Effects of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on alpha2-adrenoceptors which regulate the synthesis and release of noradrenaline in the rat brain.
N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) induces a degeneration of noradrenergic axons originating in the locus coeruleus. The sensitivity of alpha2-adrenoceptors which regulate the synthesis and release of noradrenaline was investigated in three brain regions which receive an unequal innervation from locus coeruleus, 21 days after DSP4 (50 mg/kg) administration. After giving treated rats a dopa decarboxylase inhibitor, the in vivo tyrosine hydroxylase activity and the tissue concentrations of noradrenaline were also evaluated. Relevant reductions of noradrenaline levels were found in hippocampus and parietal 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-dihydroxyphenylalanine, in hippocampus and parietal cortex (75% and 50.5%, respectively; P<0.001), but not in hypothalamus. The inhibitory effect of clonidine on tyrosine hydroxylase activity was markedly reduced in hippocampus of rats treated with DSP4 (10+/-5% vs 57+/-3% in the control group, P<0.001) but was not changed in parietal cortex and hypothalamus. Moreover, in hippocampus, a lack of functionality of the alpha2-adrenoceptors which regulate K(+)-evoked [3H]noradrenaline release was determined. However, in cortical synaptosomes the concentration-effect curve for the oxymetazoline shifted to the right. The administration of the neurotoxin did not modify the inhibitory effects of the agonist in hypothalamus. These results support the previously described selectivity of DSP4 for noradrenergic terminals arising from locus coeruleus and suggest a more severe lesioning of the hippocampus than the parietal cortex.
Department of Pharmacology, Faculty of Medicine and Odontology, University of the Basque Country, Leioa, Vizcaya, Spain.
M
M
Prieto
M T
MT
Giralt
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000187:drug effects; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D010109:Oxymetazoline / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism
D001596:Benzylamines; D009498:Neurotoxins; D014179:Neurotransmitter Uptake Inhibitors; D018341:Receptors, Adrenergic, alpha-2; D004295:Dihydroxyphenylalanine; D010109:Oxymetazoline; C012102:DSP 4; D009638:Norepinephrine