Acute and chronic noradrenergic regulation of neurotrophin messenger RNA expression in rat hippocampus: Evidence from lesions and organotypic cultures

Noradrenergic neurons from the locus coeruleus innervate several brain regions, such as hippocampus and cortex. The hippocampus exhibits the highest concentration of the neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the brain. To study the role of the noradrenergic system in the chronic regulation of neurotrophin messenger RNA expression, chemical [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, 6-hydroxydopamine] and mechanical (knife-cut axotomy) lesions were performed, in the rat, and neurotrophin messenger RNAs analysed after 14 and 35 days. The intensity of the lesion was verified by characterization of the noradrenergic system using immunohistochemistry and in situ hybridization for dopamine-beta-hydroxylase and the measurement of noradrenaline tissue levels. To study the acute regulation, hippocampal organotypic slice cultures were prepared and neurotrophin messenger RNAs analysed after incubation in different concentrations of noradrenaline. We report that the noradrenergic N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine depletion significantly increased nerve growth factor and brain-derived neurotrophic factor messenger RNAs but not neurotrophin-3 messenger RNA in hippocampal areas 35 days after the lesion, while the knife-cut axotomy had a less pronounced effect and the 6-hydroxydopamine lesion did not change the neurotrophins. When incubating the organotypic hippocampal cultures with different concentrations of noradrenaline, nerve growth factor and brain-derived neurotrophic factor messenger RNAs but not neurotrophin-3 messenger RNA were significantly reduced in the dentate gyrus. We conclude that nerve growth factor and brain-derived neurotrophic factor but not neurotrophin-3 expression are inhibited by noradrenaline, arising from the locus coeruleus.