title: A comprehensive analysis of the effect of DSP4 on the locus coeruleus noradrenergic system in the rat.
abstract: Degeneration of the noradrenergic neurons in the locus coeruleus (LC) is a major component of Alzheimer's (AD) and Parkinson's disease (PD), but the consequence of noradrenergic neuronal loss has different effects on the surviving neurons in the two disorders. Therefore, understanding the consequence of noradrenergic neuronal loss is important in determining the role of this neurotransmitter in these neurodegenerative disorders. The goal of the study was to determine if the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) could be used as a model for either (or both) AD or PD. Rats were administered DSP4 and sacrificed 3 days 2 weeks and 3 months later. DSP4-treatment resulted in a rapid, though transient reduction in norepinephrine (NE) and NE transporter (NET) in many brain regions receiving variable innervation from the LC. Alpha(1)-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in alpha(2)-AR was observed in many different brain regions 2 weeks and 3 months after DSP4. These changes observed in forebrain regions occurred without a loss in LC noradrenergic neurons. Expression of synthesizing enzymes or NET did not change in amount of expression/neuron despite the reduction in NE tissue content and NET binding site concentrations at early time points, suggesting no compensatory response. In addition, DSP4 did not affect basal activity of LC at any time point in anesthetized animals, but 2 weeks after DSP4 there is a significant increase in irregular firing of noradrenergic neurons. These data indicate that DSP4 is not a selective LC noradrenergic neurotoxin, but does affect noradrenergic neuron terminals locally, as evident by the changes in transmitter and markers at terminal regions. However, since DSP4 did not result in a loss of noradrenergic neurons, it is not considered an adequate model for noradrenergic neuronal loss observed in AD and PD.
authors.affiliation: Northwest Network for Mental Illness Research, Education, and Clinical Center, Veterans Administration Puget Sound Health Care System, Seattle, WA 98108, USA. szot@u.washington.edu
authors.forename: P
authors.initials: P
authors.lastname: Szot
authors.forename: C
authors.initials: C
authors.lastname: Miguelez
authors.forename: S S
authors.initials: SS
authors.lastname: White
authors.forename: A
authors.initials: A
authors.lastname: Franklin
authors.forename: C
authors.initials: C
authors.lastname: Sikkema
authors.forename: C W
authors.initials: CW
authors.lastname: Wilkinson
authors.forename: L
authors.initials: L
authors.lastname: Ugedo
authors.forename: M A
authors.initials: MA
authors.lastname: Raskind
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001596:Benzylamines / Q000633:toxicity*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D009498:Neurotoxins / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D013995:Time; D013997:Time Factors
chemical_list: D001596:Benzylamines; D009498:Neurotoxins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018340:Receptors, Adrenergic, alpha-1; C012102:DSP 4; D009638:Norepinephrine