During chronic ingestion of ethanol, both humans and animals develop a lowered sensitivity to the CNS effects of this drug. This effect, termed tolerance, shifts the balance between the aversive and reinforcing effects of ethanol, promoting a greater intake of ethanol and greater organ damage. Many recent reports have shown that the membranes from tolerant animals are less sensitive to the disordering effects of ethanol. When certain lipid fractions are removed from these membranes, they have the ability to confer upon artificial lipid vesicles a decreased sensitivity to ethanol. Whereas changes in lipids may be involved in the development of tolerance, it has been reported that vasopressin, acting through CNS vasopressin V1 receptors, may mediate, at least in part, the maintenance of tolerance. Following the development of tolerance, doses of vasopressin too low to elicit any physiological responses can maintain tolerance in the absence of ethanol ingestion. In addition, the i.c.v. injection of V1 antagonists can thwart the development of tolerance, suggesting a critical role for endogenous vasopressin and vasopressin receptors. Other studies have also suggested that specific guanine nucleotide-binding regulatory proteins (G-proteins) may be specific targets for .ethanol action. We propose to utilize our laboratory's expertise in the purification and functional reconstitution of the vasopressin V1 receptor and receptor/G-protein coupling in an effort to integrate the possible involvement of lipids and the vasopressin/vasopressin V1 receptor system in the development and maintenance of tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Small Research Grants (R03)
Project #
7R03AA008985-02
Application #
3422109
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1993-04-01
Project End
1994-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Eunice Kennedy Shriver Center Mtl Retardatn
Department
Type
DUNS #
City
Waltham
State
MA
Country
United States
Zip Code
02254