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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rutter, Joni
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Scripps Research Institute
La Jolla
United States
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Tyndale, Rachel F; Payne, Jennifer I; Gerber, Alexandra L et al. (2007) The fatty acid amide hydrolase C385A (P129T) missense variant in cannabis users: studies of drug use and dependence in Caucasians. Am J Med Genet B Neuropsychiatr Genet 144B:660-6
Flanagan, Jonathan M; Gerber, Alexandra L; Cadet, Jean Lud et al. (2006) The fatty acid amide hydrolase 385 A/A (P129T) variant: haplotype analysis of an ancient missense mutation and validation of risk for drug addiction. Hum Genet 120:581-8
Sipe, J C; Waalen, J; Gerber, A et al. (2005) Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes (Lond) 29:755-9
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Chiang, Kyle P; Gerber, Alexandra L; Sipe, Jack C et al. (2004) Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet 13:2113-9