Hippocampal cholinergic alterations and related behavioral deficits after early exposure to phenobarbital

Rogel-Fuchs, Yael; Newman, Morris; Trombka, David; Zahalka, Eias A.; Yanai, Joseph

doi:10.1016/0361-9230(92)90002-f

Cited by 52 publications

(31 citation statements)

References 24 publications

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“…Both the apparatus and the test procedure that were originally developed for rats 31 were adapted to enable testing with mice, as previously described. 32 The test was performed in a tank with a diameter of 87 cm filled with opaque white water (by adding powdered milk) at 241 C. A clear platform, 10 Â 8 Â 9 cm high, was submerged 1 cm under water. In the place test, the mice were given two blocks of four trials on each day of the test.…”

Section: Specific Methodsmentioning

confidence: 99%

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

2007

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Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg À1 heroin on gestation days 9-18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P < 0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P < 0.006) and reversed the behavioral defects (P < 0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.

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Section: Specific Methodsmentioning

confidence: 99%

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

2007

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“…Prior studies in rodents focused only on a single drug, examining only one or two behavioral assays. For example, phenobarbital exposure impaired spontaneous alternation in a T maze (Pick and Yanai, 1983;Pereira de Vasconcelos et al, 1990), water maze performance (Rogel-Fuchs et al, 1992;Stefovska et al, 2008), and rat exploratory behavior in the open field (Pereira de Vasconcelos et al, 1990). Only mouse motor function has been assessed after early life exposure to phenytoin.…”

Section: Behavioral Sequelae Of Neonatal Aed Exposure In Rats 563mentioning

confidence: 99%

“…These changes provide at least one mechanism by which early injury can have long-lasting impacts on cortical function . Longer duration of treatment with phenobarbital resulted in reduced GABA receptor expression (Ruiz et al, 1989), increased muscarinic receptor expression in hippocampus (Rogel-Fuchs et al, 1992;Pick et al, 1993), and decreased cerebral glucose utilization (Pereira de Vasconcelos et al, 1990). In addition to these changes, hippocampal neurogenesis is impaired after early life exposure to phenobarbital (Stefovska et al, 2008).…”

Section: Behavioral Sequelae Of Neonatal Aed Exposure In Rats 563mentioning

confidence: 99%

“…Phenobarbital exposure from postnatal day 2 (P2) to P35 caused deficits in Morris water maze learning and open-field exploration in adult rats (Pereira de Vasconcelos et al, 1990;Rogel-Fuchs et al, 1992;Stefovska et al, 2008), whereas phenytoin given from P2 to P4 caused deficits in spontaneous locomotion and rotorod performance in adult mice . Phenobarbital exposure has not been examined for its effects on rotorod performance, and phenytoin exposure has not been examined for water maze learning.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Neonatal Antiepileptic Drug Exposure on Cognitive, Emotional, and Motor Function in Adult Rats

Forcelli

Kozlowski²,

Snyder³

et al. 2012

The Journal of Pharmacology and Experimental Therapeutics

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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.

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“…Such exposures cause Purkinje cell death, reduced cerebellar weight, reduction in the number of granule cells in the cerebellum (Yanai and Iser, 1981;Fishman et al, 1983;Yanai and Waknin, 1985), and reduction of both pyramidal and granule cell number in the hippocampus (Yanai et al, 1979;Bergman et al, 1982). Neurochemical studies indicated limited effects on norepinephrine, dopamine, and GABA neurotransmitter systems (Middaugh et al, 1981;Pick et al, 1993) and a more robust effect on cholinergic neurotransmission in the hippocampus (Rogel-Fuchs et al, 1992;AbuRoumi et al, 1996).…”

Section: B Antiepileptic Drugsmentioning

confidence: 99%

Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects

Costa

Steardo

Cuomo

2004

Pharmacological Reviews

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Hippocampal cholinergic alterations and related behavioral deficits after early exposure to phenobarbital

Cited by 52 publications

References 24 publications

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

Effects of Neonatal Antiepileptic Drug Exposure on Cognitive, Emotional, and Motor Function in Adult Rats

Structural Effects and Neurofunctional Sequelae of Developmental Exposure to Psychotherapeutic Drugs: Experimental and Clinical Aspects

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