Addiction is a serious public health problem in the United States with opiates ranking among the top drugs of dependence. 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. Conversely, chronic opiate use and withdrawal are stressors and can potentially predispose individuals to stress-related psychiatric disorders. Because the interaction of opiates with stress response systems has potentially widespread clinical consequences, it is important to delineate how specific substrates of the stress response and endogenous opioid systems interact and the specific points at which stress circuits and endogenous opioid systems intersect. The locus coeruleus (LC)-norepinephrine (NE) system is reciprocally regulated by endogenous opioids and the stress-related neuropeptide, corticotropin-releasing factor (CRF). Our prior studies have shown that chronic morphine exposure sensitizes the LC-NE system to CRF and stress, providing a potential mechanism that could link opiate use and vulnerability to stress-related psychiatric disorders. Withdrawal from opiates engages CRF and other stress-related systems including noradrenergic pathways, which produce heightened anxiety-like states and dysphoria that can increase susceptibility to relapse. Our research has unveiled the complex circuitry by which CRF and endogenous opioids co-regulate activity of the LC-NE system. Our findings indicate that CRF and enkephalin (ENK, acting at mu-OR) exert a postsynaptic opposing regulation. Our most recent studies revealed a novel presynaptic regulation of afferent inputs via kappa-OR modulation of excitatory (glutamate) and CRF afferents to the LC. The circuitry that links these peptides to the LC-NE system and the conditions that engage this circuitry were identified and highlighted the central nucleus of the amygdala as a key structure in its afferent regulation. Additionally, we demonstrated that chronic morphine disturbs this regulation. Given how LC activity is finely tuned by the integration of CRF and endogenous opioid inputs, upsetting the CRF:opioid balance in the LC could influence the stress-sensitivity of this system or its sensitivity to opiates. In the competing renewal application, mechanistic studies are proposed to elucidate how chronic morphine or chronic stress dysregulate the LC-NE system and its consequent behavioral implications.
AIM 1 will identify mechanisms by which LC neurons become dysregulated by chronic morphine at a systems or cellular level such that they are more sensitive to stress.
AIM 2 will define stress- induced molecular and cellular plasticity that alters LC activity and predisposes to substance abuse.
AIM 3 will determine the influence of sex on opiate-induced LC neuronal activity. The proposed work will elucidate how dysregulation of the LC-NE system impacts stress and opiate sensitivity, decisions underlying substance abuse, and sex differences in opiate actions.

Public Health Relevance

The proposed studies will use a mechanistic approach to examine the reciprocal regulation of opiates and stress on the noradrenergic system. The proposed experiments will elucidate how chronic morphine or chronic stress dysregulate the locus coeruleus-norepinephrine system. Understanding these processes will lead to new knowledge and will be used to develop improved therapies for the treatment of addiction and stress-induced anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA009082-16
Application #
8669952
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
Project Start
1994-09-30
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
16
Fiscal Year
2014
Total Cost
$450,903
Indirect Cost
$114,102
Name
Drexel University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
Wood, Susan K; Valentino, Rita J (2016) The brain norepinephrine system, stress and cardiovascular vulnerability. Neurosci Biobehav Rev :
Wood, Christopher S; Valentino, Rita J; Wood, Susan K (2016) Individual differences in the locus coeruleus-norepinephrine system: Relevance to stress-induced cardiovascular vulnerability. Physiol Behav :
Reyes, Beverly A S; Kravets, J L; Connelly, K L et al. (2016) Localization of the delta opioid receptor and corticotropin-releasing factor in the amygdalar complex: role in anxiety. Brain Struct Funct :
Kravets, J L; Reyes, B A S; Unterwald, E M et al. (2015) Direct targeting of peptidergic amygdalar neurons by noradrenergic afferents: linking stress-integrative circuitry. Brain Struct Funct 220:541-58
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
Enman, Nicole M; Sabban, Esther L; McGonigle, Paul et al. (2015) Targeting the Neuropeptide Y System in Stress-related Psychiatric Disorders. Neurobiol Stress 1:33-43
Retson, T A; Hoek, J B; Sterling, R C et al. (2015) Amygdalar neuronal plasticity and the interactions of alcohol, sex, and stress. Brain Struct Funct 220:3211-32
Valentino, Rita J; Van Bockstaele, Elisabeth (2015) Endogenous Opioids: The Downside of Opposing Stress. Neurobiol Stress 1:23-32

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