Abstract
BackgroundAdministration 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].ResultsWater 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.ConclusionThese 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.
Highlights
Administration of the N-methyl-D-aspartate (NMDA) antagonist ketamine during the perinatal period can produce a variety of behavioral and neuroanatomical changes
There was a significant drug effect indicating that ketamine-treated rats spent less time treading water than did saline-treated controls [F(1, 153) = 15.972; p < 0.001]
Nor does it exclude the possibility of differing drug sensitivities of rats and humans. Both these factors will influence the clinical relevance of the studies reported here. These studies were aimed at determining the long-term behavioral effects of ketamine administration on Embryonic day 18 (E18) and E19 as a means of assessing the durability, intensity and generalizability of the ketamine paradox [21]
Summary
Administration of the N-methyl-D-aspartate (NMDA) antagonist ketamine during the perinatal period can produce a variety of behavioral and neuroanatomical changes. In adult animals, NMDA receptor blockade is known to produce psychotomimetic side effects [3], impair memory formation [4,5,6,7], and may produce neurotoxicity [3,8,9,10,11]. This neurotoxicity is evidenced by vacuolization of cortical neurons [3,10] and has been linked to programmed cell death (apoptosis) during development [12,13,14]. The selection of an acute or chronic dosing regimen may modulate the neurobehavioral outcomes and the permanence of the neurological changes that can be expected [9,13,15,16,17,18]
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