eLife (Nov 2024)
Large-scale characterization of cocaine addiction-like behaviors reveals that escalation of intake, aversion-resistant responding, and breaking-points are highly correlated measures of the same construct
- Giordano de Guglielmo,
- Lieselot Carrette,
- Marsida Kallupi,
- Molly Brennan,
- Brent Boomhower,
- Lisa Maturin,
- Dana Conlisk,
- Sharona Sedighim,
- Lani Tieu,
- McKenzie J Fannon,
- Angelica R Martinez,
- Nathan Velarde,
- Dyar Othman,
- Benjamin Sichel,
- Jarryd Ramborger,
- Justin Lau,
- Jenni Kononoff,
- Adam Kimbrough,
- Sierra Simpson,
- Lauren C Smith,
- Kokila Shankar,
- Selene Bonnet-Zahedi,
- Elizabeth A Sneddon,
- Alicia Avelar,
- Sonja Lorean Plasil,
- Joseph Mosquera,
- Caitlin Crook,
- Lucas Chun,
- Ashley Vang,
- Kristel K Milan,
- Paul Schweitzer,
- Bonnie Lin,
- Beverly Peng,
- Apurva S Chitre,
- Oksana Polesskaya,
- Leah C Solberg Woods,
- Abraham A Palmer,
- Olivier George
Affiliations
- Giordano de Guglielmo
- ORCiD
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Lieselot Carrette
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Marsida Kallupi
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Molly Brennan
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Brent Boomhower
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Lisa Maturin
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Dana Conlisk
- Department of Neuroscience, The Scripps Research Institute, La Jolla, San Diego, United States
- Sharona Sedighim
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Lani Tieu
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- McKenzie J Fannon
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Angelica R Martinez
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Nathan Velarde
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Dyar Othman
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Benjamin Sichel
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Jarryd Ramborger
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Justin Lau
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Jenni Kononoff
- Department of Neuroscience, The Scripps Research Institute, La Jolla, San Diego, United States
- Adam Kimbrough
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Sierra Simpson
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Lauren C Smith
- Department of Psychiatry, University of California, San Diego, La Jolla, United States; Department of Neuroscience, The Scripps Research Institute, La Jolla, San Diego, United States
- Kokila Shankar
- Department of Psychiatry, University of California, San Diego, La Jolla, United States; Department of Neuroscience, The Scripps Research Institute, La Jolla, San Diego, United States
- Selene Bonnet-Zahedi
- Department of Psychiatry, University of California, San Diego, La Jolla, United States; Institut de Neurosciences de la Timone, Aix-Marseille Université, Marseille, France
- Elizabeth A Sneddon
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Alicia Avelar
- Department of Psychiatry, University of California, San Diego, La Jolla, United States; Department of Neuroscience, The Scripps Research Institute, La Jolla, San Diego, United States
- Sonja Lorean Plasil
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Joseph Mosquera
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Caitlin Crook
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Lucas Chun
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Ashley Vang
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Kristel K Milan
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Paul Schweitzer
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Bonnie Lin
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Beverly Peng
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Apurva S Chitre
- ORCiD
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- Oksana Polesskaya
- ORCiD
- Department of Psychiatry, University of California, San Diego, La Jolla, United States; Institute for Genomic Medicine, University of California, San Diego, La Jolla, United States
- Leah C Solberg Woods
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, United States
- Abraham A Palmer
- ORCiD
- Department of Psychiatry, University of California, San Diego, La Jolla, United States; Institute for Genomic Medicine, University of California, San Diego, La Jolla, United States
- Olivier George
- ORCiD
- Department of Psychiatry, University of California, San Diego, La Jolla, United States
- DOI
- https://doi.org/10.7554/eLife.90422
- Journal volume & issue
-
Vol. 12
Abstract
Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 hr/daily). We analyzed individual differences in escalation of intake, progressive ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.
Keywords
