An estimated 25% of infants in this country are exposed prenatally to drugs of abuse, a significant proportion of which are illicit drugs. Furthermore, a significant number of newborn infants, many of them premature, are exposed to opioids for pain relief following surgical or traumatic events, the long-term consequences for which are little understood. Beyond well documented developmental disabilities, the possibility that individuals exposed to drugs of abuse early in life are rendered more likely to abuse drugs as adults is a particularly alarming prospect, and has been suggested in a number of clinical studies. A critical role for glial cells (e.g., microglia, astrocytes) in addiction is becoming increasingly apparent. For instance, it has recently been demonstrated that morphine and cocaine directly activate glial cells within the CNS in a non-classical opioid receptor manner, via the innate immune system's pattern recognition receptor, toll-like receptor (TLR) 4, and, in the case of morphine, that this glial activation contributes strongly to their rewarding properties. Thus, glial inhibitors or selective TLR4 antagonists markedly reduce opioid-induced dependence, tolerance, and reward. In infants, glial cells are critical for many aspects of normal brain development, including apoptosis, axonal growth, angiogenesis, and synaptogenesis. As the primary """"""""immuno-competent"""""""" cells of the brain, they also respond vigorously to virtually any disturbance of homeostasis, such as injury or infection, and this activation may cause long-term alterations in their function. This proposal has been designed to test the hypothesis that events occurring during the perinatal period of life often produce enduring effects on brain and behavior, including abuse liability later in life, via their influence on glial cell activity and subsequent neural development. This hypothesis will be tested by examining the following questions, using gene expression, protein expression, pharmacological and behavioral techniques: (1) What is the impact of perinatal exposure to morphine and cocaine on glial and neural cell development and function? (2) What is the role for alterations in glial cell development and/or function in later life abuse liability? and (3) Will attenuating glial activation early in life protect from increased abuse liability in adulthood? These collective data will provide novel insight into the role that early life noxious events, including drug exposure, have on neural and glial cell development within the CNS, as well as the role that glial cells play in substance abuse at a behavioral and pharmacological level.

Public Health Relevance

An estimated 25% or more of infants in this country are exposed prenatally to drugs of abuse, and a significant number of newborn infants, many of them premature, are exposed to opioids for pain relief following surgical or traumatic events, the long-term consequences for which are little understood. A critical role for glial cells (e.g., microglia, astrocytes) in addiction is becoming increasingly apparent. The data collected from this proposal will provide novel insight into the role that early life noxious events, including drug exposure, have on neural and glial cell development within the CNS, the role that glial cells play in substance abuse at a behavioral and pharmacological level, and ultimately treatment decisions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA025978-02
Application #
7688521
Study Section
Special Emphasis Panel (ZDA1-MXH-H (11))
Program Officer
Sorensen, Roger
Project Start
2008-09-30
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2009
Total Cost
$261,989
Indirect Cost
Name
Duke University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Posillico, Caitlin K; Terasaki, Laurne S; Bilbo, Staci D et al. (2015) Examination of sex and minocycline treatment on acute morphine-induced analgesia and inflammatory gene expression along the pain pathway in Sprague-Dawley rats. Biol Sex Differ 6:33
Bilbo, Staci D (2013) Frank A. Beach award: programming of neuroendocrine function by early-life experience: a critical role for the immune system. Horm Behav 63:684-91
Schwarz, Jaclyn M; Bilbo, Staci D (2013) Adolescent morphine exposure affects long-term microglial function and later-life relapse liability in a model of addiction. J Neurosci 33:961-71
Schwarz, Jaclyn M; Smith, Susan H; Bilbo, Staci D (2013) FACS analysis of neuronal-glial interactions in the nucleus accumbens following morphine administration. Psychopharmacology (Berl) 230:525-35
Bilbo, Staci D; Schwarz, Jaclyn M (2012) The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33:267-86
Schwarz, Jaclyn M; Bilbo, Staci D (2012) Sex, glia, and development: interactions in health and disease. Horm Behav 62:243-53
Schwarz, Jaclyn M; Sholar, Paige W; Bilbo, Staci D (2012) Sex differences in microglial colonization of the developing rat brain. J Neurochem 120:948-63
Schwarz, Jaclyn M; Hutchinson, Mark R; Bilbo, Staci D (2011) Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression. J Neurosci 31:17835-47
Schwarz, Jaclyn M; Bilbo, Staci D (2011) LPS elicits a much larger and broader inflammatory response than Escherichia coli infection within the hippocampus of neonatal rats. Neurosci Lett 497:110-5