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Leptin protects against the development and expression of cocaine addiction-like behavior in heterogenous stock rats

View ORCID ProfileL.L.G. Carrette, C. Coral, C. Crook, B. Boomhower, M. Brennan, C. Ortez, View ORCID ProfileK. Shankar, View ORCID ProfileS. Simpson, L. Maturin, View ORCID ProfileG. de Guglielmo, View ORCID ProfileL. Solberg Woods, View ORCID ProfileA. A. Palmer, View ORCID ProfileO. George
doi: https://doi.org/10.1101/2021.07.22.453426
L.L.G. Carrette
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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  • ORCID record for L.L.G. Carrette
C. Coral
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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C. Crook
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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B. Boomhower
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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M. Brennan
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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C. Ortez
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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K. Shankar
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
2Department of Neuroscience, The Scripps Research Institute, La Jolla CA 92037
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S. Simpson
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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L. Maturin
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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G. de Guglielmo
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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L. Solberg Woods
3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157
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A. A. Palmer
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
4Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093
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O. George
1Department of Psychiatry, UC San Diego, La Jolla, CA 92093
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  • For correspondence: olgeorge@health.ucsd.edu
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Abstract

In addition to its pleasurable effects, weight control is a significant contributor to initiation, maintenance and relapse of cocaine use. This suggests that individual differences in bodyweight control and feeding hormones, such as leptin may contribute to the vulnerability to cocaine use disorder. While pre-clinical studies have shown a mutually inhibitory relationship between leptin and cocaine, they have used small sample sizes and did not investigate individual differences in a large heterogeneous population. Here, we tested if individual differences in bodyweight and blood leptin level is associated with high or low vulnerability to addiction-like behaviors using data from 500 heterogenous stock rats and 160 blood samples from the Cocaine Biobank, using a model of extended access to intravenous self-administration of cocaine. Finally, we tested a separate cohort to evaluate the causal effect of exogenous leptin administration on cocaine seeking. Bodyweight, while changing due to cocaine self-administration in males, was not related to the vulnerability to addiction-like behavior. Blood leptin levels after ~6 weeks of cocaine self-administration did not correlate with addiction-like behaviors, however, baseline blood leptin levels before any access to cocaine negatively predicted addiction-like behavior. Finally, administration of leptin reduced cocaine intake after acute withdrawal and cocaine seeking after 6 weeks of protracted abstinence. These results demonstrate that high blood leptin level before access to cocaine may be a protective factor against the development of cocaine addiction-like behavior, that exogenous leptin reduces the motivation to take and seek cocaine, but that blood leptin level and bodyweight changes in current users are not good biomarkers for addiction-like behaviors.

Competing Interest Statement

The authors have declared no competing interest.

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Posted July 23, 2021.
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Leptin protects against the development and expression of cocaine addiction-like behavior in heterogenous stock rats
L.L.G. Carrette, C. Coral, C. Crook, B. Boomhower, M. Brennan, C. Ortez, K. Shankar, S. Simpson, L. Maturin, G. de Guglielmo, L. Solberg Woods, A. A. Palmer, O. George
bioRxiv 2021.07.22.453426; doi: https://doi.org/10.1101/2021.07.22.453426
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Leptin protects against the development and expression of cocaine addiction-like behavior in heterogenous stock rats
L.L.G. Carrette, C. Coral, C. Crook, B. Boomhower, M. Brennan, C. Ortez, K. Shankar, S. Simpson, L. Maturin, G. de Guglielmo, L. Solberg Woods, A. A. Palmer, O. George
bioRxiv 2021.07.22.453426; doi: https://doi.org/10.1101/2021.07.22.453426

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