Prenatal Diazepam Exposure Functionally Alters the GABAA Receptor That Modulates [3H]Noradrenaline Release from Rat Hippocampal Synaptosomes

Carla Cannizzaro, Silvia Maurizi, Debora Altobelli, Paolo Preziosi, Maria Martire

Risultato della ricerca: Article

18 Citazioni (Scopus)

Abstract

In rats, exposure to diazepam (DZ) during the last week of gestation is associated with behavioral alterations (in some cases sexually dimorphic) that appear when the animals reach adulthood. This study was conducted to evaluate the effects of prenatal DZ exposure on the function of the -aminobutyric (GABA)A receptor complex. The method used - perfusion of rat hippocampal nerve terminals labeled with [3H]noradrenaline (NA) - allowed us to evaluate the effects of DZ on a specific native GABAA receptor subtype which is located on hippocampal noradrenergic nerve endings and mediates the release of NA. Muscimol stimulated synaptosomal release of [3H]NA in a concentration-dependent manner; maximal stimulation (50%) was achieved with a concentration of 30 µM, and the ED50 was 1.7 µM. The effect of muscimol was potentiated by the positive allosteric modulators DZ and 3-pregnan-5-ol-20-one (3,5-P; allopregnanolone), which displayed similar maximal effects and affinities. In the presence of DZ (0.1 µM), muscimol stimulated the release of [3H]NA with an ED50 of 0.5 µM; in the presence of 3,5-P (0.1 µM), the ED50 of muscimol was 0.3 µM. Prenatal DZ exposure did not modify the concentration-effect curve for muscimol, but it did abolish the potentiating effects of DZ and 3,5-P. These findings demonstrate that prenatal exposure to DZ produces functional modifications of the GABAA receptor subtype we investigated. This effect may be related to the relative contributions of the various protein subunits that compose the GABAA receptor complex. Exposure to DZ while the GABAA receptors are developing might influence the expression of these subunits, giving rise to a receptor that can be activated by muscimol but is not susceptible to allosteric modulation by DZ or 3,5-P.
Lingua originaleEnglish
pagine (da-a)71-78
Numero di pagine8
RivistaDevelopmental Neuroscience
Volume24
Stato di pubblicazionePublished - 2002

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Synaptosomes
GABA-A Receptors
Diazepam
Norepinephrine
Muscimol
Pregnanolone
Nerve Endings
Protein Subunits
Perfusion
Pregnancy

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience

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Prenatal Diazepam Exposure Functionally Alters the GABAA Receptor That Modulates [3H]Noradrenaline Release from Rat Hippocampal Synaptosomes. / Cannizzaro, Carla; Maurizi, Silvia; Altobelli, Debora; Preziosi, Paolo; Martire, Maria.

In: Developmental Neuroscience, Vol. 24, 2002, pag. 71-78.

Risultato della ricerca: Article

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abstract = "In rats, exposure to diazepam (DZ) during the last week of gestation is associated with behavioral alterations (in some cases sexually dimorphic) that appear when the animals reach adulthood. This study was conducted to evaluate the effects of prenatal DZ exposure on the function of the -aminobutyric (GABA)A receptor complex. The method used - perfusion of rat hippocampal nerve terminals labeled with [3H]noradrenaline (NA) - allowed us to evaluate the effects of DZ on a specific native GABAA receptor subtype which is located on hippocampal noradrenergic nerve endings and mediates the release of NA. Muscimol stimulated synaptosomal release of [3H]NA in a concentration-dependent manner; maximal stimulation (50{\%}) was achieved with a concentration of 30 µM, and the ED50 was 1.7 µM. The effect of muscimol was potentiated by the positive allosteric modulators DZ and 3-pregnan-5-ol-20-one (3,5-P; allopregnanolone), which displayed similar maximal effects and affinities. In the presence of DZ (0.1 µM), muscimol stimulated the release of [3H]NA with an ED50 of 0.5 µM; in the presence of 3,5-P (0.1 µM), the ED50 of muscimol was 0.3 µM. Prenatal DZ exposure did not modify the concentration-effect curve for muscimol, but it did abolish the potentiating effects of DZ and 3,5-P. These findings demonstrate that prenatal exposure to DZ produces functional modifications of the GABAA receptor subtype we investigated. This effect may be related to the relative contributions of the various protein subunits that compose the GABAA receptor complex. Exposure to DZ while the GABAA receptors are developing might influence the expression of these subunits, giving rise to a receptor that can be activated by muscimol but is not susceptible to allosteric modulation by DZ or 3,5-P.",
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T1 - Prenatal Diazepam Exposure Functionally Alters the GABAA Receptor That Modulates [3H]Noradrenaline Release from Rat Hippocampal Synaptosomes

AU - Cannizzaro, Carla

AU - Maurizi, Silvia

AU - Altobelli, Debora

AU - Preziosi, Paolo

AU - Martire, Maria

PY - 2002

Y1 - 2002

N2 - In rats, exposure to diazepam (DZ) during the last week of gestation is associated with behavioral alterations (in some cases sexually dimorphic) that appear when the animals reach adulthood. This study was conducted to evaluate the effects of prenatal DZ exposure on the function of the -aminobutyric (GABA)A receptor complex. The method used - perfusion of rat hippocampal nerve terminals labeled with [3H]noradrenaline (NA) - allowed us to evaluate the effects of DZ on a specific native GABAA receptor subtype which is located on hippocampal noradrenergic nerve endings and mediates the release of NA. Muscimol stimulated synaptosomal release of [3H]NA in a concentration-dependent manner; maximal stimulation (50%) was achieved with a concentration of 30 µM, and the ED50 was 1.7 µM. The effect of muscimol was potentiated by the positive allosteric modulators DZ and 3-pregnan-5-ol-20-one (3,5-P; allopregnanolone), which displayed similar maximal effects and affinities. In the presence of DZ (0.1 µM), muscimol stimulated the release of [3H]NA with an ED50 of 0.5 µM; in the presence of 3,5-P (0.1 µM), the ED50 of muscimol was 0.3 µM. Prenatal DZ exposure did not modify the concentration-effect curve for muscimol, but it did abolish the potentiating effects of DZ and 3,5-P. These findings demonstrate that prenatal exposure to DZ produces functional modifications of the GABAA receptor subtype we investigated. This effect may be related to the relative contributions of the various protein subunits that compose the GABAA receptor complex. Exposure to DZ while the GABAA receptors are developing might influence the expression of these subunits, giving rise to a receptor that can be activated by muscimol but is not susceptible to allosteric modulation by DZ or 3,5-P.

AB - In rats, exposure to diazepam (DZ) during the last week of gestation is associated with behavioral alterations (in some cases sexually dimorphic) that appear when the animals reach adulthood. This study was conducted to evaluate the effects of prenatal DZ exposure on the function of the -aminobutyric (GABA)A receptor complex. The method used - perfusion of rat hippocampal nerve terminals labeled with [3H]noradrenaline (NA) - allowed us to evaluate the effects of DZ on a specific native GABAA receptor subtype which is located on hippocampal noradrenergic nerve endings and mediates the release of NA. Muscimol stimulated synaptosomal release of [3H]NA in a concentration-dependent manner; maximal stimulation (50%) was achieved with a concentration of 30 µM, and the ED50 was 1.7 µM. The effect of muscimol was potentiated by the positive allosteric modulators DZ and 3-pregnan-5-ol-20-one (3,5-P; allopregnanolone), which displayed similar maximal effects and affinities. In the presence of DZ (0.1 µM), muscimol stimulated the release of [3H]NA with an ED50 of 0.5 µM; in the presence of 3,5-P (0.1 µM), the ED50 of muscimol was 0.3 µM. Prenatal DZ exposure did not modify the concentration-effect curve for muscimol, but it did abolish the potentiating effects of DZ and 3,5-P. These findings demonstrate that prenatal exposure to DZ produces functional modifications of the GABAA receptor subtype we investigated. This effect may be related to the relative contributions of the various protein subunits that compose the GABAA receptor complex. Exposure to DZ while the GABAA receptors are developing might influence the expression of these subunits, giving rise to a receptor that can be activated by muscimol but is not susceptible to allosteric modulation by DZ or 3,5-P.

UR - http://hdl.handle.net/10447/37779

M3 - Article

VL - 24

SP - 71

EP - 78

JO - Developmental Neuroscience

JF - Developmental Neuroscience

SN - 0378-5866

ER -