Chronic developmental exposure to phenytoin has long‐term behavioral consequences

Abstract

Anti-epileptic compounds have been linked to several developmental disorders. Specifically, fetal exposure to phenytoin is linked to fetal hydantoin syndrome in humans. We have developed a rat model of fetal hydantoin syndrome in an effort to explore the relationship between drug exposure, development, and learning and memory. Previous studies of this animal model have used various embryological periods of exposure; however, the human syndrome is reported in the offspring of mothers that maintain drug regimens throughout gestation and nursing. To that end, the present study investigated associative learning in rats exposed to therapeutic levels of phenytoin throughout prenatal development and the postnatal pre-weaning period. We used an instrumental appetitive-to-aversive transfer paradigm, which has hippocampal-dependent components, and an avoidance-conditioning paradigm to test simple associative learning and higher-order learning and memory. Compared to controls, we report increased rates of acquisition and performance by the phenytoin group in both the appetitive and the avoidance learning paradigm, and a substantial impairment in avoidance learning following the transfer from appetitive to aversive conditioning. The positive deficit observed with simple associative learning and the negative transfer effect associated with higher order learning suggests that chronic exposure to phenytoin throughout gestation disrupts hippocampal development, which subsequently leads to impaired function in adulthood.

Diphenylhydantoin Promotes Proliferation in The Subventricular Zone and Dentate Gyrus

“…Similar findings have been reported in Sprague Dawley ® rats (Mowery et al ., 2008). However, another report indicated that phenytoin administration at early-postnatal stages reduced food intake and weight gain (Mowery et al ., 2008).…”

“…However, another report indicated that phenytoin administration at early-postnatal stages reduced food intake and weight gain (Mowery et al ., 2008). These changes were reversible when phenytoin supplementation was suspended or when administrated at older development stages (Mowery et al ., 2008; Okada et al ., 2001; Okada et al . 1997).…”

Cognitive outcomes of prenatal antiepileptic drug exposure

“…More recently, studies have been conducted in which the maternal rat was exposed to phenytoin for the duration of the pregnancy and pre-weaning period to more closely resemble a human mother’s experience of taking the medication throughout pregnancy and nursing. Higher order learning in which rats transitioned from appetitive (positive reinforcement) to aversive conditioning was impaired (Mowery et al, 2008), and the authors suggested a mechanism of impaired hippocampal development, which has been seen histologically in mice and rats exposed to phenytoin and other AEDs perinatally (Ogura et al, 2002; Vorhees et al, 1990). …”

The effects of valproic acid on appetitive and aversive instrumental learning in adult rats

“…This paradigm was developed to study appetitive and aversive learning in the same subjects, and has been used in past work to evaluate learning, memory, and impairments that accompany cerebellar, hippocampal, cingulate, and prefrontal cortex lesions (Steinmetz et al, 1993; Logue, 1994). We have used this behavioral paradigm to evaluate the effects of phenytoin and carbamazapine in adult rats (Banks et al, 1999, 2001; McDowell et al, 2004), rats exposed to phenytoin in utero (Mowery et al, 2008), rats with lesions of the basal nucleus of Meynart (Butt et al, 2003), ovariectomized female rats with or without estradiol replacement (Goodman et al, 2004), and rats undergoing chronic restraint (McDowell et al, 2013). …”