Long-term behavioral effects of phenobarbital in suckling rats

McBride, Margaret C.; Rosman, N. Paul; Davidson, Samuel J.; Oppenheimer, Edgar Y.

doi:10.1016/0014-4886(85)90265-1

Cited by 7 publications

(4 citation statements)

References 13 publications

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“…Our behavioral results with phenobarbital extend previous data showing deficits in spatial learning and memory in adults animals exposed to AEDs during early postnatal development (McBride et al., 1985; Pick & Yanai, 1985; Pereira de Vasconcelos et al., 1990; Rogel‐Fuchs et al., 1992; Jevtovic‐Todorovic et al., 2003; Stefovska et al., 2008). Taken together, the findings highlight the importance of drug treatment in infancy as a risk factor for neurologic, psychiatric, and cognitive abnormalities in adolescence and adulthood (Vestergaard et al., 2005; Tekgul et al., 2006; Glass et al., 2009).…”

Section: Functional Implications For Aed Use In Infancysupporting

confidence: 89%

“…Most studies of behavioral effects of phenobarbital exposure in immature rodents have given the drug daily, starting during the first postnatal week and continuing for well over 2 weeks, in some cases beyond P30 (McBride et al., 1985; Pick & Yanai, 1985; Rogel‐Fuchs et al., 1992). These studies observed deficits in adults tested for spatial learning and memory in water maze, radial arm maze, and T‐maze tasks.…”

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confidence: 99%

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Therapeutic strategies to avoid long‐term adverse outcomes of neonatal antiepileptic drug exposure

et al. 2010

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SUMMARYAntiepileptic drugs (AEDs) such as phenobarbital, phenytoin, and valproic acid, when given in therapeutic doses to neonatal rats, cause pronounced neuronal apoptotic cell death. This effect is especially pronounced in the striatum and cortex during the second postnatal week, a period corresponding to the ''brain growth spurt'' (third trimester of gestation and early infancy) in humans. Of particular concern is the fact that phenobarbital is the most frequently used therapy for neonatal epilepsy. If AED-induced neuronal cell death leads to long-term functional impairment, then it becomes crucial to find therapies that avoid this neurotoxicity in the sensitive period. Herein we examine short-and long-term functional effects following exposure of neonatal rat pups to phenobarbital; the functions tested include striatal c-aminobutyric acid (GABA)ergic synaptic responses and reflex development in pups, and fear conditioning, emotionality, and sensory-motor gating in adults. In all cases, phenobarbital exposure during the second postnatal week was sufficient to cause significant impairment. In contrast, adult animals exposed as pups to lamotrigine (given in a dose that does not cause apoptotic neuronal death) were not impaired on the tasks we examined. Our data suggest that treatments devoid of proapoptotic actions may be promising therapies for avoiding adverse outcomes after neonatal exposure. In addition, our findings identify early exposure to certain AEDs as an important potential risk factor contributing to psychiatric and neurologic abnormalities later in life.

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Section: Functional Implications For Aed Use In Infancysupporting

confidence: 89%

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confidence: 99%

Therapeutic strategies to avoid long‐term adverse outcomes of neonatal antiepileptic drug exposure

et al. 2010

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“…However, it would be premature to conclude that circuitry for memory and anxiety are not disrupted by neonatal phenobarbital exposure, since we have only examined the effects of a single acute phenobarbital treatment. In fact, other studies have reported spatial memory impairment in adult animals following chronic exposure to phenobarbital during the neonatal period (McBride et al 1985; Pick and Yanai 1984, 1985; Rogel-Fuchs et al 1992; Stefovska et al 2008). However, the type of memory assessed in the current study (non-spatial, long term memory) differs from spatial memory previously assessed.…”

Section: Discussionmentioning

confidence: 96%

Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat

et al. 2012

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Previous work has indicated an association between seizures early in life and increased risk of psychiatric disorders, including schizophrenia. However, because early life seizures are commonly treated with antiepileptic drugs (AEDs) such as phenobarbital, the possibility that drug treatment may affect later-life psychiatric outcomes needs to be evaluated. We therefore tested the hypothesis that phenobarbital exposure in the neonatal rat increases the risk of schizophrenia-like behavioral abnormalities in adulthood. Thus, in this study, we examined the effects of a single acute neonatal exposure to phenobarbital on adult behavioral outcomes in the rat neonatal ventral hippocampal (nVH) lesion model of schizophrenia. We compared these outcomes to those in rats a) without nVH lesions and b) with nVH lesions, without phenobarbital. The tasks used for behavioral evaluation were: amphetamine-induced locomotion, prepulse inhibition, elevated plus-maze, and novel object recognition task. We found that neonatal phenobarbital treatment (in the absence of nVH lesions) was sufficient to disrupt sensorimotor gating (as tested by prepulse inhibition) in adulthood to an extent equivalent to nVH lesions. Additionally, neonatal phenobarbital exposure enhanced the locomotor response to amphetamine in adult animals with and without nVH lesions. Our findings suggest that neonatal exposure to phenobarbital can predispose to schizophrenia-like behavioral abnormalities. Our findings underscore the importance of examining AED exposure early in life as a potential risk factor for later-life neuropsychiatric abnormalities in clinical populations.

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“…However, not all studies have demonstrated adverse effects of PB treatment. McBride et al (249) reported that immature rats treated from P6 to P36 with PB and tested at 10 days actually performed better than controls in the T maze. In prepubertal Pupio pupio baboons, therapy with therapeutic dosages of PB or diazepam produced modest improvements in learning performance (250).…”

Section: Age-related Effects Of Aedsmentioning

confidence: 99%

Epilepsy in the Developing Brain: Lessons from the Laboratory and Clinic

1997

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Summary:Children with epilepsy present unique challenges to the clinician. In addition to having differences in clinical and EEG phenomena, children differ from adults in regard to etiological factors, response to antiepileptic drugs (AEDs), and outcome. It is now recognized that the immature brain also differs from the mature brain in the basic mechanisms of epileptogenesis and propagation of seizures. The immature brain is more prone to seizures due to an imbalance between excitation and inhibition. y-Aminobutyric acid (GABA), the major CNS inhibitory neurotransmitter in the mature brain, can lead to depolarization in the hippocampal CA3 region in very young rats. There are also age-related differences in response to GABA agonists and antagonists in the substantia nigra, a structure important in the propagation of seizures. These age-related Epilepsy is a common disorder, leading to staggering costs, both in regard to human suffering and to economics. Because epilepsy frequently begins during childhood and has a higher incidence during the first decade of life than at any other time (l), issues of morbidity and mortality represent a major concern in pediatrics.Clinicians caring for children with epilepsy and developmental neuroscientists have long been aware that the immature brain differs considerably from the mature brain in the development and propagation of seizures, the behavioral and EEG features of the seizures, and their consequences. It is becoming increasingly clear that lessons learned about the mature brain in regard to the pathophysiology and treatment of seizures can not always be applied to the developing brain. An understanding of the unique features of epileptogenesis during development is essential before progress can be made in improving treatment. Despite the significance of the health care problem, it is surprising that relatively little differences in response to GABAergic agents provide further evidence that the pathophysiology of seizures in the immature brain differs from that in the mature brain. Although prolonged seizures can cause brain damage at any age, the extent of brain damage after prolonged seizures is highly age dependent. Far less histological damage and fewer disturbances in cognition result from prolonged seizures in the immature brain than from seizures of similar duration and intensity in mature animals. However, detrimental effects of AEDs may be greater in the immature brain, than in the mature brain. These lessons from the animal laboratory raise questions about the appropriateness of current therapeutic approaches to childhood seizure disorders. Key Words: Epilepsy-Developing brain-Electroencephalography-Epileptogenesis-Pathophysiology . attention has been directed toward developing treatment strategies that specifically address these age-related factors.In this article, features of epileptogenesis during brain development are reviewed and age-related differences in response to seizures and antiepileptic drugs (AEDs) are discussed. Table 1 shows some of the major p...

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Long-term behavioral effects of phenobarbital in suckling rats

Cited by 7 publications

References 13 publications

Therapeutic strategies to avoid long‐term adverse outcomes of neonatal antiepileptic drug exposure

Therapeutic strategies to avoid long‐term adverse outcomes of neonatal antiepileptic drug exposure

Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat

Epilepsy in the Developing Brain: Lessons from the Laboratory and Clinic

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