There is increasing evidence that brain acidic phospholipids (i.e. PS, PA, PI and poly-PI) as well as the receptor-mediated signal transduction mechanism pertaining to turnover of poly- phosphoinositides are altered due to acute and chronic ethanol administration. The overall objective of this research program is to further delineate the molecular site of perturbation of ethanol on the poly-PI- cycle, and to relate the physiological significance of thes changes. We hypothesize that due to an increase in acidic phospholipids (especially phosphatidylserine), chronic ethanol administration is asociated with an increase in the membrane- bound protein kinase C activity. In turn, other cellular changes may occur as a consequence of the alteration of the protein kinase C activity. We will continue to use the Sprague-Dawley rats as an experimental model.
The specific aims are: 1. Quantitative determination of metabolites involved in poly-PI metabolsim with respect to acute and chronic ethanol administration. 2. To use the in vivo labeling procedure to examine changes in brain phospholipids (especially poly-PI) with respect to acute and chronic ethanol administration. Label precursors such as (32P)- ATP, (3H)-inositol, (14C)-arachidonic acid and (14C)-acetate will be injected intracerebrally into the rat brain. With this labeling procedure, the effects of ethanol on uptake as well as breakdown of the brain acidic phospholipids will be determined. In addition, attempts will be made to identify brain regions that may exhibit high sensitivity to the effects of ethanol. With brains prelabeled by these various precursors, agents known to alter the response of signal-tranduction mechanism (e.g. lithium) will be evaluated for their effects in the treatment of alcoholism. 3. In vitro experiments will be carried out to investigate the effects of ethonal and other aliphatic alcohols on enzymes responsible for metabolism of poly-PI in brain subcellular membranes. The long-term goal is to understand the molecular action of ethanol on the signal transduction mechanism involving poly-PI turnover. These investigations may give new insights towards explaining the biochemical mechanism(s) of tolerance and the physiological manifestation of hypersensitivity during ethanol withdrawal.
Showing the most recent 10 out of 39 publications
