Marijuana is the illicit drug most frequently used by teenagers, and exposure to cannabis normally predates the use of "heavy" drugs and psychiatric disorders. Such data appear to support the controversial "gateway" hypothesis of cannabis as a stepping stone towards abuse of other drugs. Despite strong epidemiological evidence of an association between cannabis use during adolescence and later drug abuse, few one-to-one neurobiological correlations between early cannabis use and subsequent drug abuse vulnerability exist. Reproducible animal data has shown that cannabis exposure during adolescence potentiated adult heroin self-administration behavior and caused discrete alterations of preproenkephalin (PENK), a gene important for reward and hedonic state, in the nucleus accumbens (Acb), a limbic-related brain area central to reward. The proposed work will directly test whether there is a causal link between PENK disturbance seen with early-onset cannabis use and progression to the use of other illicit drugs. Virus-mediated gene transfer (PENK overexpression) and RNA interference (PENK knockdown) will be used as genetic approaches to study the behavioral and neurochemical states associated with drug abuse.
Specific Aim 1 will determine whether direct manipulation of the PENK gene in the Acb shell alters heroin self-administration behavior. Disturbances of neurotransmitters in brain areas linked to reward will be identified by studying whether genetic manipulation of PENK alters opiate-induced dopamine levels in the Acb shell using in vivo microdialysis (Specific Aim 2). To characterize specific molecular alterations that could underlie behavioral and neurochemical differences observed in association with genetic manipulation of PENK, brains will be analyzed for expression of genes and receptors linked to the opioid, DAergic, and cannabinoid neural systems (Specific Aim 3). Substance abuse is a major public health issue, and understanding risk factors predisposing to drug abuse disorders will be crucial to the prevention and treatment of these illnesses. Altogether, this project will provide insight as to whether there exists a long-term impact of cannabis exposure during development to substantiate a neurobiological "gateway" hypothesis and, if so, help to identify potential risk factors in adolescence that influence the vulnerability for drug abuse in adulthood.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DA024929-05
Application #
8246491
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Babecki, Beth
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$46,182
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029