Adolescence is a neurobiologically distinct developmental period characterized by high rates of experimental drug use and vulnerability to the development of substance abuse. Adolescent substance abuse increases the likelihood of developing lifelong addiction, and cocaine addiction emerges with particular virulence-for example, 15-16% of adolescent cocaine users will develop dependence within 10 years of first exposure. Thus, identifying mechanisms of cocaine vulnerability is a critical research imperative. Cocaine and other amphetamine-like psychostimulants potently regulate dendritic spine morphology in the prefrontal cortex. Whether the long-term consequences of cocaine exposure on neural structure are causally related to adolescent vulnerabilities represents a lively debate in field, however direct evidence supporting any single position is limited. This is in part becaus few labs are equipped with the tools to model addiction in animal systems, to capture and enumerate dendritic spine structure, and to manipulate the molecular regulators of dendritic spine structure to isolate causal relationships. We will develop and refine tools by which to identify the impact of cocaine-induced dendritic spine reorganization on decision-making and cocaine vulnerability with the goal of reversing the adverse consequences of early-life cocaine exposure. Throughout, we will focus on ?1-integrin systems. ?1-integrin is a receptor for extracellular matrix proteins, and it is implicated in cocaine addiction in humans. Because of widespread expression throughout the CNS, ?1-integrin is an unrealistic target in developing treatments for addiction;however its downstream effector in cortical neurons, p190RhoGAP, offers a promising target for intervention. p190RhoGAP stabilizes prefrontal cortical cell structure directly by inhibiting actomyosin contraction and indirectly by increasing mRNA expression of Brain-derived neurotrophic factor (Bdnf). Therefore, we propose to develop tools to: 1) inhibit p190RhoGAP function in vivo using viral vector approaches. This presents a significant advance beyond existing tools (the p190rhogap heterozygous mouse), which lack anatomical and temporal selectivity. 2) selectively manipulate the high-affinity BDNF receptor, trkB. This is essential because although BDNF is implicated in addiction etiology, its receptor target in this context remains unknown. This is despite the recent development of a brain-penetrant trkB agonist with therapeutic-like benefits in other mental health domains. 3) pharmacologically reverse the adverse consequences of early-life cocaine exposure. We will develop pharmacological interventions that act on regulators of the actin cytoskeleton (such as BDNF-trkB systems) rather than traditional neurotransmitter targets. We will apply these tools to mice administered cocaine in adolescence with the goal of blocking maladaptive decision-making in adulthood. We will identify correlative relationships between spine structure and behavioral outcomes using high-resolution confocal microscopy, and causal relationships by refining techniques by which to directly manipulate dendritic spine structure in vivo.

Public Health Relevance

Abundant epidemiological evidence indicates that adolescence is a period of increased vulnerability to the development of addiction and that cocaine exposure during adolescence has both immediate and long-term negative consequences for decision-making and drug vulnerability. These outcomes likely relate to the effects of psychostimulants on prefrontal cortical neuronal refinement during adolescence. We will identify developmentally-regulated molecular signaling cascades of action in order to pharmacologically target specific mechanisms towards therapeutic-like outcomes.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA034808-02
Application #
8676766
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Pilotte, Nancy S
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Hinton, Elizabeth A; Wheeler, Marina G; Gourley, Shannon L (2014) Early-life cocaine interferes with BDNF-mediated behavioral plasticity. Learn Mem 21:253-7