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


CONCLUSIONS
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.
Mickley
G Andrew
GA
Department of Psychology and the Neuroscience Program, Baldwin-Wallace College, 275 Eastland Road, Berea, OH 44017-2088, USA.
Kenmuir
Cynthia L
CL
Department of Psychology and the Neuroscience Program, Baldwin-Wallace College, 275 Eastland Road, Berea, OH 44017-2088, USA.
McMullen
Colleen A
CA
Department of Psychology and the Neuroscience Program, Baldwin-Wallace College, 275 Eastland Road, Berea, OH 44017-2088, USA.
Snyder
Alicia
A
Department of Psychology and the Neuroscience Program, Baldwin-Wallace College, 275 Eastland Road, Berea, OH 44017-2088, USA.
Yocom
Anna M
AM
Department of Psychology and the Neuroscience Program, Baldwin-Wallace College, 275 Eastland Road, Berea, OH 44017-2088, USA.
Likins-Fowler
Deborah
D
Department of Psychology and the Neuroscience Program, Baldwin-Wallace College, 275 Eastland Road, Berea, OH 44017-2088, USA.
Valentine
Elizabeth L
EL
Department of Psychology and the Neuroscience Program, Baldwin-Wallace College, 275 Eastland Road, Berea, OH 44017-2088, USA.
Weber
Bettina
B
Department of Psychology and the Neuroscience Program, Baldwin-Wallace College, 275 Eastland Road, Berea, OH 44017-2088, USA.
Biada
Jaclyn M
JM
Department of Psychology and the Neuroscience Program, Baldwin-Wallace College, 275 Eastland Road, Berea, OH 44017-2088, USA.
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D022124:Hyperammonemia / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008568:Memory / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D017869:Cyclic GMP-Dependent Protein Kinases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006162:Guanylate Cyclase