, Volume 234, Issue 3, pp 393–401 | Cite as

Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle

  • Katherine N. Wright
  • Caroline E. Strong
  • Marjorie N. Addonizio
  • Naomi C. Brownstein
  • Mohamed KabbajEmail author
Original Investigation



Repeated intermittent exposure to ketamine has rapid and long-lasting antidepressant effects, but the abuse potential has only been assessed at high doses. Furthermore, while females are more susceptible to depression and more sensitive to ketamine’s antidepressant-like effects, the abuse potential for ketamine in females is unknown.


The objectives of this study are to determine the reinforcing properties of low-dose intermittent ketamine in adult rats of both sexes and determine whether cycling gonadal hormones influence females’ response to ketamine. In male rats, we also aimed to determine whether reinstatement to intermittent ketamine is comparable to intermittent cocaine.


Male rats intravenously self-administered cocaine (0.75 mg/kg/infusion) or ketamine (0.1 mg/kg/infusion) once every fourth day, while intact cycling female rats self-administered ketamine only during preidentified stages of their 4-day estrus cycle, when gonadal hormones are either high (proestrus) or low (diestrus). After acquiring self-administration, rats underwent daily extinction training followed by cue-primed and drug-primed reinstatement to assess drug-seeking behavior.


Diestrus-trained females fail to maintain ketamine self-administration and did not display reinstatement to ketamine-paired cues. Males and proestrus-trained females reinstated to ketamine-paired cues. Ketamine-primed reinstatement was dependent on simultaneous cue presentation. Male rats reinstated to cocaine priming independent of cue presentation.


These findings indicate that females’s responsivity to this dose of ketamine depends on stage of cycle, as only proestrus-trained females and males respond to ketamine’s reinforcing effects under this treatment paradigm.


Ketamine Self-administration Females Estrous cycle Intermittent Reinstatement Relapse 



This research was supported by R01MH 087583 and R01MH 099085 to MK. Special thanks to Samantha Pavlock, Elsa Johnson, and Amanda Dossat for their technical assistance. KNW and MK designed the experiments. KNW, CES, and MNA carried out the behavioral testing. KNW, NCB, and MK performed the data analysis. KNW and MK wrote the manuscript. All authors provided editorial input for the final draft.

Compliance with ethical standards

All protocols were approved by the Florida State University Institutional Animal Care and Use Committee.

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Katherine N. Wright
    • 1
  • Caroline E. Strong
    • 1
  • Marjorie N. Addonizio
    • 1
  • Naomi C. Brownstein
    • 2
    • 3
  • Mohamed Kabbaj
    • 1
    • 4
    Email author
  1. 1.Program in Neuroscience, Department of Biomedical SciencesFlorida State UniversityTallahasseeUSA
  2. 2.Department of Behavioral Sciences and Social MedicineFlorida State UniversityTallahasseeUSA
  3. 3.Department of StatisticsFlorida State UniversityTallahasseeUSA
  4. 4.College of Medicine, Department of Biomedical SciencesFlorida State UniversityTallahasseeUSA

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