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

NEUROPHARMACOLOGY

卷:101

Article

Szot, Patricia^1,2  Franklin, Allyn¹  Miguelez, Cristina^3,5  Wang, Yangqing¹  Vidaurrazaga, Igor³  Ugedo, Luisa³  Sikkema, Carl⁴  Wilkinson, Charles W.^2,4  Raskind, Murray A.^1,2 

[1] Vet Adm Puget Sound Hlth Care Syst, Educ & Clin Ctr, Mental Illness Res, Seattle, WA USA

[2] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[3] Univ Basque Country, UPV EHU, Dept Pharmacol, Leioa, Spain

[4] Vet Adm Puget Sound Hlth Care Syst, Educ & Clin Ctr, Geriatr Res, Seattle, WA USA

[5] Univ Basque Country, UPV EHU, Dept Pharmacol, Vitoria, Spain

关键词: Locus coeruleus;    6-Hydroxydopamine;    Forced swim test;    Electrophysiology;    Depression;   

DOI  :  10.1016/j.neuropharm.2015.09.003

来源: Elsevier

【 摘 要 】

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 mu g/mu l), animals administered the 5 mu g/mu l of 6-OHDA demonstrated a significant increase in immobility, indicating depressive-like behavior. This increase in immobility at the 5 mu g/mu l dose was observed with a minimal loss of LC noradrenergic neurons as compared to LC neuronal loss observed at 10 and 14 mu g/mu l 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 mu g/mu l dose of 6-OHDA with a second behavior test, sucrose consumption. FST increased immobility following 6-OHDA (5 mu g/mu l) was reversed by the administration of a single dose of L-1-3-4-dihydroxyphenylalanine (DOPA) or t-threo-3,4-dihydroxyphenylserine (DOPS) prior to behavioral assessment. Surviving LC neurons 3 weeks after 6-OHDA (5 mu g/mu l) 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. Published by Elsevier Ltd.

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