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

Psychopharmacology (Berl). 2017 Feb;234(3):393-401. doi: 10.1007/s00213-016-4470-z. Epub 2016 Nov 11.


Rationale: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Estrous cycle; Females; Intermittent; Ketamine; Reinstatement; Relapse; Self-administration.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Cocaine / administration & dosage*
  • Conditioning, Psychological / drug effects
  • Cues
  • Diestrus
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Drug-Seeking Behavior / drug effects*
  • Estrus*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Extinction, Psychological / drug effects*
  • Female
  • Ketamine / pharmacology*
  • Male
  • Proestrus
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology*
  • Self Administration
  • Sex Factors


  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Antagonists
  • Ketamine
  • Cocaine