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Neonatal polyamine depletion by alpha-difluoromethylornithine: effects on adenylyl cyclase cell signaling are separable from effects on brain region growth.

Publication ,  Journal Article
Slotkin, TA; Ferguson, SA; Cada, AM; McCook, EC; Seidler, FJ
Published in: Brain Res
December 22, 2000

Ornithine decarboxylase (ODC) and the polyamines play an essential role in brain cell replication and differentiation. We administered alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, to neonatal rats on postnatal days 5-12, during the mitotic peak of the cerebellum, a treatment regimen that leads to selective growth inhibition and dysmorphology. In adulthood, cell signaling responses mediated through the adenylyl cyclase pathway were evaluated in order to determine if synaptic dysfunction extends to regions that appear to be otherwise unaffected by DFMO. Total adenylyl cyclase catalytic activity, evaluated with the direct enzymatic stimulant, Mn(2+), was significantly elevated in male rats both in the cerebellum and in brain regions showing no growth retardation (cerebral cortex, brainstem); there were no significant effects in females. In contrast, signaling mediated through the G proteins that couple neurotransmitter receptors to adenylyl cyclase showed a deficit in the DFMO group, as evaluated with the response to fluoride; in males, there was no corresponding increase in activity as would have been expected solely from the enhancement of adenylyl cyclase, and in females, there was actually a significant decrease in the response to fluoride. Again, the deficits were not restricted to the cerebellum. Stimulation of adenylyl cyclase by isoproterenol, a beta-adrenergic receptor agonist that acts through G(s), likewise displayed deficits in both males and females, and without distinction by brain region. These results indicate that the ODC/polyamine pathway plays a role in the development of cell signaling, and hence in neurotransmission, above and beyond its role in cell replication and differentiation. Given the fact that numerous drugs and environmental contaminants have been shown to alter ODC and the polyamines in the developing brain, our findings suggest that changes in brain region growth or structure are inadequate to predict the targeting of specific neurotransmitter or signaling pathways, and that gender-selective functional defects may be present despite the absence of morphological differences.

Duke Scholars

Published In

Brain Res

DOI

ISSN

0006-8993

Publication Date

December 22, 2000

Volume

887

Issue

1

Start / End Page

16 / 22

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Sex Factors
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Polyamines
  • Neurology & Neurosurgery
  • Male
  • Isoproterenol
  • Enzyme Inhibitors
 

Citation

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ICMJE
MLA
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Slotkin, T. A., Ferguson, S. A., Cada, A. M., McCook, E. C., & Seidler, F. J. (2000). Neonatal polyamine depletion by alpha-difluoromethylornithine: effects on adenylyl cyclase cell signaling are separable from effects on brain region growth. Brain Res, 887(1), 16–22. https://doi.org/10.1016/s0006-8993(00)02961-9
Slotkin, T. A., S. A. Ferguson, A. M. Cada, E. C. McCook, and F. J. Seidler. “Neonatal polyamine depletion by alpha-difluoromethylornithine: effects on adenylyl cyclase cell signaling are separable from effects on brain region growth.Brain Res 887, no. 1 (December 22, 2000): 16–22. https://doi.org/10.1016/s0006-8993(00)02961-9.
Slotkin, T. A., et al. “Neonatal polyamine depletion by alpha-difluoromethylornithine: effects on adenylyl cyclase cell signaling are separable from effects on brain region growth.Brain Res, vol. 887, no. 1, Dec. 2000, pp. 16–22. Pubmed, doi:10.1016/s0006-8993(00)02961-9.
Journal cover image

Published In

Brain Res

DOI

ISSN

0006-8993

Publication Date

December 22, 2000

Volume

887

Issue

1

Start / End Page

16 / 22

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Sex Factors
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Polyamines
  • Neurology & Neurosurgery
  • Male
  • Isoproterenol
  • Enzyme Inhibitors