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 mechanism 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 86 adolescent drinking model with in-vivo neurochemical and pharmacological approached 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- and 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 of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM103642-01A1
Application #
8465621
Study Section
Special Emphasis Panel (ZGM1-TWD-B (CB))
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$257,092
Indirect Cost
$81,092
Name
University of Puerto Rico Med Sciences
Department
Type
DUNS #
948108063
City
San Juan
State
PR
Country
United States
Zip Code
00936
Delgado-Peraza, Francheska; Ahn, Kwang H; Nogueras-Ortiz, Carlos et al. (2016) Mechanisms of Biased β-Arrestin-Mediated Signaling Downstream from the Cannabinoid 1 Receptor. Mol Pharmacol 89:618-29
Padilla-Morales, Luis F; Colón-Sáez, José O; González-Nieves, Joel E et al. (2016) Functionality and stability data of detergent purified nAChR from Torpedo using lipidic matrixes and macroscopic electrophysiology. Data Brief 6:433-7
Duprey-Díaz, Mildred V; Blagburn, Jonathan M; Blanco, Rosa E (2016) Exogenous Modulation of Retinoic Acid Signaling Affects Adult RGC Survival in the Frog Visual System after Optic Nerve Injury. PLoS One 11:e0162626
Melendez, Roberto I; Roman, Cristina; Capo-Velez, Coral M et al. (2016) Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice. J Neurovirol 22:358-65
Colón, Jennifer M; Torrado, Aranza I; Cajigas, Ámbar et al. (2016) Tamoxifen Administration Immediately or 24 Hours after Spinal Cord Injury Improves Locomotor Recovery and Reduces Secondary Damage in Female Rats. J Neurotrauma 33:1696-708
Ramos, Félix M; Delgado-Vélez, Manuel; Ortiz, Ángel L et al. (2016) Expression of CHRFAM7A and CHRNA7 in neuronal cells and postmortem brain of HIV-infected patients: considerations for HIV-associated neurocognitive disorder. J Neurovirol 22:327-35
Nogueras-Ortiz, Carlos; Yudowski, Guillermo A (2016) The Multiple Waves of Cannabinoid 1 Receptor Signaling. Mol Pharmacol 90:620-626
Morales-Cruz, Moraima; Cruz-Montañez, Alejandra; Figueroa, Cindy M et al. (2016) Combining Stimulus-Triggered Release and Active Targeting Strategies Improves Cytotoxicity of Cytochrome c Nanoparticles in Tumor Cells. Mol Pharm 13:2844-54
Báez-Pagán, Carlos A; Del Hoyo-Rivera, Natalie; Quesada, Orestes et al. (2016) Heterogeneous Inhibition in Macroscopic Current Responses of Four Nicotinic Acetylcholine Receptor Subtypes by Cholesterol Enrichment. J Membr Biol 249:539-49
Martinez, Namyr A; Ayala, Alondra M; Martinez, Magdiel et al. (2016) Caveolin-1 Regulates the P2Y2 Receptor Signaling in Human 1321N1 Astrocytoma Cells. J Biol Chem 291:12208-22

Showing the most recent 10 out of 58 publications