Long-term age-dependent behavioral changes following a single episode of fetal N-methyl-D-Aspartate (NMDA) receptor blockade

G Andrew Mickley, Cynthia L Kenmuir, Colleen A McMullen, Alicia Snyder, Anna M Yocom, Deborah Likins-Fowler, Elizabeth L Valentine, Bettina Weber, Jaclyn M Biada

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


BACKGROUND: Administration of the N-methyl-D-aspartate (NMDA) antagonist ketamine during the perinatal period can produce a variety of behavioral and neuroanatomical changes. Our laboratory has reported reliable changes in learning and memory following a single dose of ketamine administered late in gestation. However, the nature of the drug-induced changes depends on the point during embryonic development when ketamine is administered. Embryonic day 18 (E18) rat fetuses pre-treated with ketamine (100 mg/kg, i.p. through the maternal circulation) and taught a conditioned taste aversion (CTA) learn and remember the CTA, whereas E19 fetuses do not. The current study sought to determine if long-term behavioral effects could be detected in animals that received ketamine or a saline control injection on either E18 or E19. Rat behavior was evaluated on two different measures: spontaneous locomotion and water maze learning. Measurements were collected during 2 periods: Juvenile test period [pre-pubertal locomotor test: Postnatal Day 11 (P11); pre-pubertal water maze test: P18] or Young-adult test period [post-pubertal locomotor test: P60; post-pubertal water maze test: P81].

RESULTS: Water maze performance of ketamine-treated rats was similar to that of controls when tested on P18. Likewise, the age of the animal at the time of ketamine/saline treatment did not influence learning of the maze. However, the young-adult water maze test (P81) revealed reliable benefits of prenatal ketamine exposure - especially during the initial re-training trial. On the first trial of the young adult test, rats treated with ketamine on E18 reached the hidden platform faster than any other group - including rats treated with ketamine on E19. Swim speeds of experimental and control rats were not significantly different. Spontaneous horizontal locomotion measured during juvenile testing indicated that ketamine-treated rats were less active than controls. However, later in development, rats treated with ketamine on E18 were more active than rats that received the drug on E19.

CONCLUSION: These data suggest that both the day in fetal development when ketamine is administered and the timing of post-natal behavioral testing interact to influence behavioral outcomes. The data also indicate that the paradoxical age-dependent effects of early ketamine treatment on learning, previously described in fetuses and neonates, may also be detected later in young adult rats.

Original languageEnglish
Pages (from-to)28
JournalBMC Pharmacology
StatePublished - Oct 28 2004


  • 3',5'-Cyclic-GMP Phosphodiesterases/metabolism
  • Animals
  • Cyclic GMP-Dependent Protein Kinases/metabolism
  • Excitatory Amino Acid Antagonists/pharmacology
  • Guanylate Cyclase/metabolism
  • Humans
  • Hyperammonemia/physiopathology
  • Long-Term Potentiation/drug effects
  • Memory/drug effects
  • Rats
  • Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors


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