There are large individual differences in reactivity to drugs of abuse, but the causes of these differences are not well understood. The recent experience of """"""""stress"""""""" is a factor known to potentiate drug reward processes in both humans and animals, but the aspects of stress that are critical and the neural mechanisms involved are not fully known. The proposed research explores the role of the degree of behavioral control that the individual has over the stressor as a feature modulating wither the stressor will alter drug reactivity, and focuses on stressor-induced sensitization of serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) as a mediator. The hypothesis to be tested is that 1) uncontrollable (but not controllable) stressors sensitize DRN 5-HT neurons for a period of time, leading to exaggerated release of 5-HT in projection regions when the neurons are activated; 2) 5-HT released in the nucleus accumbens (NAc) and/or medial prefrontal cortex (mPFC) by neurons projecting from the DRN increases the extracellular level of DA in the these regions that is produced by drugs of abuse; 3) 5-HT released in the paraventricular nucleus increases the blood levels of corticosterone (CORT); 4) Drugs that activate DRN 5-HT neurons (e.g., morphine) in addition to acting on brain reward structures, will therefore produce greater levels of extracellular DA in the NAc/mPFC and CORT in blood for subjects that have recently received uncontrollable stressors; 4) uncontrollable (but not controllable) stressors will therefore potentiate behavioral responses to drugs that depend on NAc/mPFC DA and/or CORT, and this potentiation will occur for drugs that activate DRN 5-HT neurons. Conditioned place preference and locomotor activation are the behaviors to be examined, and morphine, amphetamine, heroin, nicotine, cocaine, and ethanol are the drugs that will be tested.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA013159-01A1
Application #
6259395
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Wetherington, Cora Lee
Project Start
2001-02-01
Project End
2006-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
1
Fiscal Year
2001
Total Cost
$343,189
Indirect Cost
Name
University of Colorado at Boulder
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
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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