Effects of DSP-4 on monoamine and monoamine metabolite levels and on beta adrenoceptor binding kinetics in rat brain at different times after administration

Abstract

Effects of DSP-4 on noradrenaline (NA), 3-methoxy-4-hydroxyphenyl glycol (MHPG), serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) levels and on beta adrenoceptor binding kinetics (Bmax and KD) in rat hippocampus, cortex and hypothalamus were studied between 24 hours and 14 days after systemic administration. Beta adrenoceptor numbers in hippocampus and cortex, but not in hypothalamus, were significantly increased after DSP-4. No significant changes in KD values were observed in hypothalamus, but significant increases in this parameter were measured in hippocampus and cortex. NA and MHPG levels were significantly decreased in all three brain regions, but MHPG/NA ratios were increased in hippocampus, decreased in cortex and unchanged in hypothalamus. Very prominent increases in 5-HIAA levels were observed in all three brain regions, but only at one day after DSP-4. The greatest increases in 5-HIAA levels occurred in the hippocampus, but this effect of DSP-4 appeared to be slightly diminished by pre-treatment with fluoxetine. In cortex and hippocampus 5-HT levels were slightly, but significantly decreased after DSP-4.

Overflow of noradrenaline and dopamine in frontal cortex after [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (DSP-4) treatment: in vivo microdialysis study in anaesthetized rats

“…Also, local mechanisms may play a role in compensation. The density of cortical b-adrenoceptors, stimulation of which has been shown to enhance NA release (Murugaiah and O'Donnell 1995), is increased after DSP-4 treatment (Jonsson et al 1981;Theron et al 1993).…”

“…Although the morphological, biochemical and behavioural effects of DSP-4 treatment are relatively well characterised (Delini-Stula et al 1984;Fritschy et al 1990;Theron et al 1993;Harro et al 1995), it is not known how the release of NA in the terminal areas of the LC is changed after NA depletion. Furthermore, little is known about the adaptive changes that could occur in the release of other neurotransmitters after DSP-4 treatment.…”

A partial noradrenergic lesion induced by DSP-4 increases extracellular noradrenaline concentration in rat frontal cortex: a microdialysis study in vivo

“…In fact, a decrease in the uptake of [ 3 H]noradrenaline into synaptosomes prepared from the cortex of DSP-4-treated rats is evident as early as 1 day after treatment (Ross 1976). Heal and colleagues (1993) have also reported a reduction in the number of cortical presynaptic a 2 -adrenoceptors 3 days after DSP-4 administration, while b-adrenoceptor numbers are increased in the cortex and hippocampus after only 1 day (Theron et al 1993).…”

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

“…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 . 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).…”

“…The appeal of DSP4 as a noradrenergic neurotoxin over other methods (like 6OHDA) is that DSP4 can produce this central affect by peripheral administration. DSP4 produces a rapid, though transient, reduction in terminal NE concentrations in the frontal cortex, hippocampus and cerebellum Harro et al, 1999a, b;Hughes & Stanford, 1996, 1998Jonsson et al, 1981;Kask et al, 1997;Ross, 1976;Szot et al, 2011;Theron et al, 1993;Wolfman et al, 1994). 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.…”