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Sex Differences in Animal Models: Focus on Addiction
Open accessAbstract
The purpose of this review is to discuss ways to think about and study sex differences in preclinical animal models. We use the framework of addiction, in which animal models have excellent face and construct validity, to illustrate the importance of considering sex differences. There are four types of sex differences: qualitative, quantitative, population, and mechanistic. A better understanding of the ways males and females can differ will help scientists design experiments to characterize better the presence or absence of sex differences in new phenomena that they are investigating. We have outlined major quantitative, population, and mechanistic sex differences in the addiction domain using a heuristic framework of the three established stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Female rats, in general, acquire the self-administration of drugs and alcohol more rapidly, escalate their drug taking with extended access more rapidly, show more motivational withdrawal, and (where tested in animal models of "craving") show greater reinstatement. The one exception is that female rats show less motivational withdrawal to alcohol. The bases for these quantitative sex differences appear to be both organizational, in that estradiol-treated neonatal animals show the male phenotype, and activational, in that the female phenotype depends on the effects of gonadal hormones. In animals, differences within the estrous cycle can be observed but are relatively minor. Such hormonal effects seem to be most prevalent during the acquisition of drug taking and less influential once compulsive drug taking is established and are linked largely to progesterone and estradiol. This review emphasizes not only significant differences in the phenotypes of females and males in the domain of addiction but emphasizes the paucity of data to date in our understanding of those differences.
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“Female rodents become addicted faster than males and this is believed to be due to a greater activation of the reward circuit (Becker & Koob, 2016).”
From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as Becker & Koob, 2016
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“For alcohol, women are more likely to experience blackouts, liver inflammation, brain atrophy, cognitive deficits, certain cancers, negative affect during withdrawal, and stress-or anxiety-induced relapse (Becker and Koob, 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Becker and Koob, 2016
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Female rodents become addicted faster than males and this is believed to be due to a greater activation of the reward circuit (Becker & Koob, 2016).”
From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as Becker & Koob, 2016
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“Female rodents also drink more alcohol than males (Eriksson and Pikkarainen, 1968;Becker and Koob, 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Becker and Koob, 2016
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“To date, little work has focused on preclinical studies of gender differences in animal models of hyperkatifeia and negative reinforcement with opioids (Becker and Koob, 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Becker and Koob, 2016
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“In animal models, female rodents generally acquire morphine and heroin self-administration faster than males and exhibit higher motivation to self-administer opioids (Lynch and Carroll, 1999;Cicero et al., 2003;Becker and Koob, 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Becker and Koob, 2016
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“For alcohol, males generally exhibit a greater withdrawal response and slower recovery from acute alcohol withdrawal (Becker and Koob, 2016).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Becker and Koob, 2016
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Cites
Koob, G. F., & Volkow, N. D. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.110 · Cited by 5,340
Self-citationDrug Addiction, Dysregulation of Reward, and Allostasis
Koob, G. (2001) · Neuropsychopharmacology · doi:10.1016/s0893-133x(00)00195-0 · Cited by 2,953
Self-citationDrug abuse: hedonic homeostatic dysregulation
Koob, G. F., & Moal, M. L. (1997) · Science · doi:10.1126/science.278.5335.52 · Cited by 2,535
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Self-citationRobinson, T. E., & Becker, J. B. (1986) · Brain Research Reviews · doi:10.1016/0165-0173(86)90002-0 · Cited by 1,796
Self-citationThe reinstatement model of drug relapse: history, methodology and major findings
Shaham, Y., Shalev, U., Lu, L., de Wit, H., & Stewart, J. (2003) · Psychopharmacology · doi:10.1007/s00213-002-1224-x · Cited by 1,615
Transition from Moderate to Excessive Drug Intake: Change in Hedonic Set Point
Ahmed, S. H., & Koob, G. F. (1998) · Science · doi:10.1126/science.282.5387.298 · Cited by 1,186
Self-citationThe ecology and sociology of the Norway rat
Calhoun, J. B. (1963) · doi:10.5962/bhl.title.112283 · Cited by 1,040 · cited 1×
“A male rat will defend a territory of ;30 m in diameter, so the number of males a female encounters is limited by food availability and how far she must travel to forage (Barnett, 1963; Calhoun, 1963).”
BackgroundKoob, G. F., Sanna, P. P., & Bloom, F. E. (1998) · Neuron · doi:10.1016/s0896-6273(00)80557-7 · Cited by 1,026
Self-citationBecker, J. B., & Hu, M. (2008) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2007.07.003 · Cited by 1,003
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Items 701–720 of 720
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Valverde, O., Frontera, J. L., Orihuel, J., Medrano, M., Bis‐Humbert, C., & Puig-Reyné, X. (2026) · Research Square · doi:10.21203/rs.3.rs-10483694/v1
Gaulden, A. D., Chase, K., & McReynolds, J. R. (2026) · Neuropharmacology · doi:10.1016/j.neuropharm.2026.111139
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Salin, A., Lardeux, V., Dugast, E., Balado, É., Thiriet, N., Jaber, M., Solinas, M., & Belujon, P. (2026) · Neuropharmacology · doi:10.1016/j.neuropharm.2026.111232
Metadata
- Authors
- Becker, J. B., & Koob, G. F.
- Affiliations
- National Institutes of Health (US)
- Venue
- Pharmacological Reviews
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 68
- Issue
- 2
- Pages
- 242-263
- ISSN
- 0031-6997 (ISSN-L)
- PMC
- PMC4813426
- OpenAlex
- W2286968510
- Cited by
- 725
- References
- 226
- Citations by year
- 2026: 60 · 2025: 59 · 2024: 74 · 2023: 86 · 2022: 87 · 2021: 83 · 2020: 72 · 2019: 61 · 2018: 53 · 2017: 57 · 2016: 31
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Pharmacological Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r21da032747-02)
- National Institute on Alcohol Abuse and Alcoholism
- National Institute on Drug Abuse (R21-DA-032747, 5R21DA032747)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Keywords
- sex differences, addiction, preclinical animal models, self-administration, alcohol self-administration, craving, reinstatement, estradiol, progesterone, gonadal hormones, estrous cycle, binge drinking, female rats
- MeSH terms
- Animals, Disease Models, Animal, Humans, Sex Characteristics, Substance-Related Disorders
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