Drug addiction exacts a heavy toll on the affected individuals, their families and civilized society. This basic research proposal in response to PA #00-115 approaches the problem of drug abuse and addiction by identifying, characterizing and biochemically testing genetic variants in fatty acid amide hydrolase (FAAH), the principal catabolic regulator of endocannabinoid levels and the brain endogenous cannabinoid system (ECS) tone that may contribute to vulnerability in this genetically complex disorder. The brain ECS is a recently discovered but evolutionary ancient retrograde signaling pathway with the capacity to continuously modulate (downregulate) neurotransmitter release in many critical neuronal systems, including the mesolimbic dopamine addiction/reward system. It has long been known that cannabis use may be associated with drug abuse and addiction in some vulnerable individuals and animal studies indicate that cannabinoids play a role in addiction. Because brain endogenous cannabinoids have the same receptor targets and activity as exogenous cannabis, the central hypothesis of this proposal is that functionally abnormal genetic variants of FAAH may contribute to the risk of vulnerability for drug abuse and addiction. The long term objectives and aims of this proposal are to identify and biochemically test significant FAAH mutations in anonymous subjects with specific types of drug abuse and to link these mutations as risk factors for vulnerability to drug abuse or dependence. This proposal focuses on genetic mutations identified in preliminary studies of the human FAAH gene. The plan is to genetically, biochemically and functionally evaluate significant human FAAH mutations and to confirm the risk of specific mutant proteins in a large cohort of anonymous DNA samples from specific drug addictions, stratified for age, gender, race/ethnicity to compare with matched controls. Collectively, these experimental aims seek to validate naturally occurring FAAH genetic variants as predictors of vulnerability to drug abuse and dependence so that individuals at greatest risk may be identified early and treatment strategies tested for this major public health problem.
