The nucleus locus coeruleus (LC) has been implicated in both the physical signs and adverse withdrawal effects of opiates. The physiological basis postulated for these actions includes opioid activation of receptive sites of noradrenergic neurons and may also involve interactions with serotonin and glutamate. The proposed studies will examine the cellular mechanisms underlying these important physiological interactions. The methods include dual labeling electron microscopic immunocytochemistry and combined immunoelectron microscopy and in vivo intracellular physiology in adult rat brain.
Aim I will examine the cellular basis for modulation of noradrenergic neurons by enkephalin opioid peptides. Potential sites of interaction to be examined include (1) direct synaptic input to catecholamine neurons by enkephalin terminals (2) common targets for enkephalin and/or catecholamine containing terminals. Additionally, electron microscopic immunocytochemistry combined with tract-tracing methods will be used to determine whether opioid terminals synapse onto LC neurons projecting to the frontal cortex.
Aim II will determine the cellular substrates for (1) modulation of catecholamine-containing neurons by serotonin and glutamate afferent terminals and (2) proposed interactions between these terminals and terminals containing opioid peptides in the LC.
Aim III will test the hypotheses that frontal cortical neurons recorded intracellularly in vivo respond to LC stimulation and receive direct synaptic input from noradrenergic terminals. This multidisciplinary anatomical and physiological approach will provide basic science information relative to understanding how diverse afferents (opioid, serotonin, glutamate, catecholamine) modulate noradrenergic neurons in the LC in the rat. The findings may have direct applicability to further understanding the synaptic circuitry underlying many cognitive and analgesic effects of opiates in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA009082-04
Application #
2749087
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1994-09-30
Project End
1999-07-31
Budget Start
1998-08-15
Budget End
1999-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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
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
Jaremko, Kellie M; Sterling, Robert C; Van Bockstaele, Elisabeth J (2015) Psychological and physiological stress negatively impacts early engagement and retention of opioid-dependent individuals on methadone maintenance. J Subst Abuse Treat 48:117-27
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
Reyes, B A S; Bangasser, D A; Valentino, R J et al. (2014) Using high resolution imaging to determine trafficking of corticotropin-releasing factor receptors in noradrenergic neurons of the rat locus coeruleus. Life Sci 112:2-9
Jaremko, Kellie M; Thompson Jr, Nicholas L; Reyes, Beverly A S et al. (2014) Morphine-induced trafficking of a mu-opioid receptor interacting protein in rat locus coeruleus neurons. Prog Neuropsychopharmacol Biol Psychiatry 50:53-65
Bonn, M; Schmitt, A; Lesch, K-P et al. (2013) Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Brain Struct Funct 218:421-35

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