Effects of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on alpha(2)-adrenoceptors which regulate the synthesis and release of noradrenaline inthe rat brain

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) induces a degeneration of noradrenergic axons originating in the locus coeruleus. The sensitivity of alpha (2)-adrenoceptors which regulate the synthesis and release of nora drenaline was investigated in three brain regions which receive an unequal innervation from locus coeruleus, 21 days after DSP4 (50 mg/kg) administrat ion. After giving treated rats a dopa decarboxylase inhibitor, the in vivo tyrosine hydroxylase activity and the tissue concentrations of noradrenalin e were also evaluated. Relevant reductions of noradrenaline levels were fou nd in hippocampus and parielal cortex (91% and 77.5%, respectively; P<0.001 ) together with a less pronounced reduction in hypothalamus (32%, P<0.01). The administration of the neurotoxin led to decreases of the basal tyrosine hydroxylase activity determined as the accumulation of 3,4-dihydroxyphenyl alanine, in hippocampus and parietal cortex (75% and 50.5%, respectively; P <0.001), but not in hypothalamus. The inhibitory effect of clonidine on tyr osine hydroxylase activity was markedly reduced in hippocampus of rats trea ted with DSP4 (10+/-5% vs 57+/-3% in the control group, P<0.001) but was no t changed in parietal cortex and hypothalamus. Moreover, in hippocampus, a lack of functionality of the alpha (2)-adrenoceptors which regulate K+-evok ed [H-3]noradrenaline release was determined. However, in cortical synaptos omes the concentration-effect curve for the oxymelazoline shifted to the ri ght. The administration of the neurotoxin did not modify the inhibitory eff ects of the agonist in hypothalamus. These results support the previously d escribed selectivity of DSP4 for noradrenergic terminals arising from locus coeruleus and suggest a more severe lesioning of the hippocampus than the parietal cortex.