Effect Of DSP-4 Research Articles

Effects of the noradrenaline neurotoxin DSP4 on the postnatal development of central noradrenaline neurons in the rat

The effect of the noradrenaline neurotoxin DSP4 on the postnatal development of central noradrenergic neurons in the rat has been investigated using neurochemical techniques. The results demonstrated a preferential effect of DSP4 on the locus coeruleus noradrenergic neuron system without any notable effects on the dopamine and adrenaline neurons and only a minor neurotoxic effect on the serotonin neurons. The effect of DSP4 on the serotonin neurons could be completely prevented by pretreatment with the uptake blocker zimelidine, without affecting the action of DSP4 on noradrenergic neurons. Neonatal DSP4 treatment systemically led to permanent depletions of noradrenaline in the cerebral cortex and spinal cord and marked increases of noradrenaline in the cerebellum and ponsmedulla. These effects of DSP4 were dose-dependent and could be blocked by pretreatment with the noradrenaline uptake blocker desipramine. The alterations in endogenous noradrenaline levels were quantitatively similar to changes observed in [ 3H]noradrenaline uptake in slices in vitro. There were no significant changes of these noradrenergic parameters when analysing the whole CNS after neonatal DSP4 treatment, in spite of marked regional changes in both directions. Administration of DSP4 to rats of different ages produced acutely marked depletions of noradrenaline in all regions including the pons-medulla and the cerebellum at all developmental stages. Marked and permanent depletions of noradrenaline were found in the distant noradrenergic nerve terminal projections after treatment at all ages, whereas increases in noradrenaline levels in the pons-medulla and cerebellum were only observed in rats treated with DSP4 up to the age of 3–5 days, whereas a DSP4 administration in older rats led to substantial and permanent depletions of noradrenaline in both these regions. The results indicate that the alteration of the postnatal development of noradrenergic neurons after treatment of rats up to the age of 3–5 days is mainly related to a ‘pruning effect’ of DSP4, in which prevention of the development of distant nerve terminal projections causes an increased outgrowth of nerves in collateral systems spared by the neurotoxin. The results indicate that DSP4 may be a useful denervation tool for studying various aspects of noradrenergic neurotransmission of developing locus coeruleus neurons.

DSP4-induced two-way active avoidance impairment in rats: involvement of central and not peripheral noradrenaline depletion.

N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) (50 mg/kg IP), a new selective noradrenaline (NA) neurotoxin, was found to cause a severe impairment of the acquisition of a two-way active avoidance task 1 week following administration, an effect that was blocked by the selective NA uptake inhibitor desipramine. In a second experiment, systemically injected 6-OHDA (2 x 30 mg/kg IP) was not found to cause any avoidance impairment, although its effects upon peripheral NA were still evident 21 days after administration: The peripheral NA depletion caused by DSP4 almost disappeared 14 days after injection. In a third experiment, the avoidance impairment induced by DSP4 was produced even 10 weeks after treatment. Data from both the shuttlebox experiment and an activity box experiment suggest that the acquisition impairment is not readily explained on the basis of some deficit in spontaneous behavior or an altered perception of pain. The present data suggest that the effect of DSP4 upon active avoidance acquisition is mediated via central, and not peripheral NA neurons.

Distinction between dopaminergic and serotonergic components of neuroleptic binding sites in limbic brain areas

Block of conditioned avoidance responding (CAR) in the rat is a property of all antipsychotic agents. To determine whether cerebral norepinephrine (NE) is crucial for CAR, the effect of depletion of cerebral NE was examined both during acquisition and retention of a CAR task in Sprague-Dawley and Fischer 344 male rats. In examining acquisition of CAR, DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (50 mg/kg, IP) was given to naive rats from each strain. In one control group, desmethylimipramine (DMI, 20 mg/kg, IP −30 min), which inhibits the uptake of DSP-4 and its subsequent neurotoxic effect, was given prior to DSP-4. After DSP-4, all animals were tested for acquisition of CAR in a discrete trial paradigm in which a lever press avoided a 0.7 mA shock. After the experiment, the rats were sacrificed and the cerebral cortex, striatum, and brain stem were removed for NE and dopamine assay using HPLC. In examining retention of CAR, the effect of DSP-4 on the CAR of trained rats was observed. DSP-4 produced an almost total depletion of cortical NE and about 50% reduction of NE in the brain stem in both strains and in both tests. In the first experiment, DSP-4 failed to significantly diminish CAR acquisition in either strain, although there was a trend towards a DSP-4-induced deficit. Interestingly, DSP-4 caused no decrement in CAR in trained rats of either strain, but did significantly impair further acquisition of CAR in Sprague-Dawley rats. The data demonstrate cerebral NE is not critical for retention of CAR, but suggest a possible role for NE in the acquisition of CAR.