Grants and Contracts Details
Description
Brain injury is among the most prominent effects of prolonged alcohol use or abuse and
evidence suggests that females may be more sensitive than males to the neurotoxic effect
of prolonged alcohol intake. Thus, examination of biochemical pathways involved in this
form of brain injury may be of value in identifying therapeutic targets to be exploited in
treating alcohol-related brain injury. Excess activity of N-methyl-o-asparate (NMDA)-
type glutamate receptors has been implicated in both the behavioral and neurotoxic
effects of alcoholism, particularly during alcohol withdrawal, when excess release of
glutamate and polyamines occurs. Preliminary findings suggest that the rat female brain
may be more sensitive to the toxic effects of polyamine exposure during ethanol
withdrawal. Polyamines are endogenous substances that act as allosteric activators of
NMDA receptors at NR2 subunits. Substances that further promote activity of NMDA
receptor systems, such as glucocorticoids, are hypothesized to exacerbate alcohol
withdrawal effects. Indeed, prolonged alcohol intake is associated with hypercortisolemia
resulting from alcohol effects the hypothalamic pituitary adrenal (HPA) axis. However,
the consequences of elevated stress hormone release with regard to alcohol-related
neuronal injury have been little studied, particulary with regard to potential sex
+differences that may exist. The proposed in vitro and in vivo rodent studies will test the
hypothesis that alcohol-induced activation of the HPA axis promotes NMDA receptormediated
seizure and/or neurotoxicity during alcohol withdrawal in a sex-dependent
manner by: (I) stimulating the synthesis of polyamines via upregulation of the synthetic
enzyme ornithine decarboxylase, an effect dependent upon glucocorticoid receptor (GR)
activation: and (2) upregulating the expression of polyamine-sensitive NR2B subunits,
thus, promoting NMDA channel opening and neuronal excitation and/or neurotoxicity in
a GR-dependent manner. These studies will employ biochemical, immunohistochemical,
confocal imaging, and behavioral studies using an in vivo "moderate" binge-alcohol
exposure paradigm that produces peak B.A.L.s of - 160 mg/dl and organotypic
hippocampal slice cultures, in parallel studies. The aim of these studies is to elucidate the
means by which glucocorticoids may exacerbate alcohol withdrawal effects in males and
females, as these relevant biochemical pathways may represent therapeutic targets to be
exploited in the treatment of alcohol withdrawal effects.
Project Description
Status | Finished |
---|---|
Effective start/end date | 8/1/01 → 8/31/15 |
Funding
- National Institute on Alcohol Abuse and Alcoholism: $1,700,711.00
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