Abstract
Despite the potent proapoptotic effect of several antiepileptic drugs (AEDs) in developmental rodent models, little is known about the long-term impact of exposure during brain development. Clinically, this is of growing concern. To determine the behavioral consequences of such exposure, we examined phenobarbital, phenytoin, and lamotrigine for their effects on adult behaviors after administration to neonatal rats throughout the second postnatal week. AED treatment from postnatal days 7 to 13 resulted in adult deficits in spatial learning in the Morris water maze and decreased social exploration for all drugs tested. Phenobarbital exposure led to deficits in cued fear conditioning, risk assessment in the elevated plus maze, and sensorimotor gating as measured by prepulse inhibition, but it did not affect motor coordination on the rotorod task. In contrast, phenytoin and lamotrigine exposure led to impaired rotorod performance, but no deficits in sensorimotor gating. Phenytoin, but not lamotrigine or phenobarbital, increased exploration in the open field. Phenytoin and phenobarbital, but not lamotrigine, disrupted cued fear conditioning. These results indicate that AED administration during a limited sensitive postnatal period is sufficient to cause a range of behavioral deficits later in life, and the specific profile of behavioral deficits varies across drugs. The differences in the long-term outcomes associated with the three AEDs examined are not predicted by either the mechanism of AED action or the proapoptotic effect of the drugs. Our findings suggest that a history of AED therapy during development must be considered as a variable when assessing later-life cognitive and psychiatric outcomes.
Footnotes
This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS066822] (to P.A.F.); the National Institutes of Health National Institute of Mental Health [Grant MH02040] (to A.K.); an Epilepsy Foundation fellowship (to P.A.F.); and a research grant from GlaxoSmithKline (to A.K.).
The data in this article were included in the doctoral dissertation of P.A.F.: Forcelli PA (2011) Sequelae of Neonatal Antiepileptic Drug Exposure. Ph.D. thesis, Georgetown University, Washington, DC.
The data in this article have been presented previously in abstract form: Forcelli P, Ritter J, Kondratyev A, and Gale K (2008) Long-term adverse outcomes of neonatal antiepileptic drug exposure in rats, at the American Epilepsy Society Annual Meeting, 2008 Dec 5–9, Seattle, WA, American Epilepsy Society, West Hartford, CT. Forcelli PA, Kondratyev A, and Gale K (2009) Antiepileptic drug exposure in neonatal rats leads to neuropsychiatric behavioral abnormalities in adults, at the Society for Neuroscience Annual Meeting, 2009 Oct 17–21, Chicago, IL, Society for Neuroscience, Washington, DC. Forcelli P, Kozlowski R, Snyder C, Gale K, and Kondratyev A (2009) Early-life exposure to antiepileptic drugs results in behavioral and neuropsychiatric abnormalities in adult rats, at the American Epilepsy Society Annual Meeting, 2009 Dec 4–8, Boston, MA, American Epilepsy Society, West Hartford, CT. Forcelli PA, Janssen MJ, Sweeney C, Vicini S, and Gale K (2010) Neonatal exposure to phenobarbital delays maturation of synaptic transmission in striatum with behavioral consequences, at the Society for Neuroscience Annual Meeting, 2010 Nov 13–17, San Diego, CA, Society for Neuroscience, Washington, DC. Forcelli P, Janssen M, Vicini S, and Gale K (2010) Antiepileptic drugs (AEDs) in neonatal rats disrupt striatal synaptic maturation, at the American Epilepsy Society Annual Meeting, 2010 Dec 3–7, San Antonio, TX, American Epilepsy Society, West Hartford, CT.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- AED
- antiepileptic drug
- Pn
- postnatal day
- PB
- phenobarbital
- PHT
- phenytoin
- LTG
- lamotrigine
- PPI
- prepulse inhibition
- C
- control
- NMDA
- N-methyl-d-aspartate.
- Received October 27, 2011.
- Accepted November 29, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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