The interaction between the stress axis and endogenous opioid systems has gained substantial clinical interest as it is increasingly recognized that stress predisposes to opiate abuse. For example, stress has been implicated as a risk factor in vulnerability to the initiation and maintenance of opiate abuse and is thought to play an important role in relapse in subjects with a history of abuse. However, the impact of stress-opioid interactions extends beyond vulnerability to opiate abuse. Numerous reports indicating that stress alters individual sensitivity to opiates suggest that prior stress can influence the pharmacodynamics of opiates that are used in clinical settings. Conversely, the effects of opiates on different components of the stress axis can impact on individual responsivity to stressors and potentially predispose individuals to stress- related psychiatric disorders. Because these interactions have potentially widespread clinical consequences, it is important to identify substrates of the stress response and endogenous opioid systems that interact and the specific points at which stress circuits and endogenous opioid systems intersect. During the previous funding period, we generated anatomical and physiological evidence that the locus coeruleus (LC)-norepinephrine (NE) system is reciprocally regulated by endogenous opioids and corticotropin-releasing factor (CRF). It was also demonstrated that chronic morphine sensitized the LC-NE system to CRF and stress, providing a potential mechanism that could link opiate use and vulnerability to stress-related psychiatric disorders. Importantly, new evidence was obtained for novel presynaptic actions of kappa-opioids on LC afferents, thus adding another dimension to our model of how this central NE system is co-regulated by opioids and CRF. Our general goals in this competing renewal application are to 1) identify neuroanatomical substrates for glutamate-opioid and CRF-opioid interactions that impact on the function of the LC-NE system, 2) characterize kappa-opioid receptor mediated regulation of LC spontaneous activity and afferent evoked activity, 3) characterize the impact of kappa-opioid receptor modulation of the LC on forebrain NE efflux and a behavioral endpoint of attention. This research will enhance our understanding of the interactions between stress and drug abuse and contribute to improving public health.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009082-13
Application #
7808011
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Pilotte, Nancy S
Project Start
1994-09-30
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
13
Fiscal Year
2010
Total Cost
$410,484
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Ross, Jennifer A; Gliebus, Gediminas; Van Bockstaele, Elisabeth J (2017) Stress induced neural reorganization: A conceptual framework linking depression and Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry :
Wood, Susan K; Valentino, Rita J (2017) The brain norepinephrine system, stress and cardiovascular vulnerability. Neurosci Biobehav Rev 74:393-400
Guajardo, Herminio M; Snyder, Kevin; Ho, Andrew et al. (2017) Sex Differences in ?-Opioid Receptor Regulation of the Rat Locus Coeruleus and Their Cognitive Consequences. Neuropsychopharmacology 42:1295-1304
Reyes, Beverly A S; Kravets, J L; Connelly, K L et al. (2017) Localization of the delta opioid receptor and corticotropin-releasing factor in the amygdalar complex: role in anxiety. Brain Struct Funct 222:1007-1026
Wood, Christopher S; Valentino, Rita J; Wood, Susan K (2017) Individual differences in the locus coeruleus-norepinephrine system: Relevance to stress-induced cardiovascular vulnerability. Physiol Behav 172:40-48
Carvalho, A F; Reyes, B A S; Ramalhosa, F et al. (2016) Repeated administration of a synthetic cannabinoid receptor agonist differentially affects cortical and accumbal neuronal morphology in adolescent and adult rats. Brain Struct Funct 221:407-19
Retson, T A; Sterling, R C; Van Bockstaele, E J (2016) Alcohol-induced dysregulation of stress-related circuitry: The search for novel targets and implications for interventions across the sexes. Prog Neuropsychopharmacol Biol Psychiatry 65:252-9
Reyes, Beverly A S; Zitnik, Gerard; Foster, Celia et al. (2015) Social Stress Engages Neurochemically-Distinct Afferents to the Rat Locus Coeruleus Depending on Coping Strategy. eNeuro 2:
Chaijale, Nayla N; Snyder, Kevin; Arner, Jay et al. (2015) Repeated social stress increases reward salience and impairs encoding of prediction by rat locus coeruleus neurons. Neuropsychopharmacology 40:513-23
Retson, T A; Reyes, B A; Van Bockstaele, E J (2015) Chronic alcohol exposure differentially affects activation of female locus coeruleus neurons and the subcellular distribution of corticotropin releasing factor receptors. Prog Neuropsychopharmacol Biol Psychiatry 56:66-74

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