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. Alpha1-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in α2-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.

Evaluation of Metabolic State in Striatal Rat Model of Parkinson’s Disease: before and after Deep Brain Stimulation

“…Noradrenaline depletion in the rodent by N-(2-chloroethyl) -N-ethyl-2-bromobenzylamine (DSP-4) is an approach commonly used to model human neuropsychiatric disorders in rodents [54]. Although there are yet no studies with DPS-4 and DBS, one study using only DSP-4 shows that although administration of DSP-4 to rats does not result in any obvious behavioral changes, animals that received DSP-4 initially gained weight at a slower rate than control animals [19,43].…”

“…Although there are yet no studies with DPS-4 and DBS, one study using only DSP-4 shows that although administration of DSP-4 to rats does not result in any obvious behavioral changes, animals that received DSP-4 initially gained weight at a slower rate than control animals [19,43]. However, a comprehensive analysis of the effect of DSP-4 on the locus coeruleus noradrenergic system in the rat has shown that DSP-4 does not reduce locus coeruleus noradrenergic number or function, suggesting that DSP-4 is not an appropriate rat model to study the functional effect of noradrenergic neuronal loss in PD [54].…”

The Noradrenergic System is a Major Component in Parkinson’s Disease

“…As indicated earlier, these regions receive sole innervation from the LC (Aston- Jones et al, 1995;Jones & Moore, 1977;Loughlin et al, 1986a, b;Mason & Fibiger, 1970;Moore & Bloom, 1979;Olsen & Fuxe, 1971;Ungerstedt, 1971;Waterhouse et al, 1983) so the original hypothesis was that DSP4 affected only LC neurons. NET binding sites are also reduced in specific forebrain regions, indicating a loss of innervation from the LC (Cheetham et al, 1996;Szot et al, 2010). The hypothesis that DSP4 was a neurotoxin was supported by TH-IR which demonstrated a gradual loss of LC noradrenergic neurons after by DSP4 administration .…”

“…A) L-DOPA level, B) DA and NE levels and C) DOPAC and DHPG CSF levels in control and PD subjects on L-DOPA treatment. Catecholamine levels were extracted by alumina extraction and analyzed by high performance liquid chromatography (HPLC) as previously described (Szot et al, 2010). Each point represents a single individual catecholamine value for control and PD subjects, with average and standard error means (SEM) illustrated in bars for each catecholamine analyzed.…”

“…Since these initial descriptions of DSP4 as a noradrenergic neurotoxin, there have been other publications suggesting that DSP4 does not result in a loss of LC noradrenergic neurons (Booze et al, 1988;Lyon et al, 1983 Robertson et al, 1993;Szot et al, 2010) and that DSP4 does not selectively affect LC noradrenergic terminals Kask et al, 1997;Szot et al, 2010;Theron et al, 1993;Wolfman et al, 1994). Work in our laboratory indicated that DSP4 may affect noradrenergic terminals and specific ARs in many forebrain regions (not just regions innervated by the LC), but it does so without a loss of LC noradrenergic neurons (Szot et al, 2010). Despite the data that suggests DSP4 may not result in a loss of LC noradrenergic neurons, DSP4 does result in a temporary reduction in terminal NE levels in many forebrain regions.…”