Excessive alcohol drinking among human adolescents is a major social and biomedical problem in the United States and Puerto Rico. Moreover, early initiation of alcohol use or misuse leads to greater risk of lifetime alcohol use disorders. Recent human brain imaging studies clearly show that the prefrontal cortex (PFC), which underlies various executive cognitive functions, undergoes extensive structural and functional re- organization from adolescence to adulthood. This is consistent with the notion that heightened synaptic plasticity is a cardinal feature of adolescent brain development. Although usually adaptive and beneficial, heightened plasticity may lead to greater vulnerability to substance abuse. Indeed, the mechanisms underlying synaptic plasticity are similar to the mechanisms mediating ethanol dependence. Research performed in animal models is needed because studies involving the administration of alcohol to human adolescents are illegal. We have recently developed an adolescent C57BL/6J (B6) mouse model that shows greater propensity for ethanol drinking behavior. The use of the B6 strain may be especially valuable given its wealth of available genetic information (i.e., Mouse Genome Project). Studies proposed in this application are to combine our B6 adolescent drinking model with in-vivo neurochemical and pharmacological approaches that have never been employed during the adolescent period. Our primary objective is to determine the role of extracellular glutamate homeostasis in the PFC and its projections to the nucleus accumbens (NAC). Our working hypothesis is that elevated glutamatergic transmission in the PFC-NAC circuit leads to greater propensity for alcohol drinking during adolescence. We also propose to study the effects of adolescent drinking on dendritic spines in the PFC, which are the major postsynaptic components of glutamatergic synapses. It is anticipated that prefrontal spine plasticity will be severely altered following adolescent alcohol drinking experience. Collectively, these studies will generate new and novel information regarding the role of synaptic glutamate transmission in the PFC-NAC circuitry in mediating adolescent alcohol drinking. This will provide valuable insight into this crucial clinical and social issue, as well as facilitate development of new glutamate- an neuroplasticity-based pharmacotherapies that reduce harmful consequences of alcohol abuse.

Public Health Relevance

The prevalence of alcohol dependence among human adolescents underscores the need for better understanding of the mechanisms involved. Using a well-characterized mouse model we aim to advance knowledge regarding the role of glutamate neurotransmission and plasticity in the prefrontal cortex in mediating excessive alcohol drinking during the adolescent period.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA020610-01A1
Application #
8689614
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
2014-07-10
Project End
2019-06-30
Budget Start
2014-07-10
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$337,500
Indirect Cost
$112,500
Name
University of Puerto Rico Med Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
948108063
City
San Juan
State
PR
Country
United States
Zip Code
00936