LONG‐TERM EFFECTS OF N‐2‐CHLOROETHYL‐N‐ETHYL‐2‐BROMOBENZYLAMINE HYDROCHLORIDE ON NORADRENERGIC NEURONES IN THE RAT BRAIN AND HEART

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Abstract
N‐2‐Chloroethyl‐N‐ethyl‐2‐bromobenzylamine hydrochloride (DSP 4) 50 mg/kg intraperitoneally, produced a long‐term decrease in the capacity of brain homogenates to accumulate noradrenaline with significant effect 8 months after the injection. It had no effect on the noradrenaline uptake in homogenates from the striatum (dopamine neurones) and on the uptake of 5‐hydroxytryptamine (5‐HT) in various brain regions. In vitro DSP 4 inhibited the noradrenaline uptake in a cortical homogenate with an IC50 value of 2 μm but was more than ten times less active on the dopamine uptake in a striatal homogenate and the 5‐HT uptake in a cortical homogenate. DSP 4 (50 mg/kg i.p.) inhibited the uptake of noradrenaline in the rat heart atrium in vitro but this action was terminated within 2 weeks. DSP 4 (50 mg/kg i.p.) caused a decrease in the dopamine‐β‐hydroxylase (DBH) activity in the rat brain and heart. The onset of this effect was slow; in heart a lag period of 2–4 days was noted. In brain the DBH‐activity in cerebral cortex was much more decreased than that in hypothalamus which was only slightly affected. A significant effect was still found 8 months after the injection. The noradrenaline concentration in the brain was greatly decreased for at least two weeks, whereas noradrenaline in heart was only temporarily reduced. The long‐term effects of DSP 4 on the noradrenaline accumulation, the DBH activity and noradrenaline concentration in the rat brain were antagonized by desipramine (10 mg/kg i.p.). It is suggested that DSP 4 primarily attacks the membranal noradrenaline uptake sites forming a covalent bond and that the nerve terminals, as a result of this binding, degenerate.