title: Repeated ketamine exposure induces an enduring resilient phenotype in adolescent and adult rats.
abstract: BACKGROUND
  Major depressive disorder afflicts up to 10% of adolescents. However, nearly 50% of those afflicted are considered nonresponsive to available treatments. Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist has shown potential as a rapid-acting and long-lasting treatment for major depressive disorder in adults. Thus, the effectiveness and functional consequences of ketamine exposure during adolescence were explored.
  
  
  METHODS
  Adolescent male rats (postnatal day [PD] 35) received two ketamine (0, 5, 10, or 20 mg/kg) injections, 4 hours apart, after exposure to day 1 of the forced swim test (FST). The next day, rats were reexposed to the FST to assess ketamine-induced antidepressant-like responses. Separate groups were exposed to chronic unpredictable stress to confirm findings from the FST. After these initial experiments, adolescent naive rats were exposed to either 1 or 15 consecutive days (PD35-49) of ketamine (20 mg/kg) twice daily. Ketamine's influence on behavioral reactivity to rewarding (i.e., sucrose preference) and aversive (i.e., elevated plus-maze, FST) circumstances was then assessed 2 months after treatment. To control for age-dependent effects, adult rats (PD75-89) were exposed to identical experimental conditions.
  
  
  RESULTS
  Ketamine (20 mg/kg) reversed the chronic unpredictable stress-induced depression-like behaviors in the FST. Repeated ketamine exposure resulted in anxiolytic- and antidepressant-like responses 2 months after drug exposure. None of the ketamine doses used were capable of inducing drug-seeking behaviors as measured by place preference conditioning.
  
  
  CONCLUSIONS
  Repeated ketamine exposure induces enduring resilient-like responses regardless of age of exposure. These findings point to ketamine, and its repeated exposure, as a potentially useful antidepressant during adolescence.
authors.affiliation: Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parise
authors.forename: Lyonna F
authors.initials: LF
authors.lastname: Alcantara
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Warren
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Wright
authors.forename: Roey
authors.initials: R
authors.lastname: Hadad
authors.forename: Omar K
authors.initials: OK
authors.lastname: Sial
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Kroeck
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Iñiguez
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bolaños-Guzmán
mesh_terms: D000367:Age Factors; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D003863:Depression / Q000188:drug therapy; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000188:drug therapy*; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine
keywords: Adolescence; anxiety; depression; ketamine; rats; resilience; stress