Stress is a major factor that interacts with genetic makeup &drug experience to determine vulnerability to addiction &relapse. The degree of behavioral control that an organism (rat to human) has over a stressor is arguably the most potent modulator of the behavioral &physiological impact of stressors yet discovered, &a lack of control over stressors has been found to be a predisposing factor to addiction at the human level. The research to be conducted focuses on the role of behavioral control &lack of control over stress in determining the impact of stress on behavioral and neurochemical responses tro drugs of abuse. Uncontrollable, relative to controllable stress, has been shown to sensitize serotonergic (5-HT) neurons within the dorsal raphe nucleus (DRN) so that for a period of days these neurons respond to input in an exaggerated fashion, releasing excessive amounts of 5-HT in projection regions. Research conducted during the past grant period has shown that uncontrollable stress potentiates morphine-induced conditioned place preference, psychomotor responses, nucleus accumbens dopamine release, and plasma corticosterone (CORT) for a period of many days, whereas exactly equal controllable stress does not. Furthermore, uncontrollable stress-induced sensitization of DRN 5-HT neurons &release of excessive 5-HT was shown to be necessary to produce these phenomena, as was the potentiated CORT increase. Moreover, preliminary data suggest that it is 5-HT released in the medial prefrontal cortex (mPFC) that is critical to the augmented behavioral and neurochemical responses to morphine produced by prior uncontrollable stress.
The Aims of the new proposed work are to determine a) whether 5-HT and CORT act within the mPFC to produce exaggerated responses to morphine &how this occurs;b) whether uncontrollable stress would potentiate behavioral &neurochemical responses to drugs other than opiates if they are experienced in a way that activates DRN 5-HT neurons;and c) how control over stress prevents stressors from increasing reactivity to drugs of abuse &confers resilience. This research should provide insights into the neural mechanisms that produce vulnerability &resilience to the modulatory effects of stress on reactions to drugs of abuse &suggest methods to combat the deleterious effects of stress.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Thomas, David A
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Bland, Sondra T; Beckley, Jacob T; Watkins, Linda R et al. (2010) Neonatal Escherichia coli infection alters glial, cytokine, and neuronal gene expression in response to acute amphetamine in adolescent rats. Neurosci Lett 474:52-7
Rozeske, Robert R; Der-Avakian, Andre; Bland, Sondra T et al. (2009) The medial prefrontal cortex regulates the differential expression of morphine-conditioned place preference following a single exposure to controllable or uncontrollable stress. Neuropsychopharmacology 34:834-43
Bland, Sondra T; Hutchinson, Mark R; Maier, Steven F et al. (2009) The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release. Brain Behav Immun 23:492-7
Der-Avakian, Andre; Rozeske, Robert R; Bland, Sondra T et al. (2007) The effects of a single session of inescapable tailshock on the subsequent locomotor response to brief footshock and cocaine administration in rats. Psychopharmacology (Berl) 191:899-907
Der-Avakian, Andre; Bland, Sondra T; Rozeske, Robert R et al. (2007) The effects of a single exposure to uncontrollable stress on the subsequent conditioned place preference responses to oxycodone, cocaine, and ethanol in rats. Psychopharmacology (Berl) 191:909-17
Der-Avakian, Andre; Bland, Sondra T; Schmid, Megan J et al. (2006) The role of glucocorticoids in the uncontrollable stress-induced potentiation of nucleus accumbens shell dopamine and conditioned place preference responses to morphine. Psychoneuroendocrinology 31:653-63
Bland, Sondra T; Schmid, Megan J; Greenwood, Benjamin N et al. (2006) Behavioral control of the stressor modulates stress-induced changes in neurogenesis and fibroblast growth factor-2. Neuroreport 17:593-7
Amat, J; Baratta, M V; Paul, E et al. (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci 8:365-71
Der-Avakian, Andre; Will, Matthew J; Bland, Sondra T et al. (2005) Surgical and pharmacological suppression of glucocorticoids prevents the enhancement of morphine conditioned place preference by uncontrollable stress in rats. Psychopharmacology (Berl) 179:409-17
Bland, Sondra T; Schmid, Megan J; Der-Avakian, Andre et al. (2005) Expression of c-fos and BDNF mRNA in subregions of the prefrontal cortex of male and female rats after acute uncontrollable stress. Brain Res 1051:90-9

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