Effects of phenobarbital given to pregnant mice on behavior of mature offspring

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

doi:10.1002/dev.420080404

Cited by 58 publications

(16 citation statements)

References 18 publications

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“…For example, Middaugh et al (18) found retarded development of several neurologic reflexes in mice whose mothers received PB in midpregnancy. A defect in sexual mating behavior after neonatal exposure to the drug has been demonstrated by Clemens et al (3).…”

Section: Discussionmentioning

confidence: 99%

Reproductive Dysfunction in Female Offspring after Prenatal Exposure to Phenobarbital: Critical Period of Action

Gupta

Yaffe

1981

Pediatr Res

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SummaryPhenobartital (PB) (40 mg/kg/day) was administered to pregnant rats at 12 to 20, 14 to 20, and 17 to 20 days of gestation and female offspring were tested for the onset of puberty, estrous cycle pattern, and fertility. Another group of rats received PB (20 mg/ kg/day) during the neonatal period (1 to 8 days). PB administration during both the pre-and postnatal periods resulted in a significant delay in the onset of puberty (control: 34.6 f 1.2 days, PB: 37.5 + 1.2 days), disorders of estrous cycle (control: normal cycles 91%, PB: normal cycles a), and infertility (control: 100% fertile PB: 50% fertile). Associated with these effects, we observed high levels of estrogen in plasma (control: 58.5 f 12.2 pg/ml, PB:155.2 + 25.1 pg/ml) and increased estrogen receptors in the uterus (control: 0.136 f 0.026 pmole/mg protein, PB: 0.242 2 0.031 pmole/mg protein. This study shows that PB administration only during the period of neuroendocrine differentiation (17 to 20 days of pregnancy and 1 to 8 postnatal days) is capable of producing all of the adverse effects of PB, indicating that its action is upon neuroendocrine development. SpeculationSince phenobarbital (PB) administration during 17 to 20 days of pregnancy is capable of producing reproductive disorders in the offspring, the results suggest that PB interferes with neuroendocrine differentiation. The mechanism of action of PB, however, has not been delineated. Neuroendocrine differentiation is mediated by gonadotropin, present during the neonatal period. PB may act at this site by interfering with gonadotrophin release or action. Support for this hypothesis is derived from the observation that PB can inhibit gonadotrophin secretion in the adult rat.Phenobarbital (PB), a psychotropic agent widely used during pregnancy, has been shown to modify reproductive development in different species (3,6,19). Clemens el al. (3) demonstrated that neonatal administration of PB produces feminine sexual behavior in male hamsters. Nishizuka (19) showed that neonatal administration of PB is capable of neutralizing the defects in reproductive function resulting from neonatal androgen administration. We have demonstrated that PB administered to pregnant rats results in reproductive dysfunction in both male (13) and female offspring (12).The results of our studies were based upon PB administration from day 12 to 19 of pregnancy. This time frame includes all periods of sexual differentiation (2,5,20,24). These are (1) the period of gonadal differentiation, when the testes start producing testosterone and the ovary synthesizes estrogen, (2) the period of somatic sexual differentiation when the seminal vesicle, prostate, Wolffian duct develop in the male and when the vagina develops (Wolftian duct regresses) in the female, and (3) the period of later somatic sexual differentiation when the development of external genitalia is initiated. At this time, the neuroendocrine axis also starts developing. In the rat, (2,7,14, 15,21,26) the chronologic sequence of these stages of sexual diffe...

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Section: Discussionmentioning

confidence: 99%

Reproductive Dysfunction in Female Offspring after Prenatal Exposure to Phenobarbital: Critical Period of Action

Gupta

Yaffe

1981

Pediatr Res

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“…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].…”

Section: Animal Studies On Behavioral Effects Of In Utero Aed Exposurementioning

confidence: 99%

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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“…In rats and mice, a large number of studies have demonstrated that prenatal phenobarbitone exposure can reduce fitter size (Middaugh et al 1975;Kuprys and Tabakoff 1981;McBride and Rosman 1984) and decrease birth weights (Kuprys and Tabakoff 1981 ;McBride and Rosman 1984). Prenatal and neonatal phenobarbitone administration can decrease subsequent growth (Middaugh et al 1975;Yanai etal.…”

Section: I)igc~onmentioning

confidence: 99%

“…In animals, prenatal or neonatal exposure to phenobarbitone can retard growth and reflex development, impair development of the brain and lead to subsequent dysfunctions of learning (Mural 1966;Brazelton 1970;Middaugh et al 1972Middaugh et al , 1975Diaz et al 1977;Yanai et al 1979Yanai et al , 1982Bergman etal. 1980;Hannah etal.…”

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confidence: 99%

Phenobarbitone: adverse effects on reproductive performance and offspring development in the Mongolian gerbil, (Meriones unguiculatus)

Chapman

Cutler

1988

Psychopharmacology

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Phenobarbitone at a concentration of 500 mg/l in drinking fluid of gerbils during pregnancy (60 mg/kg) and lactation (136 mg/kg) markedly reduced the proportion of animals bearing litters, decreased pup weights at birth and during later life and delayed development of the self-righting reflex, auditory startle reaction, eye opening and full fur coverage. It also prolonged the period of suckling. Scars of implantation were evident in uterine horns of 60% of treated and in none of control females that had failed to give birth. Treated offspring after weaning were given phenobarbitone (500 mg/l; 42-124 mg/kg) as their drinking fluid throughout life and a further group of gerbils received this concentration of the drug from the time of weaning. Seizure susceptibility was unaltered by the drug treatment, and the only evidence of behavioural change was seen in offspring gerbils at 6 weeks when the bout length of social investigation during encounters was increased. Drug-treated offspring showed no abnormality in brain weight relative to body weight. Weight gain and brain weight remained normal among the gerbils given phenobarbitone after weaning. The drug treatment reduced scent gland size in breeding males, though not in the offspring, and had no effect on weights of the testes or ovaries and uterus. no effect on weights of the testes or ovaries and uterus. Plasma concentrations of phenobarbitone in females of the postweaning group amounted on average to 4.4 mg/kg. Most of the adverse effects of this dose of phenobarbitone in the gerbil can thus be seen to be associated either with reproductive impairment or with exposure during sensitive periods of early development.

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Effects of phenobarbital given to pregnant mice on behavior of mature offspring

Cited by 58 publications

References 18 publications

Reproductive Dysfunction in Female Offspring after Prenatal Exposure to Phenobarbital: Critical Period of Action

Reproductive Dysfunction in Female Offspring after Prenatal Exposure to Phenobarbital: Critical Period of Action

Cognitive/behavioral teratogenetic effects of antiepileptic drugs

Phenobarbitone: adverse effects on reproductive performance and offspring development in the Mongolian gerbil, (Meriones unguiculatus)

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