Phenobarbital during pregnancy alters operant behavior of offspring in C57BL/6J mice

Middaugh, Lawrence D.; Santos, Carroll A.; Zemp, John W.

doi:10.1016/0091-3057(75)90030-1

Cited by 45 publications

(6 citation statements)

References 12 publications

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“…The most common drugs were phenytoin and primidone. Forty-one percent of the original cohort were examined at ages [10][11][12][13][14][15][16][17][18][19]. The large prospective population-based study by Shapiro et al [59] included 107 children exposed to a combination of phenytoin and phenobarbital.…”

Section: Polytherapymentioning

confidence: 99%

“…Perinatal phenobarbital exposure in rats reduces brain weight [6]. Mice exposed prenatally to phenobarbital have neuronal deficits, reduced brain weight, and impaired development of reflexes, open-field activity, schedule-controlled behavior, spatial learning, and cate-cholamine brain levels [7][8][9][10][11][12]. Gestational or neonatal exposure to phenytoin reduces brain weight [13,14], alters neuronal membranes in the hippocampus [15], delays neurodevelopment [16], and impairs spatial learning and motor coordination [17][18][19][20][21][22][23][24][25].…”

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confidence: 99%

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Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Meador

Baker

Cohen

et al. 2007

Epilepsy & Behavior

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The majority of children of mothers with epilepsy are normal, but they are at increased risk for developmental delay. Antiepileptic drugs (AEDs) appear to play a role. Our current knowledge is reviewed, including research design issues and recommendations for future research. In animals, exposure of the immature brain to some AEDs can produce widespread neuronal apoptosis and behavioral deficits. The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain. KeywordsAntiepileptic drugs; Anticonvulsant drugs; Pregnancy; Teratogenesis; Development; Cognition; Behavior Animal studies on behavioral effects of in utero AED exposureAnimal studies have demonstrated that in utero antiepileptic drug (AED) exposure can produce behavioral as well as anatomical defects, which can occur at dosages lower than those required to produce somatic malformations [1,2]. Gestational or neonatal exposure to benzodiazepines can affect brain chemistry and behavior causing hyperactivity or learning deficits [3,4]. Despite the common use of carbamazepine in humans, very few neurobehavioral studies in animals have been conducted with this AED. In utero carbamazepine exposure did not produce hyperexcitability in primates [5]. Perinatal phenobarbital exposure in rats reduces brain weight [6]. Mice exposed prenatally to phenobarbital have neuronal deficits, reduced brain weight, and impaired development of reflexes, open-field activity, schedule-controlled behavior, spatial learning, and cate-cholamine brain levels [7][8][9][10][11][12]. Gestational or neonatal exposure to phenytoin reduces brain weight [13,14], alters neuronal membranes in the hippocampus [15], delays neurodevelopment [16], and impairs spatial learning and motor coordination [17][18][19][20][21][22][23][24][25]. Hyperactivity has been observed in rats and primates following prenatal exposure to phenytoin [5,23,25]. Gestational primidone in rats produces learning deficits and reduces open-field activity [26]. In utero valproate exposure can alter neuronal membranes [27], decrease brain weight in mice [28], and result in adverse neurobehavioral effects [29,30].

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Section: Polytherapymentioning

confidence: 99%

mentioning

confidence: 99%

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Meador

Baker

Cohen

et al. 2007

Epilepsy & Behavior

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“…Trimethadione produced a profile more similar to phenytoin, while phenobarbital produced only small delays in swimming ontogeny with no other clear effects on the specific tests we used. Using other test procedures, l~ow-ever, others have found effects of prenatal phenobarbital on schedule-controlled behavior (Middaugh et al 1975), a type of behavior not assessed in our experiments.…”

Section: Discussionmentioning

confidence: 61%

Behavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats

Vorhees

1987

Psychopharmacology

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Pregnant Sprague-Dawley rats were treated with 0, 150 or 200 mg/kg valproic acid by gavage (VPA) on days 7-18 of gestation. These doses produced no maternal toxicity, reproductive effects or effects on offspring growth and survival. Maternal plasma VPA peak levels averaged 99 and 134 micrograms/ml 1 h after the last treatment, values approximating human therapeutic levels. VPA offspring tested after weaning exhibited reduced open-field central, but not peripheral, activity and reduced hole-board horizontal, but not vertical, activity. No activity differences were found in a figure-8 test or a preweaning activity test. The VPA offspring also showed lengthened straight channel swimming times, increased swimming maze errors, but only among the females, while producing no differences in maze times. VPA offspring exhibited reduced spontaneous alternation frequency and reduced startle responding to both auditory and tactile (air-puff) stimuli. The effects of VPA were dose dependent in some cases (straight channel swimming and water maze errors), or the effect was seen only in the high-dose group (open-field, hole-board, spontaneous alternation, startle). The conclusion was reached that prenatal VPA is behaviorally teratogenic in rats at relevant maternal blood concentrations and at non-malforming doses.

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“…Many of them have been recently reviewed [Yanai, 1981], including changes in learning ability, activity [Middaugh et al, 1975], tolerance to drugs, etc. Initial studies attempted to correlate the PhB-induced neuromorphological changes with specific behavioral changes [Pick and Yanai, 1981;.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Losses in Mice following <i>both</i> Prenatal and Neonatal Exposure to Phenobarbital

Bergman¹,

Feigenbaum²,

Yanai³

1982

Cells Tissues Organs

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Mice were given phenobarbital (PhB) during neonatal development (NeoB group) and during pre- and neonatal development (Pre- and NeoB group). Prenatal exposure was accomplished transplacentally by feeding the pregnant mothers 3 g PhB/kg milled food on gestation days 9–18. Neonatal exposure was conducted directly by injecting the neonates daily with 50 mg PhB/kg on postnatal days 2–21. The brains of these animals were studied at age 50 days using H & E staining. Consistant with previous studies, NeoB animals had a 14–20% smaller cerebellar layer area than controls, 32% fewer cerebellar Purkinje cells and 34% fewer granule cells than controls. NeoB mice had a 14–18% smaller hippocampal layer and 17% fewer hippocampal pyramidal cells than controls. The number of the hippocampal granule cells was not reduced by early PhB administration. NeoB mice had an 18% smaller cerebral cortex area and 22% fewer cortical cells than controls. The pre- and NeoB animals did not differ from controls in the area of their cerebellar layers, but they did have fewer cerebellar Purkinje and granule cells. Similarly, the Pre- and NeoB animals did not differ from controls in the area of their hippocampal layers, but they had fewer pyramidal cells. The Pre- and NeoB animals had a smaller cerebral layer area than controls but did not differ significantly from controls in the number of cortical neurons. It was suggested that exposure to PhB during prenatal and neonatal periods is not additive. On the contrary, tolerance or compensatory mechanisms may develop after prenatal exposure and lessened the effect of subsequent neonatal PhB exposure.

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Phenobarbital during pregnancy alters operant behavior of offspring in C57BL/6J mice

Cited by 45 publications

References 12 publications

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Behavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats

Neuronal Losses in Mice following <i>both</i> Prenatal and Neonatal Exposure to Phenobarbital

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