[N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4) increases the liberation of 3H-noradrenaline produced by depolarization of the nerve ending].

When injected systemically to rodents, DSP4 inhibits the uptake of noradrenaline (NA) and depletes endogenous NA levels in the central nervous system and in the periphery. Pretreatment with the NA uptake blocker desipramine (DMI), with the NA precursor l-dopa or with the MAD inhibitor, pargyline, prevents the toxic effects of the compound. To investigate the mechanism of the NA depleting action of DSP4, the release of the neurotransmitter induced by nerve stimulation was studied "in vitro" in a tissue sensitive to the neurotoxic action of DSP4 such as the rat cerebral cortex previously loaded with tritiated NA. Incubation with 10 mumol/l DSP4 increased the spontaneous release of tritium from the cortex and produced a two-fold enhancement of tritium outflow during the stimulation of the cortical slices by exposure to K+ 20 mmol/l for 1 m. When the experiments were performed in a Ca++ free medium, DSP4 increased the spontaneous tritium outflow, but did not enhance the NA release by depolarization with K+. This latter effect could be due to the interaction with alpha-adrenoceptors since DSP4 did not potentiate the action of the alpha-antagonist yohimbine (1 mumol/l). DSP4, as did other uptake blockers, reduced the inhibitory effect of clonidine (0.1 mumol/l) on the NA release. Clonidine pretreatment "in vivo" (2 mg/kg), did not counteract the effect of DSP4 (25 mg/kg), suggesting that the enhanced release of NA induced by K+ does not play an important role in the depletion caused by DSP4. This is supported by the fact that DSP4 also enhanced the release of NA evoked by field stimulation of the rat vas deferens, a tissue resistant to the NA depleting action of the compound. The results indicate that the enhancement of the stimulation-induced release caused by DSP4, does not seem to play a triggering role in the NA depletion caused by the compound.