title: Depressive-like behavior observed with a minimal loss of locus coeruleus (LC) neurons following administration of 6-hydroxydopamine is associated with electrophysiological changes and reversed with precursors of norepinephrine.
abstract: Depression is a common co-morbid condition most often observed in subjects with mild cognitive impairment (MCI) and during the early stages of Alzheimer's disease (AD). Dysfunction of the central noradrenergic nervous system is an important component in depression. In AD, locus coeruleus (LC) noradrenergic neurons are significantly reduced pathologically and the reduction of LC neurons is hypothesized to begin very early in the progression of the disorder; however, it is not known if dysfunction of the noradrenergic system due to early LC neuronal loss is involved in mediating depression in early AD. Therefore, the purpose of this study was to determine in an animal model if a loss of noradrenergic LC neurons results in depressive-like behavior. The LC noradrenergic neuronal population was reduced by the bilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA) directly into the LC. Forced swim test (FST) was performed three weeks after the administration of 6-OHDA (5, 10 and 14 μg/μl), animals administered the 5 μg/μl of 6-OHDA demonstrated a significant increase in immobility, indicating depressive-like behavior. This increase in immobility at the 5 μg/μl dose was observed with a minimal loss of LC noradrenergic neurons as compared to LC neuronal loss observed at 10 and 14 μg/μl dose. A significant positive correlation between the number of surviving LC neurons after 6-OHDA and FST immobile time was observed, suggesting that in animals with a minimal loss of LC neurons (or a greater number of surviving LC neurons) following 6-OHDA demonstrated depressive-like behavior. As the 6-OHDA-induced loss of LC neurons is increased, the time spent immobile is reduced. Depressive-like behavior was also observed with the 5 μg/μl dose of 6-OHDA with a second behavior test, sucrose consumption. FST increased immobility following 6-OHDA (5 μg/μl) was reversed by the administration of a single dose of L-1-3-4-dihydroxyphenylalanine (DOPA) or l-threo-3,4-dihydroxyphenylserine (DOPS) prior to behavioral assessment. Surviving LC neurons 3 weeks after 6-OHDA (5 μg/μl) demonstrated compensatory changes of increased firing frequency, a more irregular firing pattern, and a higher percentage of cells firing in bursts. These results indicate that depressive-like behavior in mice is observed following the administration of 6-OHDA and the loss of LC noradrenergic neurons; however, the depressive-like behavior correlates positively with the number of surviving LC neurons with 6-OHDA administration. This data suggests the depression observed in MCI subjects and in the early stages of AD may due to the hypothesized early, minimal loss of LC neurons with remaining LC neurons being more active than normal.
authors.affiliation: Mental Illness Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. Electronic address: szot@uw.edu.
authors.forename: Patricia
authors.initials: P
authors.lastname: Szot
authors.affiliation: Mental Illness Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Allyn
authors.initials: A
authors.lastname: Franklin
authors.affiliation: Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain; Department of Pharmacology, University of the Basque Country, UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Miguelez
authors.affiliation: Mental Illness Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Yangqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain.
authors.forename: Igor
authors.initials: I
authors.lastname: Vidaurrazaga
authors.affiliation: Department of Pharmacology, University of the Basque Country, UPV/EHU, Leioa, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ugedo
authors.affiliation: Geriatric Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Sikkema
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; Geriatric Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Charles W
authors.initials: CW
authors.lastname: Wilkinson
authors.affiliation: Mental Illness Research, Education and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Murray A
authors.initials: MA
authors.lastname: Raskind
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D018663:Adrenergic Agents / Q000633:toxicity*; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D003863:Depression / Q000139:chemically induced* / Q000473:pathology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005518:Food Preferences; D007980:Levodopa / Q000494:pharmacology; D008125:Locus Coeruleus / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine / Q000633:toxicity*; D010619:Phenazines / Q000494:pharmacology; D013395:Sucrose / Q000008:administration & dosage; D013550:Swimming / Q000523:psychology; D013997:Time Factors
chemical_list: D018663:Adrenergic Agents; D002395:Catecholamines; D015259:Dopamine Agents; D010619:Phenazines; C499011:dihydroxyphenoxazine; D007980:Levodopa; D013395:Sucrose; D016627:Oxidopamine
keywords: 6-Hydroxydopamine; Depression; Electrophysiology; Forced swim test; Locus coeruleus