent false neurotransmitter (FFN102)-associated DAT signal and increased T1117-associated GPR55 signal. Systemic 2-AG pretreatment reduced cocaine self-administration while restoring diminished circulating 2-AG levels. GPR55 and DAT immunofluorescent signals were colocalized in marmoset brain sections, and 2-AG enhanced cocaine-induced dopamine elevation in synaptosomal preparations. Taken together, these findings suggest that 2-AG attenuates cocaine-taking behavior and may be associated with GPR55/DAT-related dopaminergic responses in common marmosets.
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BibTeX
@misc{lee2026restoration,
title = {{Restoration of circulating 2-arachidonoylglycerol levels attenuates cocaine self-administration through endocannabinoid-dopamine interactions in common marmosets}},
author = {C. K. Lee and H. Eom and T. Yoo and S. M. Gu and J. J. Lee and H. Kwon and S.-B. Na and E. Kim and T. H. Kim and C.-W. Park and B. Y. Hwang and S. S. Yoon and D. Lee and J. Yun},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748459},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748459v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Restoration of circulating 2-arachidonoylglycerol levels attenuates cocaine self-administration through endocannabinoid-dopamine interactions in common marmosets
AU - C. K. Lee
AU - H. Eom
AU - T. Yoo
AU - S. M. Gu
AU - J. J. Lee
AU - H. Kwon
AU - S.-B. Na
AU - E. Kim
AU - T. H. Kim
AU - C.-W. Park
AU - B. Y. Hwang
AU - S. S. Yoon
AU - D. Lee
AU - J. Yun
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748459
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748459v1
AB - To date, no pharmacotherapy has been approved for cocaine use disorder. Endocannabinoid signaling is closely related to dopamine-dependent reinforcement and may regulate cocaine-related behaviors. In this study, we used common marmosets (Callithrix jacchus) to investigate whether 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid lipid, reduces cocaine reinforcement in a non-restraint oral self-administration model. Marmosets performed oral cocaine self-administration under a fixed-ratio 1 schedule, and cocaine intake was confirmed using plasma benzoylecgonine detection. Dopamine transporter (DAT)-related positron emission tomography (PET) signal, DAT and G protein-coupled receptor 55 (GPR55)-associated fluorescent signals, GPR55/DAT immunofluorescence, and synaptosomal dopamine responses were assessed using 18F-N-(3-fluoropropyl)-2{beta}-carboxymethoxy-3{beta}-(4-iodophenyl) nortropane (18F-FP-CIT) PET imaging, ex vivo fluorescent ligand imaging, confocal microscopy, and dopamine quantification. Marmosets acquired oral cocaine self-administration with preferential active lever responding. Repeated cocaine self-administration reduced striatal DAT-related 18F-FP-CIT PET signal in vivo. In striatal slices, cocaine decreased fluorescent false neurotransmitter (FFN102)-associated DAT signal and increased T1117-associated GPR55 signal. Systemic 2-AG pretreatment reduced cocaine self-administration while restoring diminished circulating 2-AG levels. GPR55 and DAT immunofluorescent signals were colocalized in marmoset brain sections, and 2-AG enhanced cocaine-induced dopamine elevation in synaptosomal preparations. Taken together, these findings suggest that 2-AG attenuates cocaine-taking behavior and may be associated with GPR55/DAT-related dopaminergic responses in common marmosets.
ER -