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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The faster addiction in female rodents is due to greater activation of the reward circuit.
“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
The Animal Models section supports the faster progression to addictive-like behavior in female rats. But the Sex Differences in Addiction section suggests the opposite of the proposed mechanism: a lower cocaine-induced dopamine response in the nucleus accumbens may contribute to their greater addiction-like behavior. The review does not attribute that progression to greater reward-circuit activation. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredFor alcohol, women are more likely than men to experience blackouts, liver inflammation, brain atrophy, cognitive deficits, certain cancers, negative affect during withdrawal, and stress- or anxiety-induced relapse.
“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
The Withdrawal/Negative Affect section (page not available) reports more rapid alcoholic liver disease and neurotoxicity in women, while the Preoccupation/Anticipation section reports greater stress-induced relapse risk for women with alcohol use. The copy does not establish the specific claims about blackouts, liver inflammation, brain atrophy, cognitive deficits, or cancers. Its evidence about longer-lasting negative affect concerns adolescent girls after heavy drinking, not specifically withdrawal; it also does not establish anxiety-induced relapse separately from stress-induced relapse. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFemale rodents become addicted faster than males.
“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
The “2. Animal Models” section says female rats progress to cocaine-related addictive-like behavior more rapidly than males, supporting the claim for that drug and model. The sentence’s proposed explanation is not supported: “IV. Sex Differences in the Neurobiology of Addiction” reports a lower cocaine-induced dopamine increase in the nucleus accumbens in females, rather than greater activation of that reward-related response. No page numbers were provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredFemale rodents drink more alcohol than males.
“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
Little work has focused on preclinical studies of gender differences in animal models of hyperkatifeia and negative reinforcement with opioids.
“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
Female rodents generally acquire morphine and heroin self-administration faster than males and exhibit higher motivation to self-administer opioids.
“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
For alcohol, males generally exhibit a greater withdrawal response and slower recovery from acute alcohol withdrawal than females.
“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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Sex and gender differences in substance use disorders
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Sex differences, gender and addiction
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Sex differences in neural mechanisms mediating reward and addiction
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Self-citationSex differences in stress-related alcohol use
Peltier, M. R., Verplaetse, T. L., Mineur, Y. S., Petrakis, I. L., Cosgrove, K., Picciotto, M. R., & McKee, S. A. (2019) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100149 · Cited by 416 · see citing works
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Dopaminergic dynamics underlying sex-specific cocaine reward
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Sex as a Biological Variable: A 5-Year Progress Report and Call to Action
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Self-citationSex differences in hippocampal cognition and neurogenesis
Yagi, S., & Galea, L. A. M. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0208-4 · Cited by 340 · see citing works
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Genomic and epigenomic mechanisms of glucocorticoids in the brain
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Sex Differences in the Neurobiology of Alcohol Use Disorder
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Sex, strain, and estrous cycle influences on alcohol drinking in rats
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Self-citationSex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning
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Considering Sex as a Biological Variable Will Be Valuable for Neuroscience Research
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Rapid effects of ovarian hormones in dorsal striatum and nucleus accumbens
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Sex Differences in Opioid and Psychostimulant Craving and Relapse: A Critical Review
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Ovarian Hormones Contribute to High Levels of Binge‐Like Drinking by Female Mice
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Reward and aversion processing by input-defined parallel nucleus accumbens circuits in mice
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Sex differences in vulnerability to addiction
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Sex differences in opioid reinforcement under a fentanyl vs. food choice procedure in rats
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The Role of Adenosine Receptors in Psychostimulant Addiction
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Sex differences in alcohol self-administration and relapse-like behavior in Long-Evans rats
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Gobinath, A. R., Choleris, E., & Galea, L. A. M. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.23872 · Cited by 87 · see citing works
The promises and pitfalls of sex difference research
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Increased Responding for Alcohol and Resistance to Aversion in Female Mice
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Behavioral and Perceptual Differences between Sexes in Dogs: An Overview
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Non-pharmacological factors that determine drug use and addiction
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Male and female mice develop escalation of heroin intake and dependence following extended access
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Balance of the Sexes: Addressing Sex Differences in Preclinical Research.
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Fentanyl vapor self-administration model in mice to study opioid addiction
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Sex as a biological variable: Drug use and abuse
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Self-citationWomen, opioid use and addiction
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Cues play a critical role in estrous cycle-dependent enhancement of cocaine reinforcement
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Minimal influence of estrous cycle on studies of female mouse behaviors
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Beyond sex differences: short- and long-term effects of pregnancy on the brain
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Sex Differences in Ethanol Reward Seeking Under Conflict in Mice
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Oxytocin, Tolerance, and the Dark Side of Addiction
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Best practices to promote rigor and reproducibility in the era of sex-inclusive research
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Regionally Specific Effects of Oxytocin on Reinstatement of Cocaine Seeking in Male and Female Rats
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- 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 · 2015: 1
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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